TAP Vol 6 Issue 23

ASH and SABCS Meeting News 1–25 | Jim Allison on Immune Checkpoint Blockade

85

| Pancreatic Cancer Clinical Trials

119

VOLUME 6, ISSUE 23

DECEMBER 25, 2015

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

ASH Annual Meeting

Impressive Results With Daratumumab Plus Lenalidomide/Dexamethasone in Multiple Myeloma

A Shot to End Cancer: HPV Vaccination

By Ronald A. DePinho, MD

By Caroline Helwick

T

he anti-CD38 monoclonal antibody daratumu­ mab (Darzalex) took center stage among multiple myeloma studies presented at the 57th American Society of Hematology Annual Meeting and Exposition.

In relapsed/refractory patients, daratumumab plus lenalidomide (Revlimid)/dexamethasone yielded an 81% response rate, with durable remissions, in the expansion cohort of the phase I/II GEN503 trial.1 Combined with pomalidomide (Pomalyst) and dexamethasone, treatment with daratumumab led to a 71% response rate.2 And as a single agent, daratumumab elicited responses in 30% of highly refractory patients,3 investigators reported at the Meeting.

Daratumumab, a human anti-CD38 IgG1k monoclonal antibody, was granted accelerated approval for treatment of patients with multiple myeloma who have received at least three prior treatments or are refractory to both a proteasome inhibitor and an immu-

A

nomodulatory drug. It is the first monoclonal antibody approved for treating multiple myeloma.

With Lenalidomide/ Dexamethasone The multinational Torben Plesner, MD study of daratumumab plus lenalidomide/dexamethasone1 was presented by Torben Plesner, MD, of Vejle Hospital in Denmark, who commented: “Daratumumab plus lenalidomide/ dexamethasone induces rapid, deep, and durable responses,” and “the drugs can be safety combined.”

“It’s my personal opinion that daratumumab is the rituximab of myeloma,” Dr. Plesner offered at a press briefing. “It is very effective when given with other continued on page 15

San Antonio Breast Cancer Symposium

Patients With Incomplete Response to Neoadjuvant Chemotherapy Benefit From Capecitabine

By Caroline Helwick

T

temic chemotherapy following neoadjuvant chemotherapy is able to prolong survival. These first efficacy results show that survival is significantly improved by the addition of capecitabine to standard therapy,” said Masakazu Toi, MD, PhD, Professor at Kyoto University Hospital in Japan. Dr. Toi is founder and Senior Director of the Japan Breast Cancer Research Group.

Clifford A. Hudis, MD, Chief of the Breast MediIt has been unclear whether cine Service at Memopostoperative systemic chemotherapy rial Sloan Kettering Cancer Center, New York, and an following neoadjuvant chemotherapy ASCO Past-President, conis able to prolong survival. These first sidered the investigation a highlight of the sympoefficacy results show that survival is sium’s presentations. significantly improved by the addition “The study showed an overall survival improveof capecitabine to standard therapy. ment. If this holds up, I —Masakazu Toi, MD, PhD

reatment with capecitabine increased diseasefree and overall survival in breast cancer patients with residual disease after neoadjuvant chemotherapy, according to a study reported by researchers from Japan and Korea at the 2015 San Antonio Breast Cancer Symposium.1 “It has been unclear whether postoperative sys-

s health-care providers, we have an obligation and a responsibility not only to care for our patients, but also to educate them—and the general public—about their cancer risk and ways to reduce or prevent it. We are living in the golden era of cancer prevention and treatment, made possible by investments in fundamental research. One major victory—truly, a scientific dream come true—is the development of the human papillomavirus (HPV) vaccine, which can protect against cancers caused by HPV infection. Regrettably, however, it’s not being used to its full potential.

Since the HPV vaccine first became available in 2006, HPV infections have dropped continued on page 172

Dr. DePinho is President of The University of Texas MD Anderson Cancer Center in Houston.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage ASH Annual Meeting ���������������������1, 6–19 San Antonio Breast Cancer Symposium ���������������������������������������� 1, 3–5 Palliative Care Symposium �������������� 26–27 NCCN Hematology Congress ����������������� 31 Lynn Sage Breast Cancer Symposium ����������������������������������������36, 38 Steven Nurkin, MD, MS, FACS, on Surgery for Rectal Cancer ���������������������59 Meena S. Moran, MD, on DCIS ����������������62 ACCP Guideline on SCLC �����������������������70 Direct From ASCO �������������������������� 88–91 David H. Johnson, MD, MACP, FASCO, on Helping Mentees Succeed ��� 124

continued on page 3

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The ASCO Post | DECEMBER 25, 2015

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Conor Lynch, Executive Editor Conor@harborsidepress.com James O. Armitage, MD Editor-in-Chief

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ASCOPost.com | DECEMBER 25, 2015

PAGE 3

San Antonio Breast Cancer Symposium Capecitabine After ­Neoadjuvant Therapy

Disease-Free and Overall Survival Improved

continued from page 1

“In 2015, the first preplanned interim analysis was carried out at the point of 2 years’ follow-up from the last patient enrollment. The data monitoring committee recommended that this study be discontinued according to the

think this is a very important observation,” Dr. Hudis told The ASCO Post.

He indicated that the results were discordant with previous studies of the drug—such as the German study pre-

The study showed an overall survival improvement. If this holds up, I think this is a very important observation.

—Clifford A. Hudis, MD

[Critics of the CREATE-X study] are confusing the other studies of capecitabine. In those [negative] studies, patients either received capecitabine with other chemotherapy or as a single agent. This study is a different setting, and it’s more like maintenance.

—Richard D. Gelber, PhD

sented here last year by von Minckwitz et al2—a point that was reinforced during the discussion by a number of other breast cancer experts who peppered Dr. Toi with questions.

Details of CREATE-X The CREATE-X study, conducted at 84 sites, enrolled 910 patients with HER2-negative breast cancer and residual invasive disease (no patients with pathologic complete response or nodepositive disease) after neoadjuvant treatment with an anthracycline and/or taxane. Most patients (80%) received an anthracycline followed by a taxane, and approximately 60% had prior fluorouracil (5-FU). Adjuvant endocrine therapy was received by approximately 40% of premenopausal patients and 25% of postmenopausal patients.

The 455 patients randomly assigned to active treatment were given capecitabine at 1,250 mg/m2 twice daily, 2 weeks on and 1 week off, for up to eight cycles. Six cycles were completed by 58%, and eight cycles were completed by 38%. Dose reductions were required by 24% and 37%, respectively, whereas 18% and 25%, respectively, discontinued the drug.

protocol,” Dr. Toi reported.

At 5 years, the disease-free survival rate (the primary endpoint) was 74.1% with capecitabine compared to 67.7% in the control arm, a statistically significant 30% reduction in risk (one-sided P = .00524). Overall survival rates were 89.2% and 83.9%, respectively, a statistically significant 40% reduction in risk (one-sided P < .01).

The benefit was observed across subgroups, with hazard ratios ranging from 0.54 to 0.84. The hormone receptor– negative subgroup experienced a 42% reduction in risk with capecitabine, Dr. Toi reported.

Hand-foot syndrome associated with capecitabine was observed in

72.3% of patients; grade 3 hand-foot syndrome occurred in 10.9%.

Neutropenia and diarrhea were also significantly higher in the capecitabine

Hope S. Rugo, MD

arm. Neutropenia ≥ grade 3 was seen in 6.6% with capecitabine and 1.6% with observation; diarrhea ≥ grade 3 occurred in 3% and 0.4%, respectively.

During the discussion, Hope S. Rugo, MD, Director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, noted that the toxicity seemed less than is observed among U.S. patients and suggested that there might be pharmacogenomic differences. Dr. Toi acknowledged that capecitabine seems to be better tolerated among Asians, concluding, “The balance of benefit and toxicity would favor the use of capecitabine in the postneoadjuvant situation, but prediction for the therapeutic benefit needs to be investigated further.”

Brisk Discussion The findings elicited brisk discussion at the meeting, mostly pertaining to the discordance between these and previous findings. Dr. Hudis pointed out, “Capecitabine as a single agent has not been that impressive in earlier studies, and prior studies in the adjuvant setting have not been positive. That’s what’s odd about this, and also that a fairly large proportion of patients had received 5-FU before they got capecitabine.”

Dr. Toi had no clear explanation, aside from the possibility that the outcomes derive from “non–cross-resistance to treatment with anthracyclines and taxanes.”

Role of Capecitabine in Breast Cancer ■■ A study in Japanese and Korean early breast cancer patients evaluated capecitabine for treatment of residual disease after neoadjuvant chemotherapy.

■■ Patients receiving capecitabine had improvements in disease-free and overall survival, compared to observation—a finding that is discordant with any previous study of the drug.

■■ At 5 years, disease-free survival rates were 74.1% vs 67.7%, and overall survival rates were 89.2% and 83.9%, both statistically significant differences.

Richard D. Gelber, PhD, Statistical Director of the International Breast Cancer Study Group and Professor of Biostatistics and Computational Biology at Dana-Farber Cancer Institute, Boston, had a different take on the findings.

In an interview with The ASCO Post, Dr. Gelber explained: “People are confusing the other studies of capecitabine.

In those [negative] studies, patients either received capecitabine with other chemotherapy or as a single agent. This study is a different setting, and it’s more like maintenance.”

Dr. Gelber said the study is akin to the IBCSG Trial 22 (in press), where patients completed treatment with standard adjuvant chemotherapy, then were randomly assigned to observation or a single year of cyclophosphamide/ methotrexate, metronomically dosed.

Results of that study in the triple-negative disease subset were positive, as were the results here with capecitabine, he said.

“Maintenance [cyclophosphamide/methotrexate] improved outcomes for triple-negative cases,” he said. “The current trial is similar in the sense that they gave neoadjuvant chemotherapy, and patients not achieving a pathologic complete response continued on single-agent capecitabine, as the maintenance component.”

Steven E. Vogl, MD, a medical oncologist in the Bronx, New York, suggested that the study involved two

Steven E. Vogl, MD

different populations with different responses to the treatment.

“You have patients with estrogen receptor–positive disease, very few of whom achieve pathologic complete response and those actually don’t do badly,” he said. “Then you have a minority of patients, where a significant advantage of capecitabine is seen. Since the curves separate very early, and early relapse is a characteristic of triple-negative disease, I suspect most of your differences are driven by triple-negative disease. This may be telling us that for patients with triple-negative disease who don’t achieve a pathologic complete response after good neoadjuvant continued on page 4

The ASCO Post | DECEMBER 25, 2015

PAGE 4

San Antonio Breast Cancer Symposium Novel Approaches

Adjuvant Denosumab Improves Disease-Free Survival in Estrogen Receptor–Positive Postmenopausal Breast Cancer

By Alice Goodman

T

here is good news about denosumab (Prolia). The primary analysis of the ABCSG-18 trial showed that adjuvant denosumab (given at low doses) reduces the risk of clinical fracture by 50% in postmenopausal women with early breast cancer who are taking an aromatase inhibitor.1 More good news is that the latest analysis of that study found that adjuvant denosumab improves

with other therapies.”

“Denosumab is given subcutaneously twice a year and can be administered by any doctor, not just an oncologist,” he told listeners at a press conference during the 2015 San Antonio Breast Cancer Symposium.

The prospective, randomized, double-blind, placebo-controlled multi-

—Michael Gnant, MD

disease-free survival in these women, and it is a safe treatment.2 The not-so-good news is that denosumab is an expensive drug that is not typically prescribed for patients with breast cancer, unless the patient has osteopenia or osteoporosis.

“This time-driven disease-free survival analysis of ABCSG-18 indicates that adjuvant denosumab reduces the risk of disease recurrence or death in postmenopausal patients with breast cancer who are taking an aromatase inhibitor. It comes down to how would you treat your mother.

I believe we should offer this to all postmenopausal women on an aromatase inhibitor. If I see a new patient, I would start her on denosumab,” said lead author Michael Gnant, MD, Professor of Surgery, Medical University of Vienna. “This benefit [of denosumab] is as least as great as

center ABCSG-18 trial enrolled 3,425 postmenopausal women from Austria and Sweden with estrogen receptor– positive and/or progesterone receptor–positive breast cancer who were taking an aromatase inhibitor, which is associated with bone loss due to estrogen deficiency.

Denosumab is a monoclonal antibody that binds to RANK ligand and is approved by the U.S. Food and Drug Administration for the treatment of women with breast cancer taking an aromatase inhibitor at risk for fracture.

Patients were randomized 1:1 to receive denosumab at 60 mg given subcutaneously every 6 months or placebo. For the primary analysis, denosumab reduced the rate of clinical fracture by 50% compared with placebo (P < .0001).

In view of the dramatic differences

Capecitabine After Neoadjuvant Therapy

tive thing to say is that we have gotten an exciting early look at these data, but like everything else, we need a final peer-reviewed manuscript to see the details.”

He concluded, “But make no mistake: Capecitabine is a broadly available, inexpensive agent, and this is an increasingly recognized setting—the lack of a pathologic complete response to preoperative treatment. Anything that improves over-

continued from page 3

P

ress conference moderator Virginia Kaklamani, MD, commented on these results from the ABCSG-18 trial: “It’s pretty clear that 3 years of adjuvant denosumab not only reduced fracture risk but improved disease-

Study Details

It comes down to how would you treat your mother. I believe we should offer this to all postmenopausal women on an aromatase inhibitor. If I see a new patient, I would start her on denosumab.

therapy, this [capecitabine] is probably a reasonable option,” he suggested.

He would not apply the findings to estrogen receptor–positive patients who lack a pathologic complete response. “I’d like to see these sets of patients separated out in the analysis,” he said.

In Dr. Hudis’ view, “The conserva-

EXPERT POINT OF VIEW

It [the use of denosumab] is a question of access and reimbursement.

—Virginia Kaklamani, MD

free survival. It’s also pretty clear that adjuvant bisphosphonates improve disease-free survival and overall survival. But at the same time, we don’t use these treatments for our patients. It is a question of access and reimbursement,” she said.

Dr. Kaklamani is leader of the Breast Cancer Program at the Cancer Therapy & Research Center and Professor of Medicine at the University of Texas Health Science Center, San Antonio.

“I try to find an angle so I can put my patients on denosumab, i.e., osteopenia or osteoporosis. The U.S. Food and Drug Administration has not approved this drug in the pure postmenopausal population. Denosumab is extremely expensive, and insurers won’t pay for it. We need two or three large prospective randomized trials for evidence to justify reimbursement,” she concluded. n Disclosure: Dr. Kaklamani reported no potential conflicts of interest.

in the primary endpoint of fracture rate, the independent data monitoring committee recommended that the study be unblinded, and patients in the placebo group should be offered 3 years of denosumab treatment.

Disease-free survival was a secondary endpoint of the trial. Prior to unblinding the trial, a time-driven analysis of disease-free survival was performed (time to any event of local or distant metastasis).

Median age of patients was 64 years;

72% had tumors smaller than 2 cm; 19% were grade 3; 83% were both estrogen receptor–positive and progesterone receptor–positive; 25% had adjuvant chemotherapy; 71% had node-negative disease; 74% had ductal invasive histology, and 6% overexpressed HER2.

all survival has to be watched.” n

juvant chemotherapy (CREATE-X, JBCRG-04). 2015 San Antonio Breast Cancer Symposium. Abstract S1-07. Presented December 9, 2015.

2. von Minckwitz G, Reimer T, Potenberg J, et al: The phase III ICE study: Adjuvant ibandronate with or without capecitabine in elderly patients with moderate or high risk early breast cancer. 2014 San Antonio Breast Cancer Symposium. Abstract S3-04. Presented December 11, 2014.

Disclosure: Dr. Toi has received a research grant from Chugai Pharmaceutical Co. Drs. Hudis, Rugo, Gelber, and Vogl reported no potential conflicts of interest.

References 1. Lee S-J, Toi M, Lee ES, et al: A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoad-

Study Results There were 203 events in the placebo arm and 167 events in the denosumab arm. An intent-to-treat analysis continued on page 5

ASCOPost.com | DECEMBER 25, 2015

PAGE 5

San Antonio Breast Cancer Symposium Adjuvant Denosumab continued from page 4

of disease-free survival showed an absolute benefit of 1.2% favoring denosumab at 3 years, a 2.1% benefit at 5 years, and a 3.1% benefit at 7 years. The differences between the two arms were of borderline significance, Dr. Gnant reported.

An exploratory subgroup analysis suggested that early initiation of denosumab, large tumors, and cancers with high luminality could identify patients likely to have greater benefit from ­denosumab.

Among 900 patients with larger tumors, the disease-free survival difference between the two arms was 4% at 2 years, 7% at 5 years, and 10% at 7 years (P = .0163).

Although this was not a head-tohead study to compare denosumab

Additional Benefit of Adjuvant Denosumab ■■ Bisphosphonates have been found to improve survival in postmenopausal patients with breast cancer.

■■ Adjuvant denosumab was found to halve the fracture rate in the large prospective ABCSG-18 trial of postmenopausal women with hormone receptor–positive breast cancer who were taking an aromatase inhibitor.

■■ Experts agree that adjuvant denosumab should be offered to this population but admit reimbursement is problematic, limiting access to this therapy.

vs bisphosphonates, “it is fair to say adjuvant denosumab has at least as much benefit in the adjuvant setting as bisphosphonates,” Dr. Gnant added.

Osteonecrosis of the jaw is a concern with high-dose denosumab (approved doses for osteopenia/osteoporosis). “With low-dose denosumab given twice a year, osteonecrosis of the jaw is extremely rare,” stated Dr. Gnant.

“In ABCSG-18, we monitored patients teeth and jaws, and of 31 cases of suspected osteonecrosis of the jaw, we did not identify a single case.”

Effect on Cancer Cells During the discussion following his presentation, Dr. Gnant speculated about the mechanism of denosumab’s effect on cancer cells. “We think it has

to do with an effect on the microenvironment, reducing osteoclastic activity and silencing the microenvironment, so it becomes more difficult for micrometastasis to develop and to awaken dormant microscopic disease.” n

Disclosure: Dr. Gnant reported no potential conflicts of interest.

References 1. Gnant M, Pfeiler G, Dubsky PC, et al: Adjuvant denosumab in breast cancer (ABCSG-18): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433-443, 2015.

2. Gnant M, Pfeiler G, Dubsky PC, et al: The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. 2015 San Antonio Breast Cancer Symposium. Abstract S2-02. Presented December 9, 2015.

Visit ASCOPost.com for Interviews Filmed Live During the 2015 San Antonio Breast Cancer Symposium The ASCO Post presents these and other important discussions: ■■ ■■ ■■ ■■ ■■

Results from NSABP B-35: Patient-Reported Outcomes TH3RESA Study: Final Overall Survival Results HR-Positive Breast Cancer: Results From the ABCSG-18 Trial Results of the CREATE-X Clinical Trial on Higher-Risk Disease Mastectomy vs Lumpectomy: Complications and Costs

Visit The ASCO Post online at ASCOPost.com

Bruce E. Johnson, MD, FASCO, Elected ASCO President for 2017-2018 Term As this issue went to press we learned that Bruce E. Johnson, MD, FASCO, was elected President of the American Society of Clinical Oncology (ASCO) for the term beginning in June 2017. He will take office as President-Elect during the ASCO Annual Meeting in Chicago in June 2016.

Watch future issues of The ASCO Post for more on the election and an interview with Dr. Johnson.

The ASCO Post | DECEMBER 25, 2015

PAGE 6

ASH Annual Meeting Geriatric Leukemia

Ibrutinib Bests Standard of Care for Elderly Patients With CLL

By Alice Goodman

F

irst-line treatment with the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) significantly reduced the risk of dying or disease progression compared with chlorambucil (Leukeran)

was standard of care for the elderly CLL population. RESONATE-2 is the first phase III direct comparison of ibrutinib vs chemotherapy in this older population (aged 65 years or older).

This phase III trial in treatmentnaive chronic lymphocytic leukemia confirmed the benefit of ibrutinib in this older population with frequent comorbidities.

—Alessandra Tedeschi, MD

These powerful clinical results show superiority over a traditional standard-of-care chemotherapy and have the potential to alter how we treat patients.

—Jan A. Burger, MD, PhD

in older treatment-naive patients with chronic lymphocytic leukemia (CLL) in the RESONATE-2 trial. At the time the study was designed, chlorambucil

Paradigm Shift?

“This phase III trial in treatmentnaive CLL confirmed the benefit of ibrutinib in this older population with

frequent comorbidities. Once-daily ibrutinib was administered, and 87% of patients are continuing on this drug with a median of 1.5 years of follow-up,” said lead author Alessandra Tedeschi, MD, Azienda Ospedaliera Niguarda Cà Granda, Milan, Italy.

“This population is frequently frail and undertreated.… Chlorambucil has been the standard of care. No other regimen has improved survival in the elderly,” she added.

“The data may signal a paradigm shift and demonstrate the value of ibrutinib in the treatment-naive setting. These powerful clinical results show superiority over a traditional standard-of-care chemotherapy and have the potential to alter how we treat patients,” said senior investigator Jan A. Burger, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston, according to a news release from AbbVie, the study sponsor.

Dr. Tedeschi presented these results at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition,1 and results were published online in The New England Journal of Medicine to coincide with her presentation.2 Ibrutinib is currently approved by the U.S. Food and Drug Administration (FDA) for patients treated with more

EXPERT POINT OF VIEW

U

ntil recently, chlorambucil (Leukeran) was the standard of care for older patients with chronic lymphocytic leukemia (CLL) in Europe. In several studies, chlorambucil combined with newer drugs—for ex-

of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research at the University of California, Irvine.

“FCR [fludarabine, cyclophosphamide, and rituximab (Rituxan)]-like regimens are too myelosuppressive

These results of RESONATE-2 are not a surprise to anyone. The relevance—in my opinion—is not the efficacy but rather that these results can serve as a registration strategy for upfront therapy.

—Susan M. O’Brien, MD

ample, anti-CD20 antibodies, obinutuzumab (Gazyva), or ofatumumab (Arzerra)—improved survival, explained Susan M. O’Brien, MD, Associate Director for Clinical Science for the Chao Family Comprehensive Cancer Center and Medical Director

for older patients with comorbidities.

These results of RESONATE-2 are not a surprise to anyone. The relevance— in my opinion—is not the efficacy but rather that these results can serve as a registration strategy for upfront therapy. I would think that ibrutinib [Im-

bruvica] will get an indication at least for upfront therapy in people aged 65 and older, which represents about 50% of all CLL patients who need treatment,” Dr. O’Brien commented.

“Obviously this is huge. Any older patient who requires therapy will get ibrutinib. What will be more controversial will be if the drug gets a broader approval for upfront therapy agewise. Chlorambucil is unacceptable for younger fit patients with CLL. Three published trials with different follow-up showed that with FCR there is a plateau for progression-free survival in younger fit patients with mutated IGVH [immunoglobulin variable region heavy chain gene], suggesting that these patients are cured by FCR. So it will be interesting to see where ibrutinib will fit in for younger patients with favorable cytogenetics,” she said. n Disclosure: Dr. O’Brien reported no potential conflicts of interest.

RESONATE-2 Trial ■■ A global phase III trial demonstrated a significant survival benefit for upfront treatment with ibrutinib vs chlorambucil in older patients with CLL. ■■ Ibrutinib reduced the risk of death or disease progression by 84% compared with chlorambucil.

■■ These findings have the potential to change the standard of care for older patients with comorbidities who are not candidates for FCR.

than one prior therapy and those who have deletions in 17p. These results may broaden the indications for FDA approval to include upfront treatment of elderly patients.

Study Details The study enrolled 269 patients aged 65 years and older with CLL. These patients had comorbidities that would preclude FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]) chemotherapy. Exclusion criteria included del(17p) and warfarin. Median age was 73 years; 70% of patients were over age 70. Forty-three patients crossed over to ibrutinib during the course of the trial.

Ibrutinib significantly prolonged progression-free survival, as determined by an independent review committee, reducing the risk of death or disease progression by 84% vs chlorambucil. Median progression-free survival was not reached in the ibrutinib group vs 18.9 months in the chlorambucil group (P < .001) at a median of 18.4 months of follow-up. Ibrutinib significantly prolonged overall survival, with an estimated overall survival of 98% at 24 months vs 85% with chlorambucil (P = .001).

In addition, ibrutinib significantly improved the overall response rate compared with chlorambucil—86% vs 35%, respectively (P < .001). Ibrutinib also significantly improved hemoglobin and platelets compared with chlorambucil.

Safety Profile The most common adverse events associated with ibrutinib were diarrhea (42%), fatigue (30%), cough (22%), continued on page 7

ASCOPost.com | DECEMBER 25, 2015

PAGE 7

ASH Annual Meeting Novel Therapies

Midostaurin: A New Standard of Care in Acute Myeloid Leukemia?

By Alice Goodman

U

pfront treatment with midostaurin added to standard chemotherapy improved survival compared with placebo plus chemotherapy in high-risk patients with acute myeloid leukemia (AML) characterized by FLT3 mutations. No new drugs have been approved for AML since 1990, and midostaurin is the first targeted

agent to improve survival in FLT3mutated AML. At a median follow-up of 57 months, midostaurin reduced the risk of death by 23% compared with placebo plus chemotherapy (P = .007).

These results of the multinational randomized, placebo-controlled, phase III CALGB 10603/RATIFY

trial were presented at the Plenary Session of the 57th American Society of Hematology Annual Meeting and Exposition.1 The study was done in partnership with the Alliance for Clinical Trials in Oncology and Novartis.

“The overall survival results for midostaurin plus standard chemotherapy in treating FLT3-mutated AML are a

EXPERT POINT OF VIEW

P

utting this trial into context, Mark J. Levis, MD, of the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, said: “Six different FLT3 inhibitors have advanced into phase III trials. Midostaurin in the only one that has made it to the ‘station.’”

We have had no new drugs for AML for many years, and we lost one— Mylotarg [gemtuzumab ozogamicin]. While we waited for this trial to accrue, allogeneic transplant has become a favored approach. Now it is time to ask whether overall sur-

While we waited for this trial to accrue, allogeneic transplant has become a favored approach. Now it is time to ask whether overall survival is the best endpoint for clinical trials that are so time-consuming.

—Mark J. Levis, MD

“The fact that midostaurin is multitargeted limits its in vivo potency against the FLT3 target and causes off-target effects, but the drug is active against both the internal tandem duplication and TKD-FLT3 mutations,” he continued.

Knowing that AML is a polyclonal disease, it makes sense that multitargeted agents would have better effects in newly diagnosed patients, such as the patient population of the ­RATIFY trial, he continued.

“It has taken RATIFY almost a decade from conception to results.

vival is the best endpoint for clinical trials that are so time-consuming.

Another endpoint might be more suitable, given the time it took to accrue patients to RATIFY,” Dr. Levis commented.

Future Directions “It was a monumental accomplishment to design and complete an intergroup study involving multiple countries and nine different laboratories,” said Mark Litzow, MD, Professor, Mayo Clinic, Rochester, Minnesota, and Chair of the ECOG-

Mark Litzow, MD

The overall survival results for midostaurin plus standard chemotherapy in treating FLT3-mutated AML are a long-awaited advance for hematologists and the AML community. This represents a new standard of care.

—Richard M. Stone, MD

ACRIN Cancer Research Group Leukemia Committee, which is planning the next generation of FLT3 AML studies.

Dr. Litzow was optimistic about midostaurin and its role in treating FLT3 AML. “The data looked like the drug was of most benefit to the patients with FLT3-TKD mutations but did also benefit patients with FLT3ITD mutations.”

“The study does have the potential to be practice-changing, and midostaurin should be considered as part of the control arm of future studies. ECOG-ACRIN is now discussing the design of future trials,” said Dr. Litzow. “A major question now is to see how other FLT3 inhibitors stack up as compared with midostaurin.” n Disclosure: Drs. Levis and Litzow reported no potential conflicts of interest.

long-awaited advance for hematologists and the AML community. This is the first step in applying the theories of personalized medicine to patients with AML, specifically those who have a FLT3 mutation, who we have shown are likely to benefit from the addition of this targeted agent, midostaurin, to standard therapy,” said Richard M. Stone, MD, Director of the Adult Leukemia Program, Dana-Farber Cancer Institute, Boston. “This represents a new standard of care,” he added.

About 30% of patients with AML carry an activating mutation of the receptor tyrosine kinase FLT3, either an internal tandem duplication (FLT3/ ITD) or a tyrosine kinase domain (TKD). FLT3/ITD mutations are more common and are associated with aggressive disease, poor prognosis, and a higher risk of relapse. AML patients continued on page 12

Ibrutinib in Older Patients continued from page 6

and nausea (22%). The most common adverse events associated with ­chlorambucil included nausea (39%), fatigue (38%), neutropenia (23%), and vomiting (20%). Toxicities were mostly grade 1, noted Dr. Tedeschi.

Grade 3 hypertension was reported in 14% of patients on ibrutinib, and this was managed by hypertensive medications with no dose reduction or treat-

ment discontinuation. Atrial fibrillation was reported in 6% of the ibrutinib arm (grade 2 in 6 patients, grade 3 in 2 patients). Two patients discontinued treatment due to atrial fibrillation, and the other patients did not require dose modification.

Adverse events leading to treatment discontinuation were 9% in the ibrutinib arm vs 23% for chlorambucil. Three deaths were reported in the ibrutinib arm and 17 deaths were re-

ported in the chlorambucil arm over the follow-up period of 18.4 months.

None of the patients who had disease progression on ibrutinib died during the follow-up period. n Disclosure: The study was funded by Pharmacyclics, an AbbVie company. Dr. Tedeschi reported no potential conflicts of interest. Dr. Burger has received research funding from Pharmacyclics. For full disclosures of other study authors, see the abstract at www. hematology.org/Annual-Meeting.

References 1. Tedeschi A, Barr PM, Robak T, et al: Results from the international, randomized phase 3 study of ibrutinib versus chlorambucil in patients 65 years and older with treatment-naive CLL/SLL (RESONATE-2). 2015 ASH Annual Meeting. Abstract 495. Presented December 7, 2015.

2. Burger JA, Tedeschi A, Barr PM, et al: Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. December 6, 2015 (early release online).

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PAGE 12

ASH Annual Meeting Midostaurin in AML continued from page 7

with either type of mutation were eligible for this trial. Several FLT3 inhibitors are under development, but midostaurin is the first to improve survival in FLT3-mutated patients in the context of a randomized phase III trial.

Midostaurin is an investigational

multitargeted kinase inhibitor in development for the treatment of patients with AML who have a FLT3 mutation.

Midostaurin inhibits multiple kinases that are involved in cancer cell proliferation, including FLT3.

RATIFY Trial Details and Results RATIFY enrolled 717 adults with

FLT3-mutated AML and randomized them in a 1:1 ratio to receive oral midostaurin or placebo in addition to standard induction (daunorubicin/ cytarabine) and consolidation chemotherapy (high-dose cytarabine).

Patients who achieved complete remission after consolidation chemotherapy continued treatment with

single-agent midostaurin or placebo for 1 year of maintenance therapy.

Midostaurin also significantly improved event-free survival compared with placebo: Median event-free survival was 8 months for midostaurin vs 3.6 months for placebo (P = .0032), representing a 21% reduction in the risk of events favoring midostaurin.

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ASCOPost.com | DECEMBER 25, 2015

PAGE 13

ASH Annual Meeting Survival Benefit Seen With FLT3 Inhibitor in AML ■■ Midostaurin is the first FLT3 inhibitor to improve overall survival in FLT3mutated acute myeloid leukemia (AML).

■■ Midostaurin plus standard chemotherapy significantly improved overall survival vs placebo plus chemotherapy, reducing the risk of death by 23%.

■■ No new drugs have been approved to treat AML since the 1990s, and midostaurin appears to be a breakthrough as a targeted therapy for AML.

Patients were prestratified according to three mutation subtypes: tyrosine kinase domain (TKD), internal tandem duplications (ITD) high, and ITD low.

ITD mutations carry a worse prognosis, and the prognosis is less uncertain with TKD mutations. Midostaurin seemed to improve overall survival as well as event-free survival in all three FLT3

subtypes vs placebo.

Patients who achieved complete remission while taking midostaurin had a disease-free survival of 25.9 months compared with 14 months for patients achieving a complete remission while taking placebo. This implies that either the quality of remission associated with

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continued on page 14

The ASCO Post | DECEMBER 25, 2015

PAGE 14

ASH Annual Meeting Midostaurin in AML continued from page 7

midostaurin use was better or deeper, or that maintenance therapy with midostaurin prolonged the remission (or perhaps both).

Many patients (57%) went on to undergo allogeneic stem cell transplantation in first remission, 28% in the

midostaurin group and 22% in the placebo group did so; midostaurin yielded a survival benefit in patients who were censored at the time of transplant.

“Overall survival post transplant is benefited by midostaurin if the transplant is done during first remission,” Dr. Stone said.

No statistically significant differ-

Concomitant strong inhibitors of CYP3A4/PgP should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions (5.9)].

Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions (5.9)].

7.2 Agents That May Decrease Everolimus Blood Concentrations CYP3A4/PgP Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information].

7.3 Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a nonCYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf).

Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary Based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, apprise the patient of the potential hazard to the fetus [see Warnings and Precautions (5.12) in the full prescribing information].

Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are

ences were observed in the overall rate of grade 3 or higher hematologic and nonhematologic adverse events (except for rash/desquamation). Thirty-seven deaths were reported, and no difference in deaths or treatment was seen between the two groups.

“The study demonstrates that an international academic-industry collabor-

excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.5 Geriatric Use In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients.

Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information].

No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information].

8.6 Females and Males of Reproductive Potential Contraception Females AFINITOR can cause fetal harm when administered to a pregnant woman.

Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.1)].

Infertility Females Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR [see Adverse Reactions (6.2, 6.4, 6.5) and Nonclinical Toxicology (13.1) in the full prescribing information].

Males AFINITOR treatment may impair fertility in male patients based on animal findings [see Nonclinical Toxicology (13.1) in the full prescribing information].

8.7 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

8.8 Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (ChildPugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

For advanced RCC, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2015-17 January 2015

ative AML study based on genotype at diagnosis is feasible,” Dr. Stone stated.

“These results suggest that midostaurin plus chemotherapy should be studied in FLT3 wild-type and/or older AML patients.” n Disclosure: The RATIFY study was sponsored by Novartis. Dr. Stone has been a consultant for Celgene, Sunesis, Amgen, Agios, Roche/Genentech, Merck, Pfizer, Arog, Celator, Juno, AbbVie, and Karyopharm Therapeutics.

Reference 1. Stone RM, Mandrekar S, Sanford BL, et al: The multi-kinase inhibitor midostaurin prolongs survival compared with placebo in combination with daunorubicin/ cytarabine induction, high-dose C consolidation, and as maintenance therapy in newly diagnosed acute myeloid leukemia patients age 18–60 with FLT3 mutations: An international prospective randomized placebo-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]).

2015 ASH Annual Meeting and Exposition.

Plenary Session Abstract 6. Presented December 6, 2015.

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

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ASCOPost.com | DECEMBER 25, 2015

PAGE 15

ASH Annual Meeting Multiple Myeloma

Daratumumab continued from page 1

core treatments, with no added toxicity,” he said, adding that future research will determine the optimal pairings with the drug.

Dr. Plesner updated the safety and efficacy data from the ongoing phase I/II GEN503 trial of daratumumab in combination with lenalidomide/dexamethasone in 32 relapsed/refractory patients in the expansion cohort, who had received a median of 2 prior lines of therapy. Median follow-up was 15.6 months.

Patients received standard dosing of lenalidomide/dexamethasone plus infusions of daratumumab at 16 mg/kg or are refractory to both a proteasome inhibitor and an IMID, followed by once-monthly infusions. Patients were treated until disease progression or intolerable toxicity.

The overall response rate was 81%, with 34% of patients achieving a complete response or better and 63% achieving at least a very good partial response; these included eight (25%) stringent

complete responses, three (9%) complete responses, and nine (28%) very good partial responses.

The median time to first response was 1 month and to best response was 5.1 months. Median duration of response was not reached, and 91% were free of disease progression at 12 months. All pa-

(56%) patients had infusion-related reactions, including cough, allergic rhinitis, nausea, vomiting, dyspnea, nasal congestion, and hypertension. The two (6%) grade 3 reactions were laryngeal edema and hypertension.

“Infusion-related reactions occurred usually during the first infusion only and

It’s my personal opinion that daratumumab is the rituximab of myeloma. It is very effective when given with other core treatments, with no added toxicity.

—Torben Plesner, MD

tients had a change in paraprotein level from baseline, which exceeded a 50% reduction in all but two patients.

Median progression-free and overall survival had not been reached, but, at 18 months, overall survival was 90%, and progression-free survival was 72%.

The most common treatment-emergent adverse events were neutropenia (84%), muscle spasms (44%), cough (50%), and diarrhea (44%). Eighteen

Update on Daratumumab in Multiple Myeloma ■■ As a single agent, daratumumab produced responses in 31% of patients who were heavily pretreated and refractory to current agents.

■■ Daratumumab plus lenalidomide/dexamethasone led to responses in 81% of patients.

■■ With the use of daratumumab with pomalidomide/dexamethasone, response rates were 71% and 67% in those with double-refractory disease.

■■ Daratumumab works through immunomodulation and is already being studied in the front-line setting.

were grade 2 or less with only two exceptions. They were easily managed with premedication or by slowing the infusion rate,” Dr. Plesner said.

All patients with immune-related reactions recovered and continued to receive treatment, except for one patient with laryngeal edema, who recovered but discontinued treatment, he added.

Of 32 patients, 22 (69%) remain on treatment, at a median of 15.6 months of follow-up.

With Pomalidomide and Dexamethasone Investigators reported data from the phase 1b MMY1001 trial of daratumumab (16 mg/kg) in combination with pomalidomide (4 mg/kg) and dexamethasone (40 mg) in 98 relapsed/ refractory patients with at least 2 prior lines of treatment.2 Ajai Chari, MD, of Icahn School of Medicine at Mount Si-

nai, New York, presented these findings.

The rationale for the combination, he said, is the finding that pomalidomide increases CD38 expression in myeloma cells in a time- and dosedependent fashion. In this cohort, 100% of patients had prior exposure to a proteasome inhibitor and immunomodulating drug, and the majority of patients had double-refractory ­disease.

The response rate was 71% overall and 67% in those with double-refractory disease; 43% achieved at least a very good partial response, and 73% had a clinical benefit.

“The vast majority of patients had at least a 50% drop in M protein,” Dr. Chari added. “At a median follow-up of 4.2 months, 47 of 53 (89%) responders had not progressed.”

Serious adverse events occurred in 42% of patients. Rates of grade ≥ 3 adverse events were similar to those observed with pomalidomide/dexamethasone alone. Almost half the patients required growth factors, and one-quarter required blood transfusions during treatment. Infusion-related reactions were predominantly mild.

“Daratumumab can be safety combined with pomalidomide/dexamethasone,” stated Dr. Chari. “We observed no new safety signals.”

As a Single Agent Saad Z. Usmani, MD, of Levine Cancer Institute/Carolinas HealthCare continued on page 16

EXPERT POINT OF VIEW

A

t an educational session at the 2015 American Society of Hematology Annual Meeting and Exposition, Sagar Lonial, MD, of Emory University, Atlanta, elaborated upon this topic. The pooled analysis of daratumumab (Darzalex) monotherapy, he said, “demon-

Sagar Lonial, MD

strated significant activity and, not only this, but very prolonged duration of remission and overall survival in patients, even beyond the time when their re-

sponse to anti-CD38 antibody is gone.

This suggests that immunomodulation may be an important part of the longterm outcome of patients.”

Thierry Facon, MD, of Lille University Hospital in France, who is co-principal investigator for the frontline trial of daratumumab, said in an interview with The ASCO Post that he is eager to have access to the drug in France. “This drug is important for our patients,” stated Dr. Facon.

Dr. Facon commented that oncologists will no doubt want to use daratumumab off-label. It is currently indicated only as a single agent in patients who have received at least three lines of treatment. “The pressure for this will be immense,” he predicted. “The experts will say we have to stick to the indication for which it is approved, but I know there will be pressure from patients.”

The best use will not be as a single agent; however, this still gives a 30% response in patients who have failed everything. This is an unmet need.

—Thierry Facon, MD

Whether daratumumab will work best with lenalidomide (Revlimid) or pomalidomide (Pomalyst) remains unclear, experts said. “This is an incredibly active combination as well and speaks to the immune-mediated inflammatory disease/antibody interaction, which really does seem to enhance the activity of both agents over time,” Dr. Lonial said.

As a single agent, however, daratu-

mumab does have a place, Dr. Facon added. “The best use will not be as a single agent; however, this still gives a 30% response in patients who have failed everything. This is an unmet need.” n Disclosure: Dr. Lonial is a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx, and Janssen. Dr. Facon is a member of the Board of Directors or advisory committee and the speakers bureau for Celgene.

The ASCO Post | DECEMBER 25, 2015

PAGE 16

ASH Annual Meeting Daratumumab continued from page 15

System in Charlotte, North Carolina, reported robust single-agent activity for daratumumab, based on an analysis of the combined dataset of 148 patients receiving 16 mg/kg of daratumumab in the GEN501 and SIRIUS trials.3 “Daratumumab induced rapid, deep, and durable responses in a heavily pretreated/highly refractory population,” Dr. Usmani said. “Remarkable depth of response was observed in patients who were refractory to newer agents, including pomalidomide and carfilzomib [Kyprolis].”

The overall response rate was 31%, with 13% of patients achieving at least a very good partial response and 3% achieving a complete response or better.

“In many patients, responses deepened with continued daratumumab treatment. At a median follow-up of 14.8 months, 50% of responders were progression-free. Of 46 responders, 40 are still alive,” noted Dr. Usmani.

Median overall survival was 19.9 months, and 1-year survival was 69%. For responders, median overall survival has not been reached. For patients with minimal response or stable disease, median survival was 17.5 months, compared with 3.7 months for disease progressors.

“Daratumumab conferred an overall survival benefit, even in patients who achieved stable disease or minimal response,” he emphasized.

Two phase III trials are underway of daratumumab plus lenalidomide/dexamethasone: one in relapsed/refractory patients (Pollux) and the other in newly diagnosed patients (Maia).

Immune Modulation With Combined Treatment Each of the investigators emphasized that daratumumab is a new form of immunotherapy, one that is complementary to the current immunomodulatory drugs— lenalidomide, pomalidomide, and thalidomide (Thalomid). Daratumumab binds to CD38, which is highly and ubiquitously expressed on myeloma cells. This binding induces tumor cell death through direct and indirect mechanisms.

“It has recently also been shown that daratumumab has an important immunomodulatory function,” Dr. Plesner said. “It is able to eliminate regulatory T cell, B cells, and macrophages that inhibit T-cell cytotoxic response against myeloma cells.” n Disclosure: Dr. Plesner has received research funding or served as an advisor for Roche, Novartis, Janssen, Celgene, and Genmab. Dr. Chari has consulted for Celgene, Millennium/ Takeda, Array BioPharma, Novartis, and

Onyx. Dr. Usmani has consulted and received honoraria from Celgene and Onyx.

References 1. Plesner T, Arkenau H-T, Gimsing P, et al: Daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: Updated results of

a phase 1/2 study (GEN503). 2015 ASH Annual Meeting and Exposition. Abstract 507. Presented December 7, 2015.

2. Chari A, Lonial S, Suvannasankha A, et al: Open-label multicenter phase 1b study of daratumumab in combination with pomalidomide and dexamethasone in patients with at least 2 lines of prior therapy and relapsed or relapsed and refrac-

tory multiple myeloma. 2015 ASH Annual Meeting and Exposition. Abstract 508. Presented December 7, 2015.

3. Usmani S, Weiss B, Bahlis NJ, et al: Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma.

2015 ASH Annual Meeting and Exposition. act 29. Presented December 5, 2015.

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ASCOPost.com | DECEMBER 25, 2015

PAGE 17

Announcements

ASH Announces Top Trainee Abstracts of 2015 Annual Meeting

T

he American Society of Hematology (ASH) recognized investigators with the highest-scoring abstracts in the categories of undergraduate student, medical student, graduate student, resident physician, and postdoctoral fellow at the 57th

ASH Annual Meeting and Exhibition, December 5–8 in Orlando, Florida.

“It is truly exciting to recognize trainees who are already making notable contributions to hematology research,” said 2015 ASH President David A. Williams, MD, President of Dana-

Farber/Boston Children’s Cancer and Blood Disorders Center and Leland Fikes Professor of Pediatrics at Harvard Medical School. “ASH is pleased to honor these talented investigators and looks forward to supporting the next David A. Williams, MD

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continued on page 18

The ASCO Post | DECEMBER 25, 2015

PAGE 18

Announcements ASH Top Trainee Abstracts continued from page 17

generation of hematologists as they continue to pursue improved treatments and cures for patients with blood diseases.”

The ASH Outstanding Abstract Achievement Award recipients for 2015 are:

Undergraduate Student Hannah Rasmussen, Harvard University Oncostatin M Enhances Hematopoietic Stem Cell Homing and Engraftment (Abstract 31) Medical Student Bryan Harris, Fox Chase Cancer Center

Rpl22 Deficiency Predisposes Hematopoietic Stem and Progenitor Cells to Leukemogenesis (Abstract 899) Graduate Student Lars Klemm, MSc, University of California, San Francisco Exposure to Inflammatory Immune

Responses as Driver of Clonal Evolution in Childhood Acute Lymphoblastic Leukemia (Abstract 166) Resident Physician Ryan Moy, MD, PhD, University of Pennsylvania Perelman School of Medicine Immunologic Effects of CCR5

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ASCOPost.com | DECEMBER 25, 2015

PAGE 19

Announcements

Blockade in Graft-Versus-Host Disease Prophylaxis (Abstract 920)

Mary Rodes Gibson Memorial Award in Hemostasis and Thrombosis

Postdoctoral Fellow Noboru Asada, MD, PhD, Albert Einstein College of Medicine Distinct Contributions by Perivascular Niche Cells in Hematopoietic Stem Cell Maintenance (Abstract 661)

The Mary Rodes Gibson Memorial Award in Hemostasis and Thrombosis was established to recognize the trainee (undergraduate student, medical student, graduate student, resident physician, or postdoctoral

fellow) who is the first author and presenter of the highest-scoring abstract submitted to the ASH Annual Meeting in the field of hemostasis and thrombosis. This annual award honoring excellence in hemostasis and thrombosis is made possible by the Mary Rodes Gibson HemostasisThrombosis Foundation to continue

the legacy of Mary Rodes Gibson, who suffered from severe, type 3 von Willebrand disease.

The 2015 recipient is: Shekhar Kumar, PhD, The Children’s Hospital of Philadelphia The X-Ray Structure of a Variant of Human Factor V Provides Structural Insights Into the Procofactor Activation Paradox (Abstract 121)

Minority Graduate Student Abstract Achievement Award

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Each year, ASH offers merit-based Minority Graduate Student Abstract Achievement Awards to select graduate students to acknowledge the accomplishments of and retain minority graduate students in the field of hematology through exposure to the ASH Annual Meeting.

The 2015 Minority Graduate Student Abstract Achievement Award recipients are: Morayo Adebiyi, The University of Texas Medical School at Houston Sustained Elevation of AdenosineADORA2B Signaling Promotes Chronic Pain through Neuro-Immune Interaction in Sickle Cell Disease ­(Abstract 974) Ian Johnston, University of Pennsylvania Perelman School of Medicine A Targeted Photochemical Microfluidic Vascular Injury Model for in Vitro Thrombosis Studies: Usage in Heparin-Induced Thrombocytopenia (HIT) (Abstract 212) Randolph Lyde, University of Pennsylvania Perelman School of Medicine Towards the Care of Hemophilia A Patients Using Induced Pluripotent Stem Cell (iPSC)-Derived Megakaryocytes (iMks) Expressing Coagulation Factor (F) VIII (Abstract 2266) Katelyn Melgar, University of Cincinnati College of Medicine Novel Small Molecule FLT3 Inhibitors for the Treatment of FLT3-ITD AML (Abstract 3690) Shaneice Mitchell, The Ohio State University College of Medicine In Vitro and in Vivo Anti-Leukemic Effects of KPT-9274, a Reported PAK4 Allosteric Modulator, in Acute Myeloid Leukemia: Promising Results Justifying Further Development in This Disease (Abstract 2471) To search for individual abstracts online, please visit https://ash.confex.com/ ash/2015/webprogram/start.html. n

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication

The ASCO Post | DECEMBER 25, 2015

PAGE 20

In the Clinic Genitourinary Oncology

Nivolumab in Advanced Renal Cell Carcinoma After Antiangiogenic Therapy

By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n November 23, 2015, nivolumab (Opdivo) was approved for use in the treatment of patients with advanced renal cell carcinoma who have received prior antiangiogenic therapy.1,2

Supporting Efficacy Data Approval was based on improved overall survival in a phase III trial (CheckMate 025) in which 821 patients with advanced renal cell carcinoma who had received prior antiangiogenic therapy were randomly assigned to nivolumab at 3 mg/kg intravenously every 2 weeks (n = 410) or oral everolimus (Afinitor) at 10 mg once daily (n = 411).2,3 Patients had a median age of 62 years (40% ≥ 65 and 9% ≥ 75 years), 75% were male, 88% were white, Karnofsky performance score was 70 to 80 in 34% and 90 to 100 in 66%, 77% had received prior antiangiogenic therapy, and Memo-

OF NOTE Nivolumab prevents PD-L1 and PD-L2 from binding to the PD-1 receptor on T cells, thereby blocking PD-1 pathway–mediated inhibition of immune response, including antitumor immune response.

rial Sloan Kettering risk was favorable in 34%, intermediate in 47%, and poor in 19%.

At a prespecified interim analysis based on 70% of planned events, median overall survival, the primary endpoint, was 25.0 months (95% confidence interval [CI] = 21.7 months to not estimable) in the nivolumab group vs 19.6 months (95% CI = 17.6–23.1 months) in the everolimus group (hazard ratio = 0.73, P = .0018). A survival benefit was observed regardless of programmed cell death ligand 1 (PD-L1) expression level. The confirmed response rate was 21.5% vs 3.9%, median response duration was 23.0 vs 13.7 months, and median time to response was 3.0 to 3.7 months.

How It Works Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds the programmed cell death protein 1 (PD-1) receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2, thereby blocking PD-1 pathway–mediated inhibition of immune response, including antitumor immune response. Binding of PD-L1 and PD-L2 to the PD-1 receptor inhibits T-cell proliferation and cytokine production.

Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance.

How It Is Used The recommended dose of singleagent nivolumab in this setting is 3 mg/kg via intravenous infusion over

Nivolumab should be discontinued for grade 4 diarrhea or colitis, grade 3 or 4 pneumonitis, grade 4 hypophysitis, grade 3 or 4 adrenal insufficiency, grade 4 hyperglycemia, grade 4 rash, any life-threatening or grade 4 adverse

OF NOTE Nivolumab carries warnings/precautions for immune-mediated adverse reactions and embryofetal toxicity.

reaction, AST or ALT > 5 times the upper limit of normal or total bilirubin > 3 times the upper limit of normal, serum creatinine > 6 times the upper limit of normal, immune-mediated encephalitis, recurrence of grade 3 adverse reactions, any life-threatening or grade 4 adverse reaction, persistent grade 2 or 3 adverse reactions lasting

Nivolumab for Kidney Cancer ■■ Nivolumab (Opdivo) was approved for use in the treatment of patients with advanced renal cell carcinoma who have received prior antiangiogenic therapy.

■■ The recommended dose of single-agent nivolumab in this setting is 3 mg/kg via intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

60 minutes every 2 weeks until disease progression or unacceptable toxicity. Infusion should be interrupted or slowed in patients with mild or moderate infusion reactions. Nivolumab should be discontinued for severe or life-threatening infusion reactions.

Single-agent nivolumab should be withheld for grade 2 pneumonitis, grade 2 or 3 diarrhea or colitis, alanine transaminase (ALT) or aspartate transaminase (AST) > 3 to 5 times the upper limit of normal or total bilirubin > 1.5 to 3 times the upper limit of normal, serum creatinine > 1.5 to 6 times the upper limit of normal, grade 2 or 3 hypophysitis, grade 2 adrenal insufficiency, grade 3 hyperglycemia, grade 3 rash, encephalitis indicated by newonset moderate or severe neurologic signs/symptoms, and first occurrence of other grade 3 adverse reactions.

There are no recommended dose modifications for hypothyroidism or hyperthyroidism. No dose adjustment is required in patients with renal impairment or mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment.

≥ 12 weeks, and requirement of prednisone or equivalent dose of ≥ 10 mg for > 12 weeks.

Safety Profile In the phase III trial, the most common adverse events of any grade in the nivolumab group were asthenic conditions (56% vs 57% in everolimus group), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), and dyspnea (27% vs 31%). Grade 3 or 4 adverse events occurred in 56% vs 62% of patients, including asthenic conditions in 6% vs 7%, dyspnea in 3% vs 2%, and back pain in 3% vs 3%.

Serious adverse events occurred in 47% of nivolumab patients, with those occurring in ≥ 2% consisting of acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.

The most common grade 3 or 4 laboratory abnormalities were anemia (8% vs 16%), hyponatremia (7% vs 6%), and lymphopenia (6% vs 11%). Among patients with thyroid-stimulating hormone less than the upper limit of normal, increase to greater than upper limit of normal was more common in

the nivolumab group (26% vs 14%).

Adverse events led to treatment delay in 44% of nivolumab patients and to discontinuation in 16% (vs 19% of the everolimus group). Death during or within 30 days of treatment occurred in 4.7% vs 8.6% of patients.

Potential immune-mediated adverse events were pneumonitis (including interstitial lung disease) in 5.2% (immune-mediated pneumonitis in 4.4%) vs 18.4%; diarrhea or colitis in 25% (immune-mediated in 3.2%) vs 32%; liver test abnormalities including increases in AST in 33% vs 39%, alkaline phosphatase in 32% vs 32%, ALT in 22% vs 31%, and total bilirubin in 9% vs 3%, with immune-mediated hepatitis requiring systemic immunosuppression in 1.5% of nivolumab patients; hypophysitis in 0.5%; adrenal insufficiency in 2%; thyroid disease in 10.6% vs 3.0%, with hypothyroidism/ thyroiditis in 8.1% and hyperthyroidism in 2.5% of the nivolumab group; hyperglycemia in 9%, with diabetes or diabetic ketoacidosis in 1%; renal injury in 6.6% vs 3.0%, with immunemediated nephritis and renal dysfunction in 3.2% of the nivolumab group; and rash in 28% (immune-mediated in 7.4%) vs 36%.

Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, and embryofetal toxicity. Patients should be monitored for changes in liver, kidney, thyroid, and neurologic function and for hyperglycemia. Breastfeeding women should discontinue breastfeeding during nivolumab therapy. n References 1. U.S. Food and Drug Administration: Nivolumab (Opdivo injection). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm474092.htm.

Accessed December 7, 2015.

2. Opdivo (nivolumab) injection for intravenous use prescribing information, Bristol-Myers Squibb Company, November 2015. Available at www.accessdata.fda.gov/dr ugsatfda_docs/ label/2015/125554s012lbl.pdf. Accessed December 7, 2015.

3. Motzer RJ, Escudier B, McDermott DF, et al: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803-1813, 2015.

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The ASCO Post | DECEMBER 25, 2015

PAGE 22

ASH Annual Meeting Geriatric Leukemia

Promising Upfront Combination in Older Patients With Acute Lymphoblastic Leukemia

By Alice Goodman

F

rontline treatment with the antibody-drug conjugate inotuzumab ozogamicin plus deintensified chemotherapy is a promising option for older patients with Philadelphia chromosome–negative acute lymphoblastic leukemia (ALL). Phase II results

therapy and typically do not receive it. The mini–hyper-CVD regimen employed in this trial is a modification of hyper-CVAD, which is used in younger patients with ALL; the modifications included reduced doses of cyclophosphamide and dexamethasone, no an-

Early results for response rates and ability to achieve minimal residual disease negativity are better [with inotuzumab ozogamicin and chemotherapy] than those achieved with a chemotherapy-only approach, and this may become a new standard of care as frontline therapy for elderly ALL patients.

neutrophil recovery was 16 days and 17 days, respectively.

Notable grade 3 and 4 adverse events included thrombocytopenia (74%), infection during consolidation (74%), infection during induction (53%), and hyperglycemia (50%). Veno-occlusive disease occurred in four patients (10%).

Two-year complete response duration was 81%, and 2-year overall survival was 64%. At a median follow-up of 23 months, 9 patients in complete response died.

Additional Comment Commenting on this study, Daniel DeAngelo, MD, of Dana-Farber Cancer Institute in Boston, said: “The wave of the future is the combi-

—Elias Jabbour, MD

suggest that this combination has the ability to improve response rates and overall survival in older patients, but further study is needed to confirm these findings.

In this small phase II study, overall response rate was 97%, complete cytogenetic response rate was 100%, and minimal residual disease negativity was 100%.1 “The combination was safe and effective in elderly patients with newly diagnosed ALL. Early results for response rates and ability to achieve minimal residual disease negativity are better than those achieved with a chemotherapyonly approach, and this may become a new standard of care as frontline therapy for elderly ALL patients. Lower doses are being explored,” said lead author Elias Jabbour, MD, of MD Anderson Cancer Center in Houston. He presented these results at the 57th American Society of Hematology Annual Meeting and Exposition.

Inotuzumab ozogomycin is an antibody-drug conjugate that binds to CD22 on the tumor cell surface and releases its payload—a potent chemotherapy (calechea­micin)—into tumor cells. Its mechanism is similar to that of ado-trastuzu­mab emtansine [Kadcyla] in breast cancer.

Study Details Older patients with ALL have a poor response to conventional chemo-

thracycline, and reduced doses of methotrexate and cytarabine.

Inotuzumab ozogomycin was given on day 3 of the first 4 courses, and mini– hyper-CVD was given for 8 courses.

Rituximab (Rituxan) and intrathecal chemotherapy were given for the first four courses. Maintenance therapy with mercaptopurine, vincristine, methotrexate, and prednisone was given for 36 months.

“The combination of inotuzumab ozogamicin, and mini–hyper-CVD has the potential for high efficacy and low toxicity,” Dr. Jabbour said.

The study included 38 patients aged 60 and older with newly diagnosed Philadelphia chromosome– negative ALL. Median age was 69 (the oldest patient was 79). At the time of the 2015 ASH Meeting, 35 patients were evaluable.

Outcomes and Toxicity Following induction therapy, 34 patients achieved a complete response.

The overall response rate was 97%. No deaths were reported during the first 4 weeks of induction therapy. All 19 patients with an abnormal karyotype achieved a cytogenetic complete response; 100% achieved minimal residual disease negativity.

Median time to platelet recovery was 23 days in cycle 1 and 22 days in subsequent cycles. Median time to

nation of monoclonal antibodies plus chemotherapy. We will see extraordinary responses with this approach.

Inotuzumab is still an investigational agent, but once approved, I think we will see it combined with chemotherapy in multiple regimens and for different patient populations.” n

Disclosure: Drs. Jabbour and DeAngelo reported no potential conflicts of interest.

Reference 1. Jabbour E, O’Brien S, Sasaki K, et al: Frontline inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-hyper-CVD) for older patients with acute lymphoblastic leukemia. 2015 ASH Annual Meeting and Exposition. Abstract 83. Presented December 5, 2015.

EXPERT POINT OF VIEW

B

oth the concept of an antibody-drug conjugate combined with lessintensive chemotherapy and the actual regimen used in this study are exciting, according to Nikolai Podoltsev, MD, PhD, Assistant Professor, Division of Hematology, Yale University Medical Center, New Haven, Connecticut. “This has great potential as upfront treatment for Philadelphia chromosome–negative ALL [in those] aged 60 and older,” he declared.

Other Ongoing Studies Inotuzumab ozogamicin monotherapy is being studied in the phase III INNOVATE trial in relapsed/refractory ALL, noted Dr. Podoltsev.

“It is intuitive to bring upfront therapy we use in the relapsed/refractory setting. Response rates of more than 90% are promising,” he said.

In this study, 4 of 35 evaluable patients developed veno-occlusive dis-

The results of Dr. Jabbour’s trial in patients aged 60 to 79 years are impressive. Some patients at Yale would get this regimen.

—Nikolai Podoltsev, MD, PhD

ease. “Veno-occlusive disease is the biggest concern in both transplanted and nontransplanted patients,” noted Dr. Podoltsev.

“Philadelphia chromosome–negative ALL is difficult to treat in older patients. Very few older adults are cured, and most are on clinical trials.

Younger ALL patients aged 40 to 50 are treated with pediatric-inspired regimens. Older (i.e., over age 40) [patients] are treated with hyperCVAD or the CALGB 911 protocol,” he explained.

The ECOG 1910 phase III trial is evaluating blinatumomab (Blincyto) as part of therapy in Philadelphia chromosome–negative ALL patients between the ages of 30 and 70, and this may turn out to be a useful regimen combined with chemotherapy, he added.

“The results of Dr. Jabbour’s trial in patients aged 60 to 79 years are impressive. Some patients at Yale would get this regimen,” Dr. Podoltsev said. n Disclosure: Dr. Podoltsev reported no potential conflicts of interest.

Atezolizumab (MPDL3280A): an investigational, engineered anti-PDL1 antibody

CURRENTLY ENROLLING Clinical trials in various tumor types for atezolizumab (MPDL3280A)* Trials for atezolizumab (MPDL3280A), an investigational anti-PDL1 antibody, are currently recruiting patients in various tumor types †: • Bladder

• Kidney

— NCT02589717 (Ph IV) — NCT02450331 (Ph III) IMvigor 010 — NCT02302807 (Ph III) IMvigor 211

• Breast — NCT02425891 (Ph III) IMpassion 130 — NCT02605915

• Colorectal — NCT02291289

• Hematologic malignancies — NCT02431208 — NCT02220842 — NCT02508870

— NCT02420821 (Ph III) IMmotion 151

• Lung

• Melanoma — NCT01656642

• Solid tumors

— NCT02486718 (Ph III) — NCT02409355 (Ph III) IMpower 111 — NCT02409342 (Ph III) IMpower 110 — NCT02367794 (Ph III) IMpower 131 — NCT02367781 (Ph III) IMpower 130 — NCT02366143 (Ph III) IMpower 150 — NCT02013219

— NCT02458638 — NCT02471846 — NCT02350673 — NCT02323191 — NCT02304393 — NCT01633970 — NCT02410512 — NCT02174172 — NCT01375842

For more information about the atezolizumab (MPDL3280A) clinical trial program Visit: Find.AntiPDL1trials.com or ClinicalTrials.gov Call: Genentech Trial Information Support Line: 1-888-662-6728 (US only) Email: global.rochegenentechtrials@roche.com *Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trials and should not be construed as a recommendation for use of any product for unapproved purposes. † All trials consistent with information on ClinicalTrials.gov as of November 17, 2015.

© 2015 Genentech USA, Inc. All rights reserved. PDL/031615/0020(2) Printed in USA.

The ASCO Post | DECEMBER 25, 2015

PAGE 24

ASH Annual Meeting Adult Leukemia

Pediatric Regimen Achieves Higher-Than-Expected Survival in Young Adults With Acute Lymphoblastic Leukemia

By Alice Goodman

A

dolescents and younger adults with acute lymphoblastic leukemia (ALL) had superior outcomes on a “pediatric” regimen compared with adult treatment protocols. A multicenter phase II study included patients aged 18–50, extending the upper limit of “younger,” since most other trials of this approach include patients up to age 30 or 40.

Three-year overall survival was 75%, and 3-year disease-free survival was 73% in this trial,1 which was reported at the 57th American Society of Hematology Annual Meeting and Exposition.

“In this trial, we took our own Dana-Farber Cancer Institute pedi-

atric protocol for patients aged 1–18 and used it in patients aged 18–50.

Other trials of different pediatricinspired regimens have had similar results. It’s just a different recipe.

The take-home point is that overall survival and disease-free survival are improved compared with historical controls treated on prior adult regimens,” said lead author Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute, ­Boston.

“The regimen is tolerable in young adults with ALL and represents a major therapeutic advance,” he said, although there are still remaining challenges. Dr. DeAngelo pointed out

EXPERT POINT OF VIEW

“T

his is a group of patients who have not done very well over the years. The cure rate for children with acute lymphoblastic leukemia (ALL) is over 90%, whereas this group of patients (ie, aged 18–50) typically has a 5-year survival of 40% to 50%. Use of pediatric regimens has boosted that survival, and in this trial, we have excellent survival of more than 70%, which is much higher than expected,” said Karen Ballen, MD, Director of the Leukemia Program at Massachusetts General Hospital, Boston, and coauthor of this study.

The take-home message of this study is that younger adults should be treated with a pediatric regimen. The results in this study are among the best of the phase II trials that have been conducted.

—Karen Ballen, MD

The Dana-Farber Cancer Institute pediatric regimen has three distinguishing features: prophylactic central nervous system therapy starting on day 1; high doses of asparaginase; and non–cross-resistant drugs with different sideeffect profiles, which allow use of a number of drugs, she explained.

Take-Home Message “The take-home message of this study is that younger adults should be treated with a pediatric regimen,” she stated. “The results in this study are among the best of the phase II trials that have been conducted.”

“You can now cure more ALL with a pediatric regimen. Younger patients can tolerate aggressive therapy and be treated with the intent to cure,” she added.

Dr. Ballen said a randomized, controlled trial is not likely in this rare disease. The Dana-Farber Cancer Institute ALL Consortium plans to evaluate modified versions of the pediatric regimen in patients over the age of 50. n Disclosure: Dr. Ballen reported no potential conflicts of interest.

A surprising finding was the association between poor overall survival based on body mass index.

Underweight and normal weight patients did much better than obese patients.

—Daniel DeAngelo, MD, PhD

that there are no phase III trials of pediatric-inspired regimens in younger adults with ALL. Thus far, all have been phase II studies.

Study Details Dr. DeAngelo and colleagues previously used a pediatric drug combination that included Escherichia coli asparaginase, which achieved a 4-year disease-free survival of 67% and an overall survival rate of 69%.2 The current successor trial used the same regimen substituting weekly pegylated asparaginase, which is thought to be safer and longer ­lasting.

The study included 110 high-risk young adult patients with ALL treated with induction therapy; patients who achieved remission went on to 30 weeks of consolidation and 2 years of maintenance therapy. They were also treated with central nervous system prophylaxis consisting of intrathecal chemotherapy and radiation therapy.

“Due to toxicity concerns, we adjusted the pegylated asparaginase dose during consolidation and lengthened the interval to every 3 weeks, for a total of 10 doses instead of 15. Also, we reinserted native E coli asparaginase during induction,” Dr. DeAngelo told listeners. Anticoagulation was used during treatment with asparaginase, he added.

Of the 110 patients accrued to the trial, 65 were on the higher doses of pegylated asparaginase, and 45 were on the amended protocol. Median age was 32 years; 61% were male. Eighty percent of patients had B-cell ALL, and 20% had T-cell ALL.

Study Results and Toxicity Eighty-nine percent of patients went into complete remission; 21 patients went on to transplant. There were three deaths due to transplant-related complications.

Subgroup analysis showed that patients younger than age 30 had a 4-year overall survival of 80%–85%, which was significantly better than for other age groups. Also, patients with T-cell ALL did particularly well on this protocol, with an overall survival of 80% and 70% for B-cell Philadelphia chromosome– negative ALL. “A surprising finding was the association between poor overall survival based on body mass index. Underweight and normal weight patients did much better than obese patients. This is one more concern about obesity,” Dr. DeAngelo told listeners.

As expected, it appears that minimal residual disease–negative patients fared better than minimal residual disease– positive patients, but these data are not fully analyzed. continued on page 25

Pediatric Regimen in Young Adults With ALL ■■ Adolescents and young adults with ALL fare better on pediatric or pediatricinspired regimens.

■■ A phase II trial of a pediatric regimen showed 3-year disease-free survival of 70% in ALL patients aged 18–50, which is excellent compared with other trials.

■■ To date, studies suggest that a pediatric regimen improves survival in patients up to age 30 or 40. This trial extended the upper age limit to 50.

■■ Future trials will explore modified versions of this pediatric regimen in patients over age 50.

ASCOPost.com | DECEMBER 25, 2015

PAGE 25

Announcements

Jonathan S. Lewin, MD, Joins Emory University

E

mory University announced that Jonathan S. Lewin, MD, has been appointed Executive Vice President for Health Affairs. Dr. Lewin also will serve as Executive Director for Emory’s

Dr. Lewin currently serves as Senior Vice President for Integrated Healthcare Delivery and as Co-Chair for Strategic Planning for Johns Hopkins Medicine.

He also serves as Professor and Chair of the Russell H. Morgan Department of Radiology and Radiological Science at

Johns Hopkins University, as well as the Radiologist-in-Chief at Johns Hopkins Hospital, with secondary appointments as Professor of Oncology, Neurosurgery, and Biomedical Engineering.

Dr. Lewin is internationally recognized as a pioneer in interventional

and intraoperative magnetic resonance imaging. He has developed more than 20 patents and has been principal or co–principal investigator on more than $10 million in grants from the National Institutes of Health and other federal and state funding agencies. n

NOW ENROLLING

REFLECTIONS– Jonathan S. Lewin, MD

Woodruff Health Sciences Center, President and CEO of Emory Healthcare and Chair of the Board of Directors of Emory Healthcare. He will begin his tenure at Emory on February 1, 2016.

Pediatric Regimen continued from page 24

After the amended doses of asparaginase, grade 3 and 4 toxicities (hyperbilirubinemia, alanine transaminase level elevations, and risk of thrombotrastuzumab sis) were reduced. The investigators noted that pegylated asparaginase had greater toxicity in older adults as well as in those with a high body mass index (> 30 kg/m2).

“We now anticoagulate everyone, preferably with low–molecularweight heparin, and we have seen a dramatic reduction in line-associated clots,” he said.

“Many challenges remain, including psychosocial ones.

We need a unified rituximab infliximab adalimumab approach to make progress in ALL, and this means more cooperative group trials in adolescents and young adults with ALL,” he stated. n

a clinical trial program created by Pfizer to investigate the potential biosimilarity of several products trastuzumab

rituximab

infliximab

adalimumab

CLINICAL TRIALS

bevacizumab

STUDY DESIGN

B327-02

METASTATIC BREAST CANCER Patients with HER2+ mBC who have not received prior therapy in the first-line setting with the exception of endocrine therapy

PF-05280014 + paclitaxel vs Herceptin® (trastuzumab) + paclitaxel in the first-line treatment of patients with HER2+ metastatic breast cancer (mBC)

Target enrollment: 690 patients

A global, phase 3, comparative clinical trial evaluating the efficacy, safety, pharmacokinetics (PK), and immunogenicity of PF-05280014, an investigational compound being studied as a potential biosimilar to Herceptin.

• Primary endpoint: objective response rate (ORR) • NCT01989676

rituximab

infliximab

1:1 randomization double-blind

adalimumab

bevacizumab PF-05280014 + paclitaxel

B328-06

trastuzumab + paclitaxel

FOLLICULAR LYMPHOMA

PF-05280586 vs Rituxan®/MabThera (rituximab) for the first-line treatment of patients with CD20-positive, low tumor burden follicular lymphoma (LTB-FL)

Patients with LTB-FL who have not received prior therapy in the first-line setting Target enrollment: 394 patients

A global, phase 3, comparative clinical trial evaluating the efficacy, safety, PK, and immunogenicity of PF-05280586, an investigational compound being studied as a potential biosimilar to Rituxan/MabThera.

1:1 randomization double-blind

• Primary endpoint: ORR • NCT02213263

PF-05280586

bevacizumab

rituximab

ADVANCED NON-SQUAMOUS NSCLC

B73910-03

Disclosure: Dr. DeAngelo has been a consultant for Pfizer, Amgen, Incyte, Bristol-Myers Squibb, Agios, Ariad, Novartis, and Celgene.

PF-06439535 + paclitaxel and carboplatin vs Avastin® (bevacizumab) + paclitaxel and carboplatin in the firstline treatment of patients with advanced non-squamous NSCLC

References 1. DeAngelo DJ, Stevenson K, Neuberg DS, et al: A multicenter phase II study using a dose intensified pegylated–asparaginase pediatric regimen in adults with untreated acute lymphoblastic leukemia: A DFCI ALL Consortium trial. 2015 ASH Annual Meeting and Exposition. Abstract 80. Presented December 5, 2015.

2. DeAngelo DJ, Stevenson KE, Dahlberg SE, et al: Long-term outcome of a pediatric-inspired regimen used for adults aged 18–50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia 29:526-534, 2015.

A global, phase 3, comparative clinical trial evaluating the efficacy, safety, PK, and immunogenicity of PF-06439535, an investigational compound being studied as a potential biosimilar to Avastin.

Eligible patients with advanced non-squamous NSCLC who have not received prior therapy in the first-line treatment setting and who are eligible to receive carboplatin/paclitaxel/bevacizumab Target enrollment: 798 patients

1:1 randomization double-blind

• Primary endpoint: ORR • NCT02364999

PF-06439535 + paclitaxel and carboplatin

bevacizumab + paclitaxel and carboplatin

PF-05280014, PF-05280586, and PF-06439535 are investigational compounds.

For more information about these trials, including secondary endpoints and eligibility criteria, please visit: www.pfizercancertrials.com and www.clinicaltrials.gov or call the Pfizer clinical trial call center at 1-800-718-1021.

BIO752800-01

© 2015 Pfizer Inc.

This information is current as of April 2015.

HER2=human epidermal growth factor receptor 2; NSCLC=non-small cell lung cancer.

Herceptin® is a registered US trademark of Genentech Inc. Rituxan® is a registered US trademark of Biogen Idec Inc. MabThera is a trademark of F. Hoffmann-La Roche AG. Avastin® is a registered US trademark of Genentech, Inc.

All rights reserved.

April 2015

The ASCO Post | DECEMBER 25, 2015

PAGE 26

Palliative Care Symposium Guidance Statement

ASCO and AAHPM Define Primary Palliative Care in Oncology

By Meg Barbor

A

new guidance statement from ASCO and the American Academy of Hospice and Palliative Medicine (AAHPM) could potentially lead to more standardized primary palliative care delivery across oncology settings, according to Kathleen E. Bickel, MD, MPhil, who presented the study findings at the 2015 Palliative Care in Oncology Symposium in Boston.1 When integrated into routine oncology care, palliative care improves symptom burden, quality of life, and patient and caregiver satisfaction.

However, not all patients with cancer have access to specialist palliative medicine.

“This work is a joint guidance statement to define high-quality primary palliative care delivery in medical oncology,” said Dr. Bickel, Assistant Professor of Medicine, White River Junction Veterans Affairs Medical Center and Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. This statement provides the first formal consensus-based recommendations regarding high-quality primary palliative care in oncology.

‘Real Tools’ “Serious illness is hard, and there’s a lot we want our medical team to do for us,” Dr. Bickel said. “This guidance statement is intended to represent what oncology clinic stakeholders feel right now is reasonable, important, and feasible to implement in current practice.”

Consistent access to at least basic palliative care services would be improved if the delivery of high-quality primary palliative care services were incorporated into all medical oncology practices. “The purpose of this project is to give oncology practice real tools to improve their delivery of primary palliative care,” she said.

Investigators sought to determine which palliative care elements constitute high-quality palliative care delivery in U.S. medical oncology practices, for adult patients with advanced cancer or a high symptom burden.

Domains of Palliative Care An expert steering group of committee members from AAHPM and ASCO developed a list of 966 potential palliative care service items, divided into 9 Domains of Palliative Care in Medical Oncology Practice, each describing an

aspect of palliative care delivery for patients with advanced cancer.

The domains were defined as follows: Symptom Assessment and Management, Psychosocial Assessment and Management, Spiritual and Cultural Assessment and Management, Communication and Shared Decision-Making, Advance Care Planning (including ethical and legal issues), Coordination and Continuity of Care, Appropriate Palliative Care and Hospice Referral, Caregiver Support (family/caregiver and staff), and End-of-Life Care. Service items were also categorized by composite ratings of “include,” “uncertain,” or “exclude.”

Ranking Each Service Panelists included 22 physicians and 9 others (nurses, social workers, or patient advocates). “We wanted to ask what piece of the palliative care pie do the oncology stakeholders feel like they can own,” Dr. Bickel explained.

“Palliative care is a huge domain.

ASCO/AAHPM Guidance Statement in Palliative Care ■■ A new guidance statement for palliative care in oncology issued by ASCO and AAHPM offers the first formal consensus-based recommendations regarding high-quality primary palliative care in oncology.

■■ The statement includes 966 potential palliative care service items, divided into 9 Domains of Palliative Care in Medical Oncology Practice.

■■ Panelists endorsed the highest proportion of palliative care service items in the domains of End-of-Life Care (81%); Communication and Shared Decision-Making (79%); and Advance Care Planning (78%).

panelists’ general feelings about ‘realworld’ practice.”

Highest Consensus in End-of-Life Care Panelists endorsed the highest proportion of palliative care service items in the domains of End-of-Life Care (81%); Communication and Shared DecisionMaking (79%); and Advance Care Planning (78%). The lowest proportions were in Spiritual and Cultural Assessment and Management (35%) and Psychosocial Assessment and Management (39%).

This guidance statement is intended to represent what oncology clinic stakeholders feel right now is reasonable, important, and feasible to implement in current practice.

—Kathleen E. Bickel, MD, MPhil

We wanted to find out what oncology practices should be trying to focus on vs what they feel they should have other people help them with—what happens in the oncology practice rather than what is delivered by a palliative care specialist.”

The 31 multidisciplinary panelists ranked each service item according to importance (within the medical oncology office, how essential is this item/service to the delivery of highquality care to patients with advanced cancer), feasibility (how feasible is it for a practice like yours, or the practices you interact with most, to provide this item/service), and scope of practice (how reasonable is it to expect that this item/service should be provided by medical oncology practices).

“We did not ask panelists to consider strength of evidence or recommendations from other organizations when ranking,” said Dr. Bickel. “We wanted

“In the largest domain, Symptom Assessment and Management, there was consensus that all symptoms should be assessed and managed at a basic level, with more comprehensive management for common symptoms such as nausea, vomiting, diarrhea, dyspnea, and pain,” said Dr. Bickel.

Of the 966 potential palliative care service items, the consensus panel rated 598 items (62%) as “include” (important, feasible, and within the scope of oncology practice) and 21 (2%) as “exclude,” whereas 347 (36%) were rated as “uncertain.”

opment may be informed by the data from this consensus process.

“I think it’s critically important for there to be guidance to set forth what

Kathleen M. Foley, MD

are the domains of primary palliative care for cancer, and this is a first step in an effort that seems quite successful,” said Kathleen M. Foley, MD, Attending Neurologist Pain & Palliative Care Service, Memorial Sloan Kettering Cancer Center (MSKCC) and Chair, Society of MSKCC in Pain Research, New York.

“I see it as a first step that gives the opportunity, for everyone now, to respond to it, to see how they can implement it, and more importantly, refine it,” Dr. Foley told The ASCO Post.

“We’re not saying that everyone must do these things starting tomorrow,” added Dr. Bickel. “But this is what a group of real people in the trenches thought to be a reasonable starting place for oncologists to try to start doing palliative care themselves.”

She continued: “These goals may adapt and change over time, but we hope this work will serve as a foundation for future palliative care–related quality measures, quality improvement initiatives, and educational activities.” n

Disclosure: Dr. Bickel reported no potential conflicts of interest.

Guidance Not Guidelines Oncology providers wishing to enhance palliative care delivery may find the guidance useful to inform operational changes and quality improvement efforts, but “this is a guidance statement; these are not guidelines,” Dr. Bickel stressed. However, metric devel-

Reference 1. Bickel KE, McNiff KK, Buss MK, et al: Defining high-quality palliative care in oncology practice: An ASCO/AAHPM Guidance Statement. 2015 Palliative Care in Oncology Symposium. Abstract 108.

Presented October 10, 2015.

ASCOPost.com | DECEMBER 25, 2015

PAGE 27

Palliative Care Symposium Physician-Patient Communication

More, Earlier, and Better Goals-of-Care Conversations at the End of Life Are Feasible

By Meg Barbor

A

n intervention called the Serious Illness Care Program helps clinicians to conduct more, earlier, and better conversations about goals of care with their seriously ill patients, according to ­Rachelle E. Bernacki, MD, MS, who presented the preliminary results of a study using this approach at the 2015 Palliative Care in Oncology Symposium in Boston.1 “There is a rapidly growing evidence base to show that high-quality communication is associated with better serious illness care,” said Dr. Bernacki, Director of Quality Initiatives and Psychosocial Oncology and Palliative Care Senior Physician at the Dana-Farber Cancer Institute in Boston. “But despite this evidence base, we don’t have conversations with our seriously ill patients often enough.”

According to Dr. Bernacki, earlier conversations about patient goals and priorities are associated with more goal-

approach to training and supporting physicians and other health-care professionals in conducting more, earlier, and better conversations about goals of care with seriously ill patients and their families. The Serious Illness Conversation Guide, a seven-question, open-ended guide within the intervention, guides clinicians through these conversations.

—Rachelle E. Bernacki, MD, MS

Study Design A cluster-randomized trial is underway to test the feasibility and acceptability of the Serious Illness Care intervention for both patients and clinicians and to determine the intervention’s impact on the frequency, timing, and quality of goals-of-care conversations before death.

Physicians, physician assistants, and nurse practitioners from 10 disease centers and 2 satellite locations within the DanaFarber Cancer Institute were invited to par-

The highlight of this work is that it’s a multicomponent intervention that influences outcomes in systems of high complexity.

—Anthony L. Back, MD

concordant care and improved quality of life, but these conversations often occur too late or not at all.

“These conversations are difficult for clinicians, and they often fail to address key elements of quality discussions,” she said. As a result, patients with serious illness routinely receive treatments that are not aligned with their goals.

High-Value but Limited Resource “Palliative care, with a strong emphasis on quality communication, is a highvalue intervention. However, we do not and will not have enough palliative care clinicians to reach all patients who would benefit,” said Dr. Bernacki. “Therefore, we need scalable interventions targeted at non–palliative care generalist and specialist clinicians in order to assure universal access to serious illness conversations.”

Clinician factors such as lack of training and time are barriers to these conversations, but the Serious Illness Care Program aims to develop, implement, and evaluate a standardized

There is a rapidly growing evidence base to show that high-quality communication is associated with better serious illness care. Despite this evidence, we don’t have conversations with our seriously ill patients often enough.

ticipate in the study and enrolled on a volunteer basis. Patients at high risk of death were identified by use of the so-called Surprise Question—“Would you be surprised if this patient died within the next year?”— which is posed to clinicians involved in the care of cancer patients and has been studied in related research presented at the Palliative Care in Oncology Symposium.2 Subsequent to clinician identification of high-risk patients, the intervention group received a structured, patient-centered discussion about values and priorities conducted by trained oncology clinicians utilizing the Serious Illness Conversation Guide. The control group received usual oncology care.

Clinicians attended a 2½-hour training session on the Serious Illness Con-

versation Guide. “We chose this very deliberately,” said Dr. Bernacki. “This is a feasible time frame in which busy oncologists can come for training.”

Trained clinicians then received an email reminder to have these conversations with their patients. “We found that they really liked being prompted to have these discussions,” she added.

Patients are also prepared prior to discussion, via a letter outlining the topics that their clinician will discuss.

All information is documented with electronic medical records.

“I would call this ‘sequencing building blocks to improve early discussion,’ and it really is a terrific achievement,” said Anthony L. Back, MD, a medical oncologist at the University of Washington, Seattle.

“The highlight of this work is that it’s a multicomponent intervention that influences outcomes in systems of high complexity. By that I mean there are so many things going on with the patients that I don’t control—by the time I see them and after I see them—that I don’t think I can expect my conversation, even if it’s terrific, to be the only factor,” he said.

Widespread Acceptability Of all eligible oncology clinicians, 72% volunteered. Ninety oncology clinicians were randomly assigned in clusters to the intervention group (n = 47) or the control group (n = 43).

Of 47 intervention clinicians, 46 were trained and rated the training as effective (4.3/5). Of the trained clinicians who have received e-mail prompts, 97% have completed at least one conversation, and

The Serious Illness Care Program ■■ The Serious Illness Care Program was designed to help clinicians conduct more, earlier, and better conversations about goals of care.

■■ Preliminary data show strong feasibility and acceptability of this intervention.

the Conversation Guide has been established as acceptable (4.2/5). Further, the trigger system stimulates discussions in 90% of patients within two visits.

A total of 331 patients were enrolled in the study (163 intervention, 168 control). A preliminary chart review revealed that more goals-of-care conversations occurred before death in the intervention group compared to controls (92% vs 70%, P = .0037); intervention conversations also took place 4 months earlier than in the control group (median, 143 vs 63 days, P = .0008).

Dr. Bernacki pointed out that conversations in the intervention group were more patient-centered (95% vs 45%, P < .0001).

Conversations in the intervention group were also more readily retrievable in the electronic medical record (68% vs 28%, P < .0001), and far fewer of them used code status only (5% vs 55%, P < .0001).

Preliminary data about the Serious Illness Care systematic approach have demonstrated strong feasibility and acceptability among both clinicians and patients. The investigators concluded that this intervention results in more, earlier, and better conversations about serious illness care values and goals, also resulting in more robust, patientcentered, and comprehensive electronic medical record documentation. n

Disclosure: Dr. Back reported no potential conflicts of interest. Dr. Bernacki is Associate Director of the Serious Illness Care Program at Ariadne Labs.

References 1. Bernacki R, et al: Delivering more, earlier and better goals-of-care conversations to seriously ill oncology patients. 2015 Palliative Care in Oncology Symposium. Abstract 39. Presented October 9, 2015.

2. Vick JB, et al: The utility of the surprise question in identifying patients most at risk of death. 2015 Palliative Care in Oncology Symposium. Abstract 108. Presented October 9, 2015.

OVERALL SURVIVAL AT 5 YEARS IN DLBCL IS

60%

1 Could a better understanding of this disease be within our grasp?

Š 2015 Genentech USA, Inc. All rights reserved. HEM/062915/0011a Printed in USA.

DLBCL is an aggressive disease2 Remarkably, more than half of patients are able to survive diffuse large B-cell lymphoma (DLBCL) for 5 years or longer.1,3

Although strides have been made in the science of DLBCL, weâ&#x20AC;&#x2122;re casting an even wider net to further our knowledge of this aggressive disease

To learn more, visit BCellResearch.com

References: 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2012. National Cancer Institute website. http://seer.cancer.gov/csr/1975_2012/results_single/sect_19_table.29_2pgs.pdf. Updated April 23, 2015. Accessed June 15, 2015. 2. Jaffe ES, Harris NL, Stein H, Campo E, Pileri SA, Swerdlow SH. Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008:158-166. 3. Larouche J-F, Berger F, Chassagne-ClĂŠment C, et al. Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. J Clin Oncol.

2010;28(12):2094-2100.

The ASCO Post | DECEMBER 25, 2015

PAGE 30

In the Clinic Dermatologic Oncology

Nivolumab as Single-Agent Treatment for BRAF V600 Wild-Type Unresectable or Metastatic Melanoma

By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n November 24, 2015, nivolumab (Opdivo) was approved for use as a single agent in the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.1 Nivolumab has prior approvals in unresectable or metastatic melanoma for use as a single agent in patients with BRAF V600 mutation–positive disease and disease progression following treatment with ipilimumab (Yervoy) and a BRAF inhibitor and in combination with ipilimumab in patients with BRAF V600 wild-type disease.

Supporting Efficacy Data Approval was based on improvement in overall survival in a doubleblind phase III trial (CheckMate 066) in which 418 treatment-naive patients were randomized to receive nivolumab at 3 mg/kg every 2 weeks and dacarbazine every 3 weeks (n = 210) or dacarbazine at 1,000 mg/m2 every 3 weeks and placebo every 2 weeks (n = 208).1,2 Patients had a median age of 65 years, 59% were male, 99.5% were white, 61% had stage M1c disease, 74% had cutaneous melanoma, 11% had mucosal melanoma, 37% had elevated lactate dehydrogenase, 35% had programmed cell death ligand 1 (PD-L1) ≥ 5% tumor cell membrane expression, and 4% had a history of brain metastasis. More patients in the nivolumab group had a performance status of 0 (71% vs 58%).

In an interim analysis based on 47% of the total planned events, median overall survival (the primary endpoint) was not reached in the nivolumab group vs

OF NOTE Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds the PD-1 receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2.

10.8 months (95% confidence interval [CI] = 9.3–12.1 months) in the dacarbazine group (hazard ratio [HR] = 0.42, P < .0001). Median progression-free survival was 5.1 months (95% CI = 3.5– 10.8 months) vs 2.2 months (95% CI = 2.1–2.4 months; HR = 0.43, P < .0001).

Objective response rates were 34% (complete response in 4%) vs 9% (complete response in 1%). At the time of analysis, 88% of responders in the nivolumab group had ongoing responses, with an ongoing response of ≥ 6 months in 60%.

How It Works Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds the PD-1 receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2, thereby blocking PD-1 pathway–mediated inhibition of immune response, including antitumor immune response. Binding

times the upper limit of normal or total bilirubin > 1.5 to 3 times the upper limit of normal, serum creatinine > 1.5 to 6 times the upper limit of normal, grade 2 or 3 hypophysitis, grade 2 adrenal insufficiency, grade 3 hyperglycemia, grade 3 rash, encephalitis indicated by new-onset moderate or severe neurologic signs/symptoms, and first occurrence of other grade 3 adverse reactions. There are no recommended dose modifications for hypothyroidism or hyperthyroidism. No dose adjustment is required in patients with renal impairment or mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment.

Nivolumab should be discontinued for grade 4 diarrhea or colitis, grade 3 or 4 pneumonitis, grade 4 hypophysitis, grade 3 or 4 adrenal insufficiency, grade 4 hyperglycemia, grade 4 rash, any life-threatening or grade 4 adverse

Expanded Indication for Nivolumab in Metastatic Melanoma ■■ Nivolumab (Opdivo) was approved for use as a single agent in the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

■■ The recommended dose of single-agent nivolumab in this setting is 3 mg/kg via intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

of PD-L1 and PD-L2 to the PD-1 receptor inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance.

How It Is Used The recommended dose of single-agent nivolumab in this setting is 3 mg/kg via intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Infusion should be interrupted or slowed in patients with mild or moderate infusion reactions.

Nivolumab should be discontinued for severe or life-threatening infusion reactions.

Single-agent nivolumab should be withheld for grade 2 pneumonitis, grade 2 or 3 diarrhea or colitis, alanine transaminase (ALT) or aspartate transaminase (AST) levels > 3 to 5

reaction, AST or ALT levels > 5 times the upper limit of normal or total bilirubin > 3 times the upper limit of normal, serum creatinine > 6 times the upper limit of normal, immune-mediated encephalitis, recurrence of grade 3 adverse reactions, any life-threatening or grade 4 adverse reaction, persistent grade 2 or 3 adverse reactions lasting ≥ 12 weeks, and requirement of prednisone or equivalent dose of ≥ 10 mg for > 12 weeks.

Safety Profile In the phase III trial, the most common adverse events of any grade occurring at a frequency ≥ 5% higher in the nivolumab vs dacarbazine group were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%).

Grade 3 or 4 adverse events occurred in 41% of the nivolumab group, with the most common being increased gamma-glutamyltransferase (3.9%)

and diarrhea (3.4%). Grade 3 or 4 increases in AST, ALT, bilirubin, or alkaline phosphatase levels occurred in 2.6% to 3.6% of nivolumab patients.

Serious adverse events occurred in 36%. Adverse events led to dose interruption in 26% and permanent treatment discontinuation in 7%, with no

OF NOTE Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including immunemediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, and embryofetal toxicity.

single type accounting for a majority of treatment discontinuations.

Adverse events in patients who received nivolumab that are among immune-related reactions known to be caused by nivolumab included the following: pneumonitis (1.4% vs 0%); diarrhea or colitis (28% vs 25%); liver test abnormalities including increased ALT (25% vs 19%), AST (24% vs 19%), alkaline phosphatase (21% vs 14%), and total bilirubin levels (13% vs 6%) and immune-mediated hepatitis (0.9%); hypothyroidism (7% vs 0.9%) and hyperthyroidism (4.4% vs 0.9%); diabetes or diabetic ketoacidosis (1.0% vs 0%); and elevated creatinine (11% vs 10%).

Nivolumab carries warnings/ precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, and embryofetal toxicity. Patients should be monitored for changes in liver, kidney, thyroid, and neurologic function and for hyperglycemia. Breastfeeding women should discontinue breastfeeding while receiving nivolumab. n References 1. Opdivo (nivolumab) injection for intravenous use prescribing information, Bristol-Myers Squibb Company, November 2015. Available at www.opdivo.com. Accessed December 14, 2015.

2. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320-330, 2015.

ASCOPost.com | DECEMBER 25, 2015

PAGE 31

NCCN Annual Congress: Hematologic Malignancies Combination Therapy

Optimizing the Treatment of HIV-Associated Lymphoma

By Caroline Helwick

N

on-Hodgkin lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection generally can be treated the same as lymphoma in non–HIV-infected patients, with a few caveats, according to Lawrence D. Kaplan, MD, of the Helen Diller Family Comprehensive Cancer Center of the University of California, San Francisco (UCSF).

In particular, clinicians need to understand how best to integrate chemotherapy with antiretroviral therapy, he said

R-EPOCH Advocated for Most Treatment for HIV-infected patients involves the use of rituximab (Rituxan) upfront, infusional chemotherapy, and high-dose chemotherapy with autologous stem cell transplant for relapsed/refractory disease and the integration of antiretroviral therapy with antineoplastics.

Rituximab has been a game changer in lymphoma, but infectious deaths are a concern, primarily among patients with CD4 cell counts < 50/mm2, who are severely immunocompromised.

At UCSF, we have not yet incorporated short-course EPOCH, but we do routinely use standard dose– escalation EPOCH for patients who are not on clinical trials, and we find those patients tolerate therapy well.

—Lawrence D. Kaplan, MD

during a presentation at the 2015 Annual Congress of Hematologic Malignancies, sponsored by the National Comprehensive Cancer Network (NCCN).1

Aggressive CD20-Positive B-cell Tumors HIV-associated lymphomas, which are seen across a range of CD4 counts, are aggressive CD20-positive B-cell tumors. They are diffuse large B-cell tumors in two-thirds of patients, Burkitt lymphomas in one-quarter of patients, and other lymphoproliferative diseases in the remainder. Although among non–HIV-infected persons the incidence of these lymphomas is 10 to 20 per 100,000 person-years, the incidence among HIV-infected persons skyrockets to 170 per 100,000 person-years.

“That’s about the same incidence as breast or prostate cancer in the general population,” he noted. “In the HIV-infected group, this is a particularly problematic disease.”

Before the era of highly active antiretroviral therapy, standard chemotherapy rendered a 2-year overall survival rate of 10% to 20% in this population.

Today, with combination antiretroviral therapy and more effective chemotherapy, 2-year survival reaches 70%.

“You can see from a variety of phase II trials in the antiretroviral era that overall survival now approaches that of the general population of patients,” noted Dr. Kaplan.

“This is clearly a subgroup of patients with HIV and lymphoma who need special attention and for whom you must be careful about giving rituximab,” cautioned Dr. Kaplan. “For the rest of the patient population, the use of rituximab upfront is clearly indicated.”

As for which regimen to give with rituximab, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) “is not a wrong choice,” he suggested, but R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) should be the standard of care.

“Our experience suggests that this is a very well tolerated and perhaps more effective regimen in this patient population,” Dr. Kaplan said.

“This is not standard dose-adjusted EPOCH,” he explained. “What’s different is that the infusional agents—etopo-

side, vincristine, doxorubicin—are never dose-escalated; that’s only the cyclophosphamide. The starting dose is based on a blood CD4 count, and the maximum dose is 750 mg/m2, which is the starting dose in standard dose–adjusted EPOCH. This is a little different regimen.”

Short-Course EPOCH-RR Dr. Kaplan also described the shortcourse EPOCH-RR regimen, in which patients receive double doses of rituximab with EPOCH for two treatment cycles and then are assessed with PETCT. Patients who are PET-negative receive one additional chemotherapy cycle, whereas PET-positive patients receive up to six cycles of EPOCH-RR. In a 33-patient study of this regimen, 5-year progression-free survival was 84%, and overall survival was 68%.2 “At UCSF, we have not yet incorporated short-course EPOCH, but we do routinely use standard dose–escalation EPOCH for patients who are not on clinical trials, and we find those patients tolerate therapy well,” Dr. Kaplan said.

A pooled multivariate analysis of 19 trials of more than 1,500 patients documented the superiority of EPOCH over CHOP and R-EPOCH over R-CHOP.3 Use of rituximab was associated with a 50% reduction in both disease progression and death.

The study also showed a lack of overall survival benefit in patients with CD4 cell counts < 50/mm2 (higher treatmentrelated mortality); and improvement in outcomes with concurrent use of combination antiretroviral therapy; and in patients with Burkitt lymphoma, a greater benefit with more-intensive regimens compared with infusional regimens.

Other Considerations Focusing on the Burkitt lymphoma subset, Dr. Kaplan advised caution when

Dr. Kaplan’s recommendations for integrating antiretrovirals with chemotherapy were as follows: ■■ Avoid regimens that include zidovudine (Retrovir) with chemotherapy (as it is myelosuppressive).

■■ Be aware that ritonavir (Norvir) has numerous drug interactions (as do other protease inhibitors).

■■ Understand that regimens including an integrase inhibitor (raltegravir [Isentress]) are safest.

■■ Consult the HIV-treating physician before altering treatment.

■■ If necessary, interrupt or hold combination antiretroviral therapy until completion of chemotherapy.

using R-EPOCH (due to its intensity), until more data are in. At UCSF, he added, the standard of care for these patients is modified CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine).

A recent study of 34 patients by Noy et al evaluated CODOX-M/IVAC in a regimen that added rituximab, reduced and/or rescheduled cyclophosphamide and methotrexate, capped vincristine, and used combination intrathecal chemotherapy.4 Overall survival was 72% at 1 year and 69% at 2 years, and modification of the regimen resulted in less toxicity.

Turning to the role of autologous hematopoietic stem cell transplant in relapsed/refractory patients, he noted that transplant is associated with overall survival that is as good as that observed in non–HIV-infected patients, and treatment-related mortality is not increased.

The most common infectious complications in these patients are bacteremia and Clostridium difficile. Since cytomegalovirus reaction can be seen, he advised screening for it after transplant.

Integrating Antiretroviral Therapy “The potential benefit to continuing antiretroviral therapy is better control of HIV replication and more rapid recovery of immune function post chemotherapy. The risk is more drug interactions with chemotherapeutic agents, antibiotics, antifungals, and so forth,” according to Dr. Kaplan.

The experience with conventionally dosed chemotherapy has been favorable, even when used alongside antiretroviral regimens containing protease inhibitors. Protease inhibitors, which inhibit CYP3A4 and are both substrates and inhibitors of P glycoprotein, however, do pose a risk for drug interactions and can potentiate chemotherapy-induced neutropenia.

“Avoid zidovudine at all costs. It will worsen myelosuppression. I don’t say that for many other antiretrovirals,” Dr. Kaplan elaborated.

“Be aware that protease inhibitor– based regimens are associated with drug interactions, but you can usually get patients through this while continuing their antiretrovirals. Integrase inhibitor–based regimens are associated with far fewer drug interactions, are well tolerated, and can be continued continued on page 32

The ASCO Post | DECEMBER 25, 2015

PAGE 32

Announcements

St. Jude Names Carlos Rodriguez-Galindo, MD, Director of International Outreach Program

C

arlos Rodriguez-Galindo, MD, an international leader in pediatric solid tumor research, is joining St. Jude Children’s Research Hospital to head the International Outreach Program.

Galindo came to St. Jude in 1994 as a postdoctoral fellow and served as a clinical researcher and faculty member for more than a decade. He focused on developing new therapies for retinoblastoma,

sarcomas, and rare childhood cancers.

He returns to St. Jude from Dana-Farber Cancer Institute and Boston Children’s Hospital, where he was Director of the Pediatric Solid Tumor Program,

Medical Director of the Clinical and Translational Investigations Program, and Director of the Global Health Initiative in Pediatric Cancer and Blood Disorders. He also served as Professor

Carlos Rodriguez-Galindo, MD

Dr. Rodriguez-Galindo will serve as International Outreach Program Director and an executive vice president. He will also chair the newly created Department of Global Pediatric Medicine and hold the Four Stars of Chicago Endowed Chair in International Pediatric Research.

A native of Spain, Dr. Rodriguez-

HIV-Associated Lymphoma continued from page 31

even during high-dose chemotherapy and transplant,” he continued.

“But if necessary—for example, for the patient with intractable nausea and vomiting—you can hold these antiretroviral regimens until you complete chemotherapy and resume when done,” Dr. Kaplan added. “This is better than starting and stopping antivirals multiple times, which can result in resistance.” n Disclosure: Dr. Kaplan reported no potential conflicts of interest.

References 1. Kaplan LD: Management of HIV-associated Non-Hodgkin’s lymphomas. 2015 NCCN Annual Congress: Hematologic MalignanciesTM. October 16, 2015.

2. Dunleavy K, Little RF, Pittaluga S, et al: The role of tumor histogenesis, FDGPET, and short-course EPOCH with dosedense rituximab (SC-EPOCH-RR) in HIVassociated diffuse large B-cell lymphoma.

Blood 115:3017-3024, 2010.

3. Barta SK, Xue X, Wang D, et al: Treatment factors affecting outcomes in HIVassociated non-Hodgkin lymphomas: A pooled analysis of 1546 patients. Blood 122:3251-3262, 2013.

4. Noy A, Lee JY, Cesarman E, et al: AMC 048: Modified CODOX-M/ IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma. Blood 126:160-166, 2015.

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ASCOPost.com | DECEMBER 25, 2015

PAGE 33

Announcements

of Pediatrics at Harvard Medical School.

“Today, more than 80% of children with cancer live in low- and middle-income countries, and more than half will die from their diseases,” said James R. Downing, MD, St. Jude President and CEO. “Dr. Rodriguez-Galindo’s broad experience in global medicine and his vision for the International Outreach Pro-

gram will help St. Jude change that statistic by establishing a clinical care and research agenda that accelerates worldwide progress for children with cancer.”

International Outreach Program Established in 1998 with the goal of improving the level and quality of care for childhood cancer patients around

the world, the St. Jude International Outreach Program now includes 24 partner sites in 17 countries. The program is leading the development of integrated models of education and capacity, resulting in steady improvements in the outcomes of children with cancer in those areas.

Through the International Outreach

Program, St. Jude also fosters the development of regional networks among its international partners and collaborators. This model moves beyond the existing one-on-one partnership approach by promoting self-sufficiency and the sharing of expertise among international sites. These efforts have led to

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continued on page 35

The ASCO Post | DECEMBER 25, 2015

PAGE 34

Announcements

City of Hope Gains Immunologist, Breast Surgeon, and Geriatric Oncologist

C

ity of Hope recently announced the following new staff additions.

Bart O. Roep, PhD Internationally recognized immunologist Bart O. Roep, PhD, has joined City of Hope as Chair of the Department of Di-

Bart O. Roep, PhD

abetes Immunology within the Diabetes & Metabolism Research Institute. An expert in the potential of immune therapy to treat type 1 diabetes, Dr. Roep will expand the institution’s emphasis on developing new approaches to the treatment and cure of diabetes. Dr. Roep is also known for his

focus on T cells and his groundbreaking use of immunotherapy in the treatment of hematologic malignancies.

Dr. Roep comes to City of Hope from Leiden University Medical Center in the Netherlands, where he served as Head of the Division of Autoimmunity

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ASCOPost.com | DECEMBER 25, 2015

PAGE 35

Announcements

and Professor of Medicine, Diabetology, Immunopathology, and Immune Intervention Therapy. He earned his doctorate from Leiden University.

Veronica Jones, MD Veronica Jones, MD, has joined City of Hope as an Assistant Clinical Professor in the Department of Surgery,

Veronica Jones, MD

specializing in breast surgery. Dr. Jones joins City of Hope from Emory University, where she was Assistant Professor in the Department of Surgery.

While in medical school, she was inducted into the Alpha Omega Alpha National Medical Honor Society, and traveled to Kenya to complete clerkships in HIV/AIDS and reproductive

health. Dr. Jones continued her postdoctoral training at Baylor University Medical Center, with a categorical general surgery internship and residency.

At Baylor, Dr. Jones was honored as Chief Resident of the year. In 2014, she completed a breast surgical oncology fellowship at Emory University.

She received her medical degree from Meharry Medical College in Nashville, Tennessee.

Daneng Li, MD Daneng Li, MD, has joined City of Hope as Assistant Clinical Professor in the Department of Medical Oncology and Therapeutics, specializing in geriatric and gastrointestinal oncology.

Daneng Li, MD

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Dr. Li received his medical degree from Weill Cornell Medical College, before pursuing an internship and residency in internal medicine at New York-Presbyterian Hospital/Weill Cornell Medical Center. He recently completed a hematology/oncology fellowship at Memorial Sloan Kettering Cancer Center. n

Carlos Rodriguez-Galindo, MD continued from page 33

the creation of three successful international networks: the Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA), which includes members from Guatemala, Honduras, El Salvador, Nicaragua, Costa Rica, Dominican Republic, and Panama; the National Childhood ALL Study Group in China; and the Pediatric Oncology East and Mediterranean (POEM) Group, which encompasses partner sites and collaborating centers in more than 20 countries in the Middle East, northern Africa, and southern Asia.

“By further integrating research, innovation, and advanced education, the International Outreach Program is creating a new paradigm for global pediatric oncology care,” said Dr. ­Rodriguez-Galindo. “Our ultimate goal is to generate knowledge and innovative models so that soon all children with cancer in the world have access to ­quality care.” n

The ASCO Post | DECEMBER 25, 2015

PAGE 36

Lynn Sage Breast Cancer Symposium Targeted Therapy

Partnering Therapies for Estrogen Receptor–Positive Breast Cancer Requires Close Monitoring and Patient Communication

By Charlotte Bath

P

artnering endocrine therapy with new targeted agents for women with estrogen receptor–positive breast cancer “changes the nature of endocrine therapy from something easily tolerated, with not a lot that you have to do as physicians to monitor it,” William J. Gradishar, MD, of the Robert H. Lurie Comprehensive Cancer Center, Chicago, said in a presentation at the Lynn Sage Breast Cancer Symposium in Chicago.1 Introducing targeted agents, such as CDK 4/6 and mTOR inhibitors, also introduces a different set of toxicities, and “patients have to be made aware of what they can anticipate as they start on these treatment approaches,” Dr. ­Gradishar added.

The 5-Year Benchmark “Despite our therapies, the successes, and the debate about the duration of endocrine therapy, we still know that a significant fraction of patients with estrogen receptor–positive will recur,” Dr. Gradishar stated. In an interview with The ASCO Post, Dr. Gradishar said that although clinicians generally are aware of “the long tail of estrogen receptor–positive breast cancer” extending over many years, “patients still have in their minds the 5-year benchmark. We don’t try to dissuade them that reaching the 5-year benchmark is a good thing, but we try to make them aware that recurrences can develop even decades later.”

The extended risk of recurrence has driven the search for new partners for endocrine therapy. Guidelines from the National Comprehensive Cancer Network (NCCN) now include therapies targeting mechanisms of endocrine resistance.

“Selection is important,” Dr. Gradishar stressed. “These drugs have side effects that aren’t what you would typically associate with antihormone therapy.” They can start to resemble the toxicity profile of some chemotherapy agents.

Targeting CDK 4/6 Palbociclib (Ibrance) is the first drug approved to focus on the CDK 4/6 pathway “as a way of either overcoming resistance or enhancing the effect of endocrine therapy,” Dr. Gradishar stated.

“It basically blocks the ability of the cell to progress through the cell cycle.”

Breakthrough Therapy designation for palbociclib in 2013 was based on

a phase II trial (PALOMA-1),2 which showed “time to disease progression doubled,” Dr. Gradishar noted, with palbociclib plus letrozole vs letrozole alone as initial treatment for women with newly diagnosed advanced estrogen receptor–positive breast cancer. That led to PALOMA-3, a double-blind, phase III trial of palbociclib with fulvestrant (Faslodex) or fulvestrant with placebo in women with hormone receptor–positive, HER2-negative advanced breast cancer that relapsed or progressed on prior endocrine therapy. Final results of the study are not yet available, but a preplanned interim analysis, reported

Newer CDK 4/6 Inhibitors “There are competitors” to pablociclib, Dr. Gradishar noted. One of them, abemaciclib (LY2835219), “has been shown to have monotherapy activity” in advanced or metastatic breast cancer, he said. In a study presented at the 2014 San Antonio Breast Cancer Symposium

by Tolaney et al,4 abemaciclib monotherapy produced overall response rates of 25.5% (12 of 47 patients), but for hormone receptor–positive patients, the rate was 33.3% (12 of 36 patients), vs 0% (0 of 9 patients) for hormone receptor–negative patients.

Other data presented by Tolaney et

There are some distinct side effects that have been demonstrated with abemaciclib, and we will need larger trial results to define the toxicity profile and how it is distinct or not from palbociclib.

—William J. Gradishar, MD

recently in The New England Journal of Medicine,3 found palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone (9.2 vs 3.8 months).

“The toxicity profile seems to be largely restricted to the effects on the blood counts, and patients generally feel pretty well during treatment,” Dr. ­Gradishar revealed. The published interim analysis reported that neutropenia of any grade occurred in 78.8% of patients receiving palbociclib and fulvestrant vs 3.5% of those receiving fulvestrant with placebo. The corresponding rates for other hematologic adverse events were 45.5% vs 4.1% for leukopenia, 26.1% vs 9.9% for anemia, and 19.4% vs 0% for thrombocytopenia.

In response to a question from the audience about which patients to consider for pablociclib, Dr. Gradishar replied that for most patients treated for estrogen receptor–positive breast cancer and taking endocrine therapy, “we at least discuss it now. But patients do have to come in and have their blood counts checked. To a large extent, we are offering it to patients, because it is not a smidgen of an improvement, it is quite a bit of an improvement.”

al at the 2015 ASCO Annual Meeting5 showed changes in tumor size, mostly decreases but some increases as well, when abemaciclib was combined with letrozole, anastrozole, tamoxifen, exemestane, and exemestane plus everolimus (Afinitor). There are also ongoing trials with abemaciclib combined with those and other agents.

“There are some distinct side effects that have been demonstrated with abemaciclib,” Dr. Gradishar said, “and we will need larger trial results to define the toxicity profile and how it is distinct or not from palbociclib.” Neutropenia and leukopenia have been reported when abemaciclib was used in a phase I breast cancer study.

In October 2015, Eli Lilly and Company, the drug’s manufacturer, announced that the U.S. Food and Drug Administration granted Breakthrough Therapy designation for abemaciclib for patients with refractory hormone receptor–positive advanced or metastatic breast cancer.6 Another CDK 4/6 inhibitor, ribociclib (LEE011), is also being tested in combination with other drugs in several ongoing trials.

“If it is demonstrated that these drugs, as we would expect, do have activity in conjunction with endocrine

therapy,” Dr. Gradishar believes that several questions still need to answered.

“If they are in the same class, will they have distinct uses? Will they be able to be used after disease progression? If you happen to progress on one, would you be a candidate for another?”

Histone Deacetylase Inhibitors Several inhibitors of histone deacetylase are being tested in clinical trials of breast and other cancers, with entinostat being the farthest along in breast cancer.

According to Dr. Gradishar, there are preclinical data showing that by adding entinostat to tumors that have already demonstrated resistance to endocrine therapy alone, “you can actually drive down the growth of the tumor.”

ENCORE 301 is a phase II trial that randomized postmenopausal women with metastatic or locally advanced estrogen receptor–positive breast cancer progressing on the nonsteroidal aromatase inhibitors anastrozole or letrozole to exemestane with either entinostat or placebo. “At first blush, the result doesn’t look so good. The progression-free survival curves look almost superimposable,” Dr. Gradishar noted. “But surprisingly, despite progression-free survival not being altered in any way, overall survival was enhanced to a significant degree in this relatively small experience with the addition of entinostat.” Median overall survival was 28.13 months with exemestane plus entinostat vs 19.84 months with exemestane plus placebo.

mTOR Inhibitors mTOR inhibitors have been approved to treat several different types of cancer, including hormone receptor–positive, HER2-negative advanced breast cancer.

For instance, the phase II GINECO trial randomized 54 women to receive the mTOR inhibitor everolimus plus tamoxifen and 57 women to receive tamoxifen alone.7 “With the combination of tamoxifen plus everolimus, the fraction of patients who benefited, both those responding and with stable disease, was significantly greater than those given tamoxifen alone,” Dr. Gradishar said. In addition, “for patients who had secondary hormone resistance, those who had at one time responded to endocrine therapy seemed to gain the greatest benefit from the

ASCOPost.com | DECEMBER 25, 2015

PAGE 37

Lynn Sage Breast Cancer Symposium addition of an mTOR inhibitor.”

In the BOLERO-2 trial, postmenopausal patients with advanced breast cancer who previously received a nonsteroidal aromatase inhibitor were randomized to receive exemestane with everolimus or with placebo. “It was found that the addition of everolimus to exemestane in this population would significantly improve the progressionfree survival outcome, from 3.2 months to 7.8 months.”8 But despite looking at a number of genetic alterations, it wasn’t clearly evident who would benefit from the mTOR inhibitors, Dr. Gradishar reported. “So we don’t have a tool yet to tease out the patients who are most likely to benefit.” The improvement in progression-free survival, however, “didn’t translate, at least at this point, into an improvement in overall survival,” he added.

Everolimus is now being tested in a much larger trial, the SWOG S1222 study. Postmenopausal women with estrogen receptor– and progesterone receptor–positive and HER2-negative previously untreated metastatic breast are randomized to one of three treatment arms: fulvestrant alone, fulvestrant plus everolimus, or fulvestrant, everolimus, and anastrozole. “The rationale for fulvestrant and anastrozole is based on other studies that suggested you may get more benefit from dual antihormone therapy than one. And the strategy of putting all three together also is being evaluated,” Dr. Gradishar said.

Don’t Abandon Endocrine Monotherapy “Based on the trials done to date, you can see that there is an advantage so far that has been demonstrated for partnering endocrine therapy with some of these new agents,” Dr. ­Gradishar summarized. In the PALOMA trial, “clearly, the addition of pablociclib has made a

difference. Adding pablociclib incrementally improves the time to progression-free survival. Similarly, if you look at the addition of everolimus to an aromatase inhibitor or tamoxifen, you are also seeing that incremental improvement in outcome,” he said.

“As we go forward, this is likely to be a theme, but I don’t think it erases or

eradicates the fact that an individual patient might benefit from monotherapy with endocrine therapy. The NCCN guidelines don’t get rid of monotherapy as an option for patients with estrogen receptor–positive metastatic breast cancer but do afford you the opportunity to look at combinations,” Dr. ­Gradishar continued on page 38

Targeting the PI3K Pathway Mutations that occur in the PI3K pathway are “very common in estrogen receptor–positive breast cancer, and they become very ripe targets for looking at the addition of new agents in combination with endocrine therapy,” Dr. Gradishar stated. “We already know that activation of the PI3K pathway is a prognostic factor. Those with higher expression of PI3 kinase tend to have a worse prognosis,” he added.

“There is no shortage of drugs that are being looked at for this particular pathway,” Dr. Gradishar declared. “To date, none of them have been approved, but there is still hope that they will be.”

There are also concerns about toxicities, including skin and GI toxicities. “If these drugs, either one or as a class, become available, and they look like they are clearly advantageous, one of the things that we will have to think about is how do we make this acceptable to patients. How do we make them aware that they are going to be experiencing things that we don’t typically see with endocrine therapy?”

Who will crack the cancer code?

It’s the question that millions of people are asking. Pushing us to explore every idea, continually refining our approach, and collaborating with innovators across the globe to explore cancer genomes as never before. Leading us to identify cancer mutations and mechanisms, like PD-1 interactions and EGFR, discoveries that help all of us develop more targeted therapies. Together, we can find solutions to the toughest problems, because the more answers we find, the more lives we save.

Videos, whitepapers and more at DiscoverCareBelieve.org/code

© 2015 Dana-Farber Cancer Institute

The ASCO Post | DECEMBER 25, 2015

PAGE 38

Lynn Sage Breast Cancer Symposium Survivorship

Breast Cancer Survivors May Expect More Extensive or Frequent Follow-up Testing Than Recommended

By Charlotte Bath

P

atients who have been treated for breast cancer may overestimate the value of follow-up testing and may expect—or even ask for—more testing than recommended, Harold J. ­Burstein, MD, PhD, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, told participants at the Lynn Sage Breast Cancer Symposium in Chicago.1 “Patients place a lot of value in testing, and it takes a fair amount of work to explain to them why they are not getting tests,” Dr. Burstein said.

The major reason is “relatively limited value for surveillance chest x-rays or for laboratory studies that patients frequently get,” Dr. Burstein stated. “Even with intensive surveillance,” he noted, “less than 25% of recurrences are detected among asymptomatic patients.”

In addition, the “significant false-positive rates” of laboratory and radiologic studies “can contribute to excess evaluation and, in some instances, patient discomfort or anxiety,” Dr. Burstein said.

“False-positives do carry consequences and often lead clinical teams down a path with lots of testing that may or may not be so helpful,” Dr. Burstein noted.

“Treatment innovations in advanced breast cancer additionally diminish the potential value of earlier detection of metastatic disease. Until we come up with either locoregional therapies for metastatic disease or other compelling reasons to find cancer when it remains a very small burden,” Dr. Burstein said, the benefits of early detection remain unclear.

Dr. Burstein pointed out that both ASCO and the National Comprehensive Cancer Network (NCCN) have “been pretty aggressive in articulating a minimalist surveillance strategy.”

Why Do Patients Still Want Tests?

All patients treated for breast cancer should have a careful history and physical examination, mammography, and gynecologic follow-up.

The history and physical examination should be done every 3 to 6 months during the first 3 years after primary treatment, every 6 to 12 months in years 4 and 5 post treatment, and then annually. “We are looking for new findings in the breast or regional lymph

Although the importance of breast self-examination is currently being debated, guidelines recommend that women perform monthly breast selfexamination after a breast cancer diagnosis. They should be reminded that this does not replace mammography, Dr. Burstein added.

“Mammograms are an essential part of surveillance to look for either second tumors or ipsilateral breast recurrences,” Dr. Burstein stated. “We typically get the first one about 6 months after radiotherapy is complete to essentially establish a baseline and then more or less annually thereafter.”

Over the course of their lives, many patients have additional images of the breast with ultrasound or magnetic resonance imaging (MRI), because something in the breast feels abnormal or looks atypical on a mammo-

Partnering Therapies

7. Presented October 31, 2015.

2. Finn RS, Crown JP, Lang I, et al: The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/ TRIO-18): A randomised phase 2 study.

Lancet Oncol 16:25-35, 2015.

3. Turner NC, Ro J, André F, et al: Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 373:209-219, 2015.

4. Tolaney SM, Rosen LS, Beeram M, et

al: Clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer. 2014 San Antonio Breast Cancer Symposium. Abstract P5-19-13.

5. Tolaney SM, Beeram M, Beck JT, et al: A phase IB study of abemaciclib with therapies for metastatic breast cancer. 2015 ASCO Annual Meeting. Abstract 522. Presented May 29, 2015.

6. Lilly receives FDA breakthrough therapy designation for abemaciclib - a CDK 4 and 6 inhibitor - in advanced breast cancer.

Eli Lilly and Company press release, October 8, 2015. Available at https://investor.lilly.

continued from page 37

stated. He stressed once again that the toxicity profile changes when these agents are added to endocrine therapy, and “you have to communicate that with your patients.” n Disclosure: Dr. Gradishar reported no potential conflicts of interest.

References 1. Gradishar W: New approaches to ER positive metastatic cancer. 2015 Lynn Sage Breast Cancer Symposium. Session

If surveillance of patients treated for breast cancer is of such limited value, why do patients need to be convinced? “Because it is a counterintuitive thing in the world of cancer medicine to suggest that we want to put a premium on early detection in general for early-stage disease, but we don’t want to put a premium on early detection for metastatic disease, and it is surprisingly complicated to explain that,” Dr. Burstein said.

“The other problem is that there is tremendous practice heterogeneity, and so I have patients coming in to see me who say, ‘Well, I was sitting in the waiting room, and someone else is getting all these scans and lab tests; how come you are not doing that?’ That is a nontrivial problem,” admitted Dr. Burstein.

Most symptoms that patients experience following treatment for early-stage breast cancer “are not related to metastatic disease,” Dr. Burstein said. Most recurrences are, however, “heralded by symptoms, coughs that don’t go away, fatigue, or pain out of proportion to daily experiences, and obviously those symptoms warrant a thorough evaluation.”

Surveillance Testing for Asymptomatic Patients

nodes or symptoms that might strongly suggest recurrence of disease,” Dr. Burstein said, although they “are notoriously nonspecific.” Patients should also be counseled about symptoms of possible recurrence, such as new lumps; dyspnea; persistent headaches; and bone, chest, and abdominal pain.

gram. “But when it comes to MRI as a routine procedure after breast cancer, don’t do it,” Dr. Burstein stressed.

Routine breast MRI or ultrasound is not endorsed, even if mammography “missed” the original tumor.

Gynecologic follow-up is recommended for all women who have been

It is a counterintuitive thing in the world of cancer medicine to suggest that we want to put a premium on early detection in general for earlystage disease, but we don’t want to put a premium on early detection for metastatic disease.

—Harold J. Burstein, MD, PhD

treated for breast cancer, but it is particularly important for women who are taking tamoxifen, as they are at increased risk for developing endometrial cancer. “Neither ASCO guidelines nor association guidelines have suggested that you need an annual imaging or pelvic ultrasonography or other tests to explore whether or not there is a risk of endometrial cancer,” Dr. Burstein revealed. “Obviously, women who have atypical vaginal bleeding require evaluation, but in a healthy woman, there is no routine need for that.”

Coordination of Care “Probably one of the biggest challenges we are facing right now is continuity of care and coordination of care,” Dr. Burstein said. “As patients transition toward survivorship models, many of continued on page 44

com/releasedetail.cfm?ReleaseID=935735.

Accessed December 9, 2015.

7. Bachelot T, Bourgier C, Cropet C, et al: Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. J Clin Oncol 30:2718-2724, 2012.

8. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520-529, 2012.

If she has ovarian cancer

TEST FOR BRCA

If indicated* TREAT WITH LYNPARZA

Help her continue the fight with the first approved PARP inhibitor1

* INDICATION LYNPARZA is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

SELECT SAFETY INFORMATION Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue LYNPARZA.

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

LYNPARZA demonstrated an objective response rate of 34% in patients with BRCA-mutated advanced ovarian cancer who had been treated with 3 or more lines of chemotherapy1 The efficacy of LYNPARZA was investigated in a single-arm study of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancer. A total of 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. Efficacy was based on objective response rate and duration of response.1 Objective response rate was defined as a ≥30% reduction in target lesion size, according to RECIST criteria, as measured by CT or MRI and confirmed at least 4 weeks later.2

34

%

OBJECTIVE RESPONSE RATE (95% CI: 26, 42)

0

10

20

30

PERCENTAGE OF PATIENTS WHO RESPONDED TO THERAPY

• The rate of partial response was 32% and the rate of complete response was 2%1

7.9

MEDIAN DURATION OF RESPONSE

MONTHS (95% CI: 5.6, 9.6)

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

Warnings and Precautions Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of LYNPARZA monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with LYNPARZA. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with LYNPARZA. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with LYNPARZA in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue LYNPARZA. Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with LYNPARZA and initiate prompt investigation.

If pneumonitis is confirmed, discontinue LYNPARZA. Embryo-Fetal Toxicity LYNPARZA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Advise females of reproductive potential to avoid becoming pregnant while taking LYNPARZA. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of LYNPARZA.

Use in Nursing Mothers Nursing Mothers It is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and tolerability of LYNPARZA • LYNPARZA 400 mg twice daily was evaluated as monotherapy in 223 patients with BRCA-mutated advanced ovarian cancer who had 3 or more prior lines of chemotherapy in 6 clinical trials1

Adverse Reactions Reported in ≥20% of Patients1

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

34

18

Abdominal pain/discomfort

43

8

Decreased appetite

22

1

Nausea

64

3

Vomiting

43

4

Diarrhea

31

1

Dyspepsia

25

0

66

8

26

0

Arthralgia/musculoskeletal pain

21

0

Myalgia

22

0

BLOOD AND LYMPHATIC DISORDERS

Anemia GASTROINTESTINAL DISORDERS

GENERAL DISORDERS

Fatigue/asthenia INFECTIONS AND INFESTATIONS

Nasopharyngitis/URI MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Please see accompanying Brief Summary of Full Prescribing Information.

References: 1. LYNPARZA [package insert]. Wilmington, DE: AstraZeneca; 2014. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al.

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

LYNPARZA is a trademark of the AstraZeneca group of companies. ©2015 AstraZeneca. All rights reserved. 3118712 Last Updated 4/15

1

Laboratory Abnormalities

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

Decrease in hemoglobin (anemia)

90

15

Decrease in absolute neutrophil count (neutropenia)

25

7

Decrease in platelets (thrombocytopenia)

30

3

Decrease in lymphocytes (lymphopenia)

56

17

Mean corpuscular volume elevation

57

-

Increase in creatininea

30

2

a

Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The safety and tolerability of LYNPARZA were also evaluated in a randomized, placebo-controlled study1 â&#x20AC;˘ LYNPARZA 400 mg twice daily was evaluated as maintenance monotherapy in a randomized, placebo-controlled clinical trial of 96 patients with germline BRCA-mutated platinum-sensitive ovarian cancer who had received 2 or more lines of platinum-containing chemotherapy 1 â&#x20AC;˘ Frequently occurring adverse reactions and lab abnormalities were consistent with those seen in the 6 clinical trials, with the addition of back pain, headache, cough, rash, and dysgeusia 1

To learn more, including how to order LYNPARZA, please visit www.lynparza.com

The ASCO Post | DECEMBER 25, 2015

PAGE 44

Lynn Sage Breast Cancer Symposium Follow-up Testing continued from page 38

us are struggling with how to manage them in the confines of the oncology practice. We have tried midlevel practitioners and allied health professionals to help up with this. We need more primary care doctors as well.”

Studies have shown that these

health professionals “do a very good job of routine surveillance,” Dr. ­Burstein noted, and follow-up by primary care physicians seems to lead to the same health outcomes as followup by specialists, with good patient satisfaction. For oncologists, “what you do lose, and it is hard to quantify this,” he said, is the gratification

of seeing patients do well in the long run. In addition, symptom control and compliance with therapy “are real issues that warrant ongoing input from the oncology team on a regular basis,” added Dr. Burstein. “So I have been rather loath to part with these patients, but it is becoming a pressing challenge on a day-to-day basis.”

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LYNPARZA™ (olaparib) capsules, for oral use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGE Treatment of gBRCA-mutated advanced ovarian cancer Lynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

The indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14) in the full Prescribing Information].

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION Patient Selection Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [see Indications and Usage (1) and Clinical Studies (14) in the full Prescribing Information].

Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics.

Recommended Dosing The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.

If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time.

Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [see How Supplied/Storage and Handling (16.2) in the full Prescribing Information].

Dose Adjustments for Adverse Reactions To manage adverse reactions, consider dose interruption of treatment or dose reduction.

The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.

If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.

Dose Modifications for Use with CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [see Drug Interactions (7.2) in the full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy ( CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza.

Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza.

Embryo-Fetal Toxicity Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) in the full Prescribing Information].

Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza.

If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [see Use in Specific Populations (8.6) in the full Prescribing Information].

ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: • Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) in the full Prescribing Information] • Pneumonitis [see Warnings and Precautions (5.2) in the full Prescribing Information]

Testing That Is Not Recommended Not recommended for breast cancer surveillance are routine blood tests and routine imaging studies, including chest x-rays, bone scans, liver ultrasonography, computed tomography (CT) scans, FDG-PET (fluorodeoxyglucose–positron emission to-

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy.

In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [see Clinical Studies (14) in the full Prescribing Information] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in 20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days.

Table 1 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Adverse Reaction Blood and Lymphatic disorders Anemia Gastrointestinal disorders Abdominal pain/discomfort Decreased appetite Nausea Vomiting Diarrhea Dyspepsia General disorders Fatigue/asthenia Infections and infestations Nasopharyngitis/URI Musculoskeletal and Connective Tissue disorders Arthralgia/musculoskeletal pain Myalgia

3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % 34

18

43 22 64 43 31 25

8 1 3 4 1 0

66

8

26

0

21 22

0 0

Table 2 presents the frequency of abnormal laboratory findings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily.

Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Laboratory Parameter* 3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % Decrease in hemoglobin (anemia) 90 15 Decrease in absolute neutrophil count 25 7 (neutropenia) Decrease in platelets (thrombocytopenia) 30 3 Decrease in lymphocytes (lymphopenia) 56 17 Mean corpuscular volume elevation 57 Increase in creatinine* 30 2 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The following adverse reactions and laboratory abnormalities have been identified in 10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in 1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.

Table 3 presents adverse reactions reported in 20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCAmutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo.

Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.

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PAGE 45

Lynn Sage Breast Cancer Symposium mography) scanning, and breast MRI. “So far, tumor markers have not been valuable in the long-term prevention of cancer recurrence or better outcomes, and we try to avoid obtaining them. There are clearly false-positives,” Dr. Burstein said, and “we have all seen patients who had advanced cancer with absolutely normal serum tumor mark-

ers, so they really are not a valuable asset for the surveillance of patients.”

Cardiac Surveillance and Trastuzumab A controversial issue concerns cardiac surveillance for women with HER2-positive breast cancer who have received adjuvant trastuzumab (Her-

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LYNPARZATM (olaparib) capsules Table 3 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Adverse Reactions Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and Lymphatic disorders Anemia 25 4 7 2 Gastrointestinal disorders Abdominal pain/discomfort 47 0 58 2 Decreased appetite 25 0 14 0 Nausea 75 2 37 0 Vomiting 32 4 9 0 Diarrhea 28 4 21 2 Dyspepsia 25 0 14 0 Dysgeusia 21 0 9 0 General disorders Fatigue (including asthenia, lethargy) 68 6 53 2 Infections and infestations Nasopharyngitis/Pharyngitis/URI 43 0 16 0 Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal pain 32 4 21 0 Myalgia 25 2 12 0 Back pain 25 6 21 0 Nervous system disorder Headache 25 0 19 2 Respiratory, Thoracic, Mediastinal disorders Cough 21 0 14 0 Skin and Subcutaneous Tissue Dermatitis/Rash 25 0 14 0 Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter* Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Decrease in hemoglobin 85 8 58 2 Decrease in absolute neutrophil count 32 8 23 0 Decrease in platelets 26 6 19 0 Mean corpuscular volume elevation 85 44 Increase in creatinine* 26 0 5 0 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

DRUG INTERACTIONS Olaparib is primarily metabolized by CYP3A. Anticancer Agents Clinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

Drugs that may Increase Olaparib Plasma Concentrations In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold.

Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.4) in the full Prescribing Information].

Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information].

Drugs that may Decrease Olaparib Plasma Concentrations In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%.

Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3) in the full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions (5.3) in the full Prescribing Information] Risk summary Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy.

Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which

ceptin). The package insert carries the following black box warning from the U.S. Food and Drug Administration: Candidates for treatment with Herceptin should undergo thorough baseline cardiac assessment including history and physical exam and one or more of the following: ECG [electrocardiography], echocardiogram, and MUGA [multi-

2 resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).

In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery.

Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.

Nursing Mothers It is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and efficacy of Lynparza has not been established in pediatric patients.

Geriatric Use In clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged 65 years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE 3 which were reported more frequently in patients aged 65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference.

Females of Reproductive Potential Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza.

Hepatic Impairment The effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT 2.5 X ULN ( 5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Renal Impairment Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in the full Prescribing Information].

OVERDOSAGE There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.

17 PATIENT COUNSELING INFORMATION SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE) • Dosing Instructions: Inform patients on how to take Lynparza [see Dosage and Administration (2.1) in the full Prescribing Information]. Lynparza should be taken twice daily. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Lynparza with grapefruit or Seville oranges.

• MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions (5.1) in the full Prescribing Information].

• Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions (5.2) in the full Prescribing Information].

• Pregnancy and Females of Reproductive Potential: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least one month after receiving the last dose of Lynparza [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.6) in the full Prescribing Information].

• Nursing Mothers: Advise patients not to breastfeed while taking Lynparza [see Use in Special Populations (8.3) in the full Prescribing Information].

• Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options.

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 3079901 12/14 Issued: 12/2014

gated acquisition] scan. There are no data regarding the most appropriate method of evaluation for the identification of patients at risk for developing cardiotoxicity. Monitoring may not identify all patients who will develop cardiac dysfunction. Patients receiving Herceptin should undergo frequent monitoring for deteriorating cardiac function.

Although the FDA warning “doesn’t actually specify what that monitoring should be,” Dr. Burstein noted, “NCCN guidelines have suggested baseline, 3 month, 6 month, and 9 month monitoring, which is a lot of monitoring, and nobody here is doing that level of monitoring.” He cited a study showing that only 36% of patients taking trastuzumab received appropriate monitoring.2 “There isn’t a lot of data to give you more guidance,” Dr. Burstein told the symposium participants. “In my own practice, I get a baseline and then probably once more at around 6 months.

The guidelines currently say more frequent testing, and yet practice is tremendously discordant on that point.”

Bone Mineral Density Imaging Treatments such as aromatase inhibitor therapy or ovarian suppression affect bone health, and Dr. Burstein referred to the ASCO 2003 Bone Health Guidelines, recommending that patients with breast cancer at high risk for osteoporosis have bone mineral density determination. These high-risk patients include women with therapy-associated premature menopause and postmenopausal women receiving aromatase inhibitors.

“The question has been how this has been orchestrated, whether it is the primary care doctor’s bailiwick or the oncology office, and we go back and forth on that,” Dr. Burstein admitted. However, it is “part of a good survivorship plan and something not to be dismissed.”

Surveillance for Metastatic Disease There is “tremendous heterogeneity of practice” in surveillance for metastatic disease, Dr. Burstein noted. Some patients get scans every 3 months or so, “but at least in my clinic, it is very typical for patients who have minimal disease burdens or have long periods of tumor control to begin to space those out, so it’s more like every 6 or even every 12 months,” he added.

“We also are very influenced by protocols,” Dr. Burstein observed. Many clinical trial protocols have 6-week or 2-month intervals, “because they are continued on page 46

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Conference on Clinical Cancer Research Clinical Trial System Badly in Need of Overhaul, Say Panelists at Friends-Brookings Conference

By Margot J. Fromer

C

ancer clinical trials in three distinct phases, as they have been conducted for decades, are probably no longer the best way to bring a drug or biologic agent to market. This was the consensus of three panels at the 8th Annual Conference on Clinical Cancer Research convened by Friends of Cancer Research (FOCR) and the Center for Health Policy at the Brookings Institution in Washington, DC. Improved understanding of the way cancers behave is eroding the long-established system of beliefs about treatment.

Moreover, new tools and mechanisms of discovery have opened the door to new types of evidence and ways of thinking.

Adaptive trials, Bayesian statistics, biomarkers, surrogate endpoints, data from postmarketing studies, and other evidence beyond randomized controlled trials are the future of oncology drug research.

pharmaceutical companies—not just saying yes or no to something someone else invented. I wanted the FDA to be part of the development process.”

Dr. Pazdur has long expressed interest in toxicity and how it affects patients’ lives. He witnessed it firsthand with his wife, Mary, who died recently following several years of treatment for ovarian can-

Role of the FDA

cer. Now he sees it anew. “I underestimated it,” he said. “Toxicity is far more than a symptom or a lab test or an unpleasant reaction. It can be an all-consuming phenomenon that takes over a patient’s life.”

He also has a new appreciation for how difficult it is to obtain expanded access to as-yet-unapproved drugs. “I understand pharmaceutical companies’ position on protecting their proprietary interest, but we need more flexible criteria for who can get these drugs that can have a profound effect on remaining days.”

Dr. Pazdur emphasized that the

trials, developing informed consent instruments that people can understand, and listening more closely to patients: how they feel and what they want. It is patients who must drive the show.”

continued from page 45

Innovations in Surveillance of Metastatic Disease

looking for early signals of response and activity, which is certainly understandable from the point of view of drug discovery and new regimen development, but it is a very short interval for many of our patients,” he commented.

“When you are doing surveillance for metastatic disease, you never want to look just at once piece of data,” Dr. Burstein noted. “You want to integrate the imaging, the laboratory studies, and, more critically, the patients—where they are in the narrative of their disease and what their own day-to-day experience is like on treatment.” It’s not easy taking all these pieces of data into consideration, he acknowledged, because there are often inconsistencies or discordance among them.

“There are a couple of innovations in the surveillance of metastatic disease that are worth knowing about,” Dr. Burstein declared. One has been the critical assessment of circulating tumor cells; Dr. Burstein cited a study that found “measuring circulating tumor cells probably is prognostically significant for women,” although not therapeutically beneficial.3 “A variety of technologies have come together that have allowed people to do genomic sequencing on circulating free DNA, which is DNA that’s in the plasma and has presumably come from numerous tumor cells that died and have been liberated into the bloodstream,” Dr. Burstein explained. Some research

has found a “coarse correlation” between the level of circulating free DNA and the cancer burden. “And perhaps most interesting to me,” he added, “has been that you can begin to look for dynamic changes in cancer biology over time, and I think this holds promise of being able to create more opportunities for personalized medicine.”

Serial liquid biopsies over time “may hold the opportunity to do surveillance of cancer burden and to enable precision medicine” in managing breast cancer, Dr. Burstein stated in closing. “Hopefully, in the years to come, we are going to have new technologies such that we can revise the way we monitor tumor burden and biology and begin to further tailor our treatment recommendations based on

Before the panels convened, Ellen V. Sigal, PhD, Chair and Founder, FOCR, interviewed Richard Pazdur, MD, Director, U.S. Food and Drug Administration (FDA) Office of Hematology and Oncology Products and one of Fortune’s 50 most influential leaders for 2015. Dr. Sigal asked Dr. Pazdur why he had come to the FDA in 1999 from The University of Texas MD Anderson Cancer Center.

“I wanted to bring an academic flavor to the agency,” he replied. “I was interested in developing drugs, in working with

Follow-up Testing

FDA’s function is to ensure safety and efficacy. “We want patients to survive, of course we do. But survival—or other endpoints—is not necessarily our main goal. We are here to bring safe and effective drugs to patients who need them.”

What other issues does he think about for the agency? asked Dr. Sigal.

“Looking at new ways to do clinical

I wanted to bring an academic flavor to the agency. I was interested in developing drugs, in working with pharmaceutical companies—not just saying yes or no to something someone else invented. I wanted the FDA to be part of the development process.

—Richard Pazdur, MD

RECIST Becoming Outmoded Changes in tumor size can and do indicate the activity of treatment but are based primarily on historical precedent and were developed as supportive tools in clinical trials. They may not be the best way to measure response.

Objective criteria for evaluating tumor change were developed by the

World Health Organization (WHO) in the 1970s and consist of complete response, partial response, stable disease, and progressive disease. There have been refinements of measurement, but in general, thresholds are based on palpation.

In the early 1990s, WHO created the Response Evaluation Criteria in Solid Tumors (RECIST), which specified the minimum size of a lesion considered measurable, as well as the maximum number of lesions per organ. RECIST was updated in 2009, with a reduction in the number of lesions to be assessed, further clarification of disease progression, and additional imaging recommendations.

“RECIST is a morphologic assessment,” said Lalitha K. Shankar, MD, PhD, Chief, Diagnostic Imaging Branch, National Cancer Institute (NCI) Cancer Imaging Program.

“Changes in tumor size can be slow or static and not reflective of biological status. Moreover, [RECIST] has limited utility in malignancies such as mesothelioma and neuroendocrine tumors.”

In addition, RECIST is not useful for immunotherapy or targeted agents, treatment modalities that have potential for long-term, sustained antitumor activity—but on a different time scale from cytotoxic drugs. Delayed responses, even transient progression prior to regression, are common; therefore, metrics that take these phenomena into account need to be developed for both clinical and regulatory decision-making. continued on page 47

those kinds of observations.” n Disclosure: Dr. Burstein reported no potential conflicts of interest.

References 1. Burstein H: Surveillance imaging for the healthy breast cancer survivor and the patient with metastatic disease. 2015 Lynn Sage Breast Cancer Symposium. Session 5.

Presented October 30, 2015.

2. Chavez-MacGregor M, Niu J, Zhang N, et al: Cardiac monitoring during adjuvant trastuzumab-based chemotherapy among older patients with breast cancer. J Clin Oncol 33:2176-2183, 2015.

3. Smerage JB, Barlow WE, Hortabagyi GN, et al: Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol 32:3483-3489, 2014.

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Conference on Clinical Cancer Research Clinical Trial System continued from page 46

“The purpose of RECIST was to create a reproducible metric that could be compared among studies. The method worked well, both for ongoing studies and for historical comparisons. But it has limitations because tumors are sometimes hard to access, they are ir-

patient benefit, even after RECISTdefined progression. Continued treatment is often appropriate, and tumor growth rate is a more accurate measure of drug activity than is tumor size.

• Immune checkpoint inhibitors, such as those targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4

(CTLA-4), have had unusual response and progression kinetics. Sometimes tumor progression appears before regression, and lesions appear enlarged because of immune cell infiltrates and inflammation at tumor sites.

Geoffrey R. Oxnard, MD, a thoracic oncologist at Dana-Farber Cancer Institute, talked about response vs regression.

“In a clinical trial, the higher the response rate, the greater the likelihood of approval, but RECIST doesn’t consider the depth of response, so progression may or may not have much clinical meaning.”

Lawrence H. Schwartz, MD, James Picker Professor and Chairman of the Department of Radiology, Columbia Unicontinued on page 48

Evasion of apoptosis may be a question of balance The purpose of RECIST was to create a reproducible metric that could be compared among studies.

The method worked well, … but it has limitations because tumors are sometimes hard to access, they are irregularly shaped, and their boundaries are diffuse.

Increased BCL-2 expression helps cancer cells to survive1 BCL-2

Pro-apoptotic proteins sequestered

by BCL-2

Free pro-apoptotic proteins

Increased expression of BCL-2 impairs the pathway to programmed cell death

—Lalitha K. Shankar, MD, PhD

regularly shaped, and their boundaries are diffuse,” said Dr. Shankar.

Some limitations have been overcome by molecular or functional imaging and measurement of tumor metabolism.

However, she said, “Tumors are progressively variable, and thresholds that define discrete categories of response are arbitrary. That is, there may be only a two or three percentage point difference in tumor size, but to RECIST that might mean the difference between stable and progressive disease, thus affecting future treatment. Moreover, response rates do not necessarily reflect depth or duration.”

Other reasons why RECIST may not be appropriate: • Some targeted therapies may stabilize disease with only minimal tumor shrinkage.

• Antiangiogenics can improve survival with little tumor shrinkage.

• Objective progression may not necessarily indicate treatment failure. For instance, some tyrosine kinase inhibitors (sunitinib in renal cell carcinoma and EGFR inhibitors in non–small cell lung cancer [NSCLC]) can provide

Release of pro-apoptotic proteins may trigger apoptosis1

Like normal cells, cancer cells will often induce expression of pro-apoptotic proteins in response to stressors like limited metabolic resources, rapid cell division, or exposure to cytotoxic agents.1 Cancer cells may increase expression of the anti-apoptotic protein, BCL-2.1 Pro-apoptotic proteins are bound and sequestered by BCL-2, helping the cancer cell to avoid programmed cell death.2 Mitochondria

Pro-apoptotic proteins—if released from BCL-2—have the potential to trigger apoptosis.1

To learn more about the BCL-2 pathway, visit

researchBCL2.com References: 1. Letai AG. Diagnosing and exploiting cancer’s addiction to blocks in apoptosis. Nat Rev Cancer. 2008;8(2):121131. 2. Garcia-Saez AJ. The secrets of the Bcl-2 family. Cell Death Differ. 2012;19(11):1733-1740.

© 2015 Genentech USA, Inc. All rights reserved. BIO/102015/0191a Printed in USA.

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Conference on Clinical Cancer Research Clinical Trial System continued from page 47

versity Medical Center, agreed. “Oncology drug development is inefficient. We need to use volumetrics to assess tumor burden, and RECIST doesn’t do that.”

cludes waiting for ongoing trial outcomes.

Computed tomography images are transferred to an academic laboratory and analyzed to determine unidimensional, bidimensional, and volumetric measurements for each lesion at various times.

In a clinical trial, the higher the response rate, the greater the likelihood of approval, but RECIST doesn’t consider the depth of response, so progression may or may not have much clinical meaning.

—Geoffrey R. Oxnard, MD

Oncology drug development is inefficient. We need to use volumetrics to assess tumor burden, and RECIST doesn’t do that.

—Lawrence H. Schwartz, MD

Immune-Related Approaches One possible remedy is immune-related response criteria (irRC), based on data from phase II trials of ipilimumab (Yervoy). It describes four potential patterns of response: immediate tumor regression with no new lesions, durable stable disease, tumor regression following an initial increase in tumor volume, and regression of the index lesion in the presence of new lesions. A variation, immune-RECIST, is more in line with the original RECIST guidelines.

Both irRC and immune-RECIST more accurately predict survival in melanoma, but neither has been widely used for new melanoma immunotherapies such as ipilimumab, nivolumab (­ Opdivo), and pembrolizumab (Keytruda).

Improved Tumor Growth Metrics: VolPACT There had been no systematic way to test or validate alternate metrics until the Biomarkers Consortium of the Foundation for the National Institutes of Health created collaborations among industry, academia, and others. The result was Volumetric CT for Precision Analysis of Clinical Trial Results (VolPACT), which collects imaging data and associated metadata from completed large phase III trials in several solid tumors to study a variety of potential quantitative response metrics.

Using existing data retrospectively pre-

Phase II trials will be simulated to determine how well various metrics correlate with actual survival results. The goal is to identify metrics applicable across various therapeutic modalities and tumor types.

One stumbling block so far has been establishing a way that pharmaceutical companies can share (de-identified) patient data. In addition, images must be centrally stored, which also requires data-sharing.

Imaging for Immunotherapy Because of its unique progression characteristics, immunotherapy presents a challenge for retrospective analysis, said Dr. Oxnard. “We need improved response and progression metrics. Documentation typically results in a change in clinical management, and imaging usually stops when the disease progresses. If a patient goes off study at RECIST-defined progression, but before true clinical progression, it may be difficult to use that patient’s data to develop alternative metrics.”

However, if imaging continues, data can be used to inform the design of ongoing and future trials: evidence of progression, such as presence and characteristics of new lesions; brain metastasis; lesions where radiology can’t find them; and pretreatment disease trajectory.

The challenge lies in diseases where progression-free survival is a standard regulatory endpoint because the benefit of

immune checkpoint inhibitors may not be accurately captured, said Dr. Oxnard. But, he added, “Several agents have been approved, and we can learn from them how to facilitate future drug development.”

Patient Perspective on Adverse Events The second panel discussed how patients experience adverse events, how rarely oncologists pay enough attention to them, what this means to their treatment, and how their experiences can be used in designing future trials.

Adverse events can have a profound effect on adherence to treatment. Evidence shows that severity of symptoms is not taken seriously by clinicians, many of whom don’t ask about symptoms in the first place, thus potentially skewing both clinical trials and treatment.

In clinical trials, adverse events are (or should be) reported to and assessed by providers using the Common Terminology Criteria for Adverse Events (CTCAE), which contains 800 of them (laboratory based, observable/measurable, and symptomatic), graded on a scale of 1 to 5 for severity and effect. As Alicyn Campbell, MPH, Global Head of Patient Outcomes Research for Oncology, Genentech, said, “We have to change the way we assess patients’ experience in order to evaluate how treatment will affect outcome.”

It has become obvious that many side effects (eg, mucositis, pain, fatigue) are best heard about directly from patients who know what they feel and how strongly they feel it—that is, patient-reported outcomes.

Patty Spears, Research Specialist, North Carolina State University, defined a patient-reported outcome as any report of a patient’s health that comes directly from a patient, without interpretation by a clinician or anyone else. Patient-reported outcomes are critically important because they provide a more complete and accurate picture of treatment effect than just what shows up on a laboratory slide or x-ray—and can help regulate dose.

Moreover, she said, “Once a drug is approved, patients and physicians are faced with treatment decisions, which are often complex. Patient-reported outcomes can measure highly subjective benefits and harms, evaluating them by factoring in what matters to patients.”

Patient-reported outcomes are increasingly being used in clinical trials, but by no means universally. However, this is changing. Patients are more involved in research and want to have a voice. They need information not only from clinical investigators, but from other patients on a trial, said Ms. Spears. Unfortunately, there is no standardization in collecting

patient-reported outcomes, and the instruments used to collect data and ways to analyze them vary across the board.

In particular, few existing patientreported outcome instruments meet FDA guidance; trials conducted at multinational sites lead to even more variety; trial designs often do not account for inclusion and interpretation of patient-reported outcomes; data contain missing or incomplete components; patients can feel burdened by being asked too many questions too often; and there is a perception that patient-reported outcomes are biased, although they rarely are.

Ms. Spears had suggestions about how to collect patient-reported outcomes data in clinical trials. Start in phase I, and then develop precision instruments for later trials. The most important element, she said, is that patients have the opportunity to say what matters to them. The instrument should be easy to complete, and the information gathered should be made available to patients. “Asking the right question at the right time in the right way is critical,” she said.

PRO-CTCAE May Be a Solution NCI has developed a Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to measure adverse events related to treatment from the patient perspective.

Take mucositis, for example. The original CTCAE divided the score from 1 (asymptomatic or mild) to 5 (lifethreatening consequences)—as clinicians saw it. PRO-CTCAE asks the patient to describe the severity of mouth or throat sores and how much they interfered with usual activities. This personalized the mucositis and related it to what the patient felt, not what a clinician saw.

Patients can easily understand PROCTCAE items, and they demonstrate better validity, reliability, and responsiveness than the original scale. For instance, it takes into account moderate toxicity over a long period of time rather than only high toxicity measured at predetermined times. The latter may be relatively easily treated, whereas the former may not.

PRO-CTCAE is important as treatment agents change; that is, the side effects of biologics are different from those of cytotoxics, and administration is no longer the same: a daily tablet for a long time rather than an intravenous infusion every few weeks for six or eight cycles.

Items in the PRO-CTCAE library of symptoms and adverse events can be used across treatment modalities and can serve as a standard method of continued on page 50

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The ASCO Post | DECEMBER 25, 2015

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Conference on Clinical Cancer Research Clinical Trial System continued from page 48

patient self-reporting, as well as a way for clinical investigators to keep track of significant symptoms and toxicities.

Other uses for the library follow: • In early-phase trials, it can provide initial information about toxicity and side effects, especially severe ones, to determine future development.

• In expansion cohorts, it can elaborate on toxicity in broader populations, refine dosing, identify chronic toxicities that affect adherence, generate data to power clinical outcome assessments, and explore approaches to reducing severity.

• It could characterize symptoms at baseline.

• In postmarketing studies, particularly for accelerated approval, it can contribute to safety surveillance, comparative effectiveness research, and routine clinical practice.

Lines Between Phases No Longer Clear The traditional stepwise approach to clinical trials is increasingly difficult to maintain, as illustrated by the development of pembrolizumab.

The first human trial of this drug was begun in 2011 to determine the dose

in patients with advanced melanoma.

The striking initial response prompted an increase in sample size. The potential for activity in NSCLC added a cohort to the study. Promising results meant expanding the sample size, and even when the number exceeded 1,200, more patients were added—almost unheard of for phase II. One cohort of 173 patients with unresectable or metastatic melanoma was randomly assigned to different doses of pembrolizumab.

The agent was granted accelerated approval in September 2014—just 3 years after clinical trials began—demonstrating the potential to make transformative therapies available years before they would be at the standard pace of development. Now there are about 40 such trials nominally called phase I. But they have far more patients than usual, and the data collected are more complex.

Sometimes the ultimate goal is way beyond phase I—all the way to approval.

What has driven these changes?

Tatiana Prowell, MD, Medical Officer and Breast Cancer Scientific Lead, FDA Office of Hematology and Oncology Products, said that scientific advances have resulted in more effective drugs— or rather, “the right drug for the right patient.” The focus is on disease pathway

instead of tissue of origin, and the agency could be more efficient by avoiding delays inherent in discrete trial phases.

Expansion cohorts involve a variety of tumor types and molecular subsets.

But the paperwork can get a little fuzzy.

For some trials, the unusual sample size has not been justified, nor have descriptions of objectives for additional cohorts.

Informed consent may not have been revised to reflect the nature of the trial, and there are concerns about patient safety.

Dr. Prowell noted that the FDA wants to provide guidance for expansion cohorts. “We now have more than three dozen commercial INDs [Investigational New Drugs] with active phase I trials enrolling more than 100 patients each. Many, however, have up to 1,200 patients and up to 14 expansion cohorts of 10 to 180 patients per cohort. This new paradigm can result in quick and nimble drug development, but we still have to ensure that appropriate patient protections are in place.”

Regulations must keep pace with the new science, so the FDA has several questions and issues under discussion: • Cancer drug development could conceivably occur with a single first-inhuman protocol, which would create a need for more meetings between the agency and the sponsor and

Friends of Cancer Research Releases White Paper on Patient-Reported Outcomes

By Margot J. Fromer

O

n November 17, Friends of Cancer Research (FOCR) released a white paper report, Enhancing Use of Patient-Centered Data in Regulatory Decision Making.1 The contents of that paper are summarized below.

Improving Patient Input Many stakeholders agree that to ensure truly transformational therapies, patients must play a major role. They are uniquely equipped to identify critical gaps and unmet needs, can help set priorities, aid in the design of clinical trials that measure outcomes that matter, and define benefits that are clinically meaningful as well as risks that may or may not be acceptable.

To expand and improve patient input, new mechanisms are needed, said FOCR. They must go beyond the scope of traditional clinical trials that may not fully reflect the experience of “real-world” patients. Such data collection should involve patient registries,

electronic medical records, information about relative benefits and risks, important patient-centered outcomes, patient diversity, outreach to patients who have been adversely affected by a treatment, education, standardization of patient-reported data, and publishing negative trials.

Because only about 3% of adult cancer patients participate in clinical trials, much of what is known about a drug under investigation may be inaccurate and incomplete. Thus, approval should not be the end of testing but rather, said FOCR, the first step in gathering data about patient outcomes in clinical practice, thus creating an opportunity for enhanced safety surveillance, particularly as it pertains to off-label use.

Recommendations The white paper acknowledges the challenges of drug development and suggests corrective action:

• Increase trial participation, collect data from patients who do not meet eligibility criteria, minimize exclusion criteria, and enroll patient populations with unique genetic subsets.

• Improve the research infrastructure by encouraging institutional collaboration, reducing the number of uninterpretable safety reports in [Investigational New Drug applications], and expand the use of central institutional review boards to minimize trial delays.

• Randomize as much as possible and use observational data to identify efficacy in small subpopulations with a particular genetic ­characteristic. n Reference 1. Friends of Cancer Research: Enhancing Use of Patient-Centered Data in Regulatory Decision Making. November 17, 2015. Available at www.focr.org/ enhancing-use-patient-centered-dataregulatory-decision-making. Accessed December 9, 2015.

Tatiana Prowell, MD

would necessitate oversight by various disease experts and divisions.

• The size and quality of safety databases would come under scrutiny, as well as the adequacy of data required for approval.

• Should these types of protocols be reserved for Breakthrough Therapy designation, or can they be applied to any drug?

• What type and level of independent oversight is needed: scheduled pauses in a trial to review data observed thus far, improvement in transparency to reduce bias, or assurance of statistical rigor?

Blurring Phases, Polishing Trials Lens Mostly because of expansion cohorts, but also because of fuzzy objectives and endpoints, it is no longer clear when phase I bleeds into phase II, or even phase III. Lines need to be drawn—perhaps not as sharply as previously, but new thresholds for phase I trials could include: • When a cohort exceeds a typical phase I size (about 20 patients). At that point, the investigator would write a formal statement of hypothesis and a plan to justify the expansion.

• When randomization is introduced.

Then the study becomes comparative and can serve as a basis for statistical inference.

• When the sponsor intends to use the study for registration.

In addition, all such studies should have clear written objectives, endpoints, a statistical plan, and a statement of trial governance, including purpose, sample size, study design, minimal bar for futility or activity, early stopping rules, informed consent, institutional review board and regulatory authority notification of cohort expansion, and a patient follow-up plan. n

Disclosure: The FOCR forum and corresponding full report were supported by a grant from the Burroughs Wellcome Fund.

Drs. Sigal, Pazdur, Shankar, Oxnard, Schwartz, and Prowell, and Ms. Spears reported no potential conflicts of interest. Ms. Campbell is an employee of Genentech and a Member of the Roche Group. [The opinions and thoughts expressed by Ms. Campbell are her own and do not reflect nor represent those of F. Hoffman-La Roche AG, nor of Genentech, a Member of the Roche Group.]

ASCOPost.com | DECEMBER 25, 2015

PAGE 51

JOP Spotlight

Journal of Oncology Practice Expands Research Coverage, and Debuts a New Look

By Jo Cavallo

L

aunched by ASCO in 2005 to provide oncologists with original research on the delivery of high-quality cancer care, the Journal of Oncology Practice (JOP) enters its 11th year with a new look and feel. Beginning in January 2016, JOP will be copublished by ASCO and Harborside Press, the publisher of The ASCO Post. In addition to a redesign, readers will find a novel presentation of original research as well as new and expanded clinical content. It will also be published monthly instead of bimonthly.

JOP will continue to publish original research and editorials focusing on the multiple aspects of care delivery,

delivery research. Yet they emphasized their desire for focused, concise, authoritative clinical information,” said Dr. Cox. “We want to provide reviews on thorny clinical topics that people deal with every day. Associated with each review will be commentary, so readers will not only benefit from the information in the reviews, they will be able to see how thought leaders in oncology approached and critiqued the problem.”

Along with the clinical reviews, JOP will present illustrated case reports written by clinicians, detailing challenging clinical experiences. Each case report will include strategies

We want to provide reviews on thorny clinical topics that people deal with every day. Associated with each review will be commentary, so readers will not only benefit from the information in the reviews, they will be able to see how thought leaders in oncology approached and critiqued the problem.

—John V. Cox, DO, MBA, FACP, FASCO

including information on practice operations; health outcomes and health services research; quality of care and access to health care; public health policy and the socioeconomics of cancer care; the cost-benefit and cost-effectiveness of oncology care; and the use of technology in the care of patients.

Providing Clinical Solutions The expanded JOP features a Clinical Reviews section, which will include multiple concise clinical reviews written by thought leaders in oncology and accompanied by expert commentaries addressing key questions and opinions about a unique clinical problem. The decision to add Clinical Reviews came from the desire by readers to see more clinical content, according to John V. Cox, DO, MBA, FACP, FASCO, Editor-in-Chief of JOP. “Historically, we have not been a clinical journal, but we were told by many readers that they wanted to see clinical content along with the care

readers may apply to their own clinical practice. JOP will continue to provide digested summaries of ASCO’s Clinical Guidelines, which offer clinicians a user-friendly version of ASCO’s full clinical guidelines.

Making Care Delivery Research More Accessible “Readers told us they were not only interested in focused and to-the-point clinical reviews, but that they also wished the care delivery research presented by JOP to be easier to access, to determine if it applied to them,” said Dr. Cox. As a result, central to the design of the revamped JOP is a novel presentation of published care delivery research. All original reports will be presented in a standardized format called ReCAP (Research Contributions Abbreviated for Print).

This one-page summary of the study will highlight the central question being asked by the work and outline the main findings of the authors.

We undertake these changes, including increased publication frequency, expanded clinical content, synoptic presentation of our research, and a new design, to meet the needs of our readers and to provide a larger audience to our authors.

—James O. Armitage, MD, FASCO

ReCAP will provide more information than a classic abstract. The relevance of the work for practicing oncologists will be emphasized, as well as any factors that might affect interpretation of the study results.

The full manuscript will be available online at http://jop.ascopubs.org. The online manuscript is the official version of record—and indexed by multiple services, including PubMed—and is the version that appears via literature searches.

“We hope that ReCAP will allow our readers to recognize the blizzard of work that is transforming and informing care delivery presented in a concise, accessible way. Then if they see a given paper they wish to pursue, the complete manuscript is online,” said Dr. Cox. All original research published in JOP is peer-reviewed, and contributors to the publication include physicians, advanced practitioners, nurses, pharmacists, and practice managers working in institutional, academic, and private practice health-care settings.

Experts in business, organizational management, public policy, and payers also contribute to JOP.

• Apar Kishor Ganti, MD, MS, Associate Professor of Internal Medicine at the University of Nebraska Medical Center, will serve as Associate Editor of JOP.

Apar Kishor Ganti, MD, MS

Sagar Lonial, MD

An Editorial Team of Oncology Experts Several experts in oncology will guide the expanded editorial content of JOP: • James O. Armitage, MD, FASCO, is serving as Deputy Editor of the publication. Dr. Armitage is Professor in the Department of Internal Medicine and holds the Joe Shapiro Professor Distinguished Chair of Oncology at the University of Nebraska Medical Center in Omaha.

Dr. Armitage is also the Editor-inChief of The ASCO Post.

Arif Kamal, MD, MHS, FACP, FAAHPM

• Sagar Lonial, MD, Professor and Executive Vice Chair in the Department of Hematology and Medical Oncology at Winship Cancer Institute of Emory University, will serve as Associate Editor of JOP. • Arif Kamal, MD, MHS, FACP, FAAHPM, Assistant Professor of Medicine at Duke University School continued on page 52

The ASCO Post | DECEMBER 25, 2015

PAGE 52

JOP Spotlight JOP Expands Coverage continued from page 51

of Medicine, will serve as Associate Editor of JOP. Drs. Armitage, Ganti, and Lonial will oversee the development of Clini-

creased publication frequency, expanded clinical content, synoptic presentation of our research, and a new design, to meet the needs of our readers and to provide a larger audience to our authors.”

The online component of JOP (jop. ascopubs.org) is getting a facelift as well and will provide readers with an enhanced Web experience. The website

changes will be phased in over 2016 and should be completed by the end of 2016. Authors and reviewers will also find improvements in the editorial systems for submitting manuscripts and completing reviews.

“We fully expect that the transformation of JOP will make our content more accessible to readers and more attrac-

tive to care delivery research authors,” said Dr. Cox. “We hope JOP captures the science of how we deliver care and want authors and researchers in the care delivery space to recognize that this is a valuable place to publish their work, and that’s our goal.” n Disclosure: Dr. Cox reported no potential conflicts of interest.

Patricia Legant, MD, PhD

cal Reviews and provide expertise in the care delivery mission of the publication. Dr. Kamal will take over the responsibilities held by longtime Associate Editor Patricia Legant, MD, PhD, who is retiring.

A New Look To enhance the editorial content and make it more easily accessible to readers, JOP will be packaged in a completely new look, including a redesigned logo, illustrated covers, and new fonts for easier reading.

“Visible to our readers will be the enthusiasm and excitement of the evolution of our Journal,” said Dr. Armitage. “We undertake these changes, including in-

Scanning electron micrograph of T-cell lymphocytes attacking a cancer cell

The Editors of JOP Want to Hear From You What do you think of the expanded clinical coverage in the Journal of Oncology Practice and its redesign?

To submit comments, go to jopcontact@asco.org.

ASCOPost.com | DECEMBER 25, 2015

PAGE 53

Announcements

V. Craig Jordan, OBE, PhD, DSc, FMedSci, Receives Sir James Black Award

V

. Craig Jordan, OBE, PhD, DSc, FMedSci, a breast cancer research pioneer known for his development of the therapeutic drug tamoxifen, has been named a recipient of the Sir James Black Award from the British Pharmacological Society.

Dr. Jordan, Professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, was recognized for discoveries of important principles for drug treatment.

The award is named for Sir James

W. Black, OM, FRCP, FRS, FRSE, a ­Nobel-prize winning scientist known for his discovery of the beta-blocker propranolol and the H2 blocker cimetidine, which contributed significantly in the treatment of angina and stomach ulcers.

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Career Background Dr. Jordan is credited with reinventing a failed contraceptive (known as ICI 46,474) as a breast cancer treatment.

The drug, in existence since the 1960s, was originally created to block estrogen in the hopes of preventing pregnancy.

Dr. Jordan developed the strategy of long-term adjuvant tamoxifen therapy, as well as describing and deciphering the properties of selective estrogen receptor modulators. He was the first to discover the preventive abilities of both tamoxifen and the drug raloxifene. The U.S. Food and Drug Administration approved the medicines for reducing breast cancer incidence in high-risk women.

V. Craig Jordan, OBE, PhD, DSc, FMedSci

Dr. Jordan joined MD Anderson in 2014, where he focuses on the new biology of estrogen-induced cell death with the goal of developing translational approaches for treating and preventing cancer.

His long and distinguished career has included leadership positions at some of the world’s most prestigious biomedical institutions. Prior to joining MD Anderson, he served as Scientific Director and the Vincent T. Lombardi Chair of Translational Cancer Research at the Lombardi Comprehensive Cancer Center at Georgetown University. Dr. Jordan also served as Vice Chairman of the Department of Oncology and Professor of Oncology and Pharmacology at Georgetown University’s Medical School. In addition, he is a Visiting Professor of Molecular Medicine at the University of Leeds, and an Adjunct Professor of Molecular Pharmacology and Biological Chemistry at Northwestern University.

Dr. Jordan is a member of the National Aacdemy of sciences. In addition, he has received six honorary fellowships or degrees from universities around the world including, an honorary fellowship from the Royal Society of Medicine. He was elected president of the Royal Society of Medicine Foundation of North America. Dr. Jordan was elected as a Fellow of the Academy of Medical Sciences, the United Kingdom’s equivalent to the Institute of Medicine. n

The ASCO Post | DECEMBER 25, 2015

PAGE 54

European Cancer Congress Head and Neck Cancer

Surgery for Head and Neck Cancer Improves Survival—in Taiwan

By Alice Goodman

A

large study presented at the 2015 European Cancer Congress in Vienna found that patients with advanced oropharyngeal or hypopharyngeal cancer had improved survival if their primary treatment included surgery.1 The caveat is that these pa-

minimally invasive procedures, there is a need to revisit various treatment options and look at the overall survival of different treatment groups,” he elaborated.

“It is difficult to conduct a prospective study on surgical vs non-

With improvement in surgical techniques, including minimally invasive procedures, there is a need to revisit various treatment options and look at the overall survival of different treatment groups.

—Chih-Tao Cheng, MD, DrPH

tients were treated in Taiwan, and the results may not be generalizable to the United States or elsewhere.

“Primary surgery is associated with better overall survival and disease-free survival, even after controlling for potential confounders. Surgery should be the treatment of choice for stage IVA oropharyngeal and stage III and IVA hypopharyngeal cancers,” stated lead author Chih-Tao Cheng, MD, DrPH, a medical researcher at the Koo Foundation Sun Yat-Sen Cancer Center in Taipei City, Taiwan.

Study Background “There has been a paradigm shift regarding treatment of oropharyngeal and hypopharyngeal cancers. Concurrent chemoradiotherapy has become the standard of care for unresectable head and neck cancers, and it is being used alone, even where surgery is possible,” Dr. Cheng explained.

“Several studies have shown that nonsurgical approaches such as concurrent chemoradiotherapy can achieve comparable results to surgery and also achieve organ preservation.

But many patients treated without surgery still develop long-lasting comorbidities, including difficulty in swallowing and speech. With improvement in surgical techniques, including

surgical approaches,” he pointed out.

Therefore, Dr. Cheng and coauthors conducted a retrospective study based on national registry databases for cancers diagnosed between 2004 and 2009, health insurance, and death. They also conducted an adjusted analysis to account for potential confounding factors. Patients were followed until 2012.

The study identified 2,482 patients diagnosed with oropharyngeal cancer and 2,322 diagnosed with hypopharygeal cancers. Of them, patients with clinical stage III and IV disease could potentially benefit from surgery, and this is the group they focused on in their study: 1,698 with stage III or IV oropharyngeal cancers and 1,619 with stage III or IV hypopharyngeal cancers.

Radical surgery was performed on 35% of stage III oropharyngeal patients and 38% of stage IV oropharyngeal patients. About half of both stage III and IV hypopharyngeal cancer patients had radical surgery (55% and 49% of stage IVA patients, respectively).

Key Findings Outcomes in surgical and nonsurgical groups were compared, irrespective of whether patients were treated

Role of Surgery in Head and Neck Cancers ■■ A large retrospective study in Taiwan found that surgery improves overall survival in patients with oropharyngeal and hypopharyngeal cancer.

■■ Nonsurgical approaches are preferred for these cancers because they offer a better chance of organ preservation, but these approaches also have significant toxicity.

with concurrent chemoradiotherapy.

For both types of cancer, surgically treated patients were significantly more likely to survive at 5 years than those who did not have surgery. Fiveyear overall survival rates were 59% of the surgery group vs 48% of the nonsurgery group. Among patients with stage IVA oropharyngeal cancer, 5-year overall survival rates were 51% for the surgery group vs 40% for the nonsurgery group.

The 5-year survival rate for stage III hypopharyngeal cancer was 54% among the surgical group and 33% among the nonsurgical group. For stage IV disease, overall survival rates were 39% and 26%, respectively.

“Surgery had a somewhat greater survival benefit in the hypopharyngeal cancers compared with oropharyngeal cancers,” Dr. Cheng reported.

Due to the potential for selection bias, an adjusted analysis was performed to control for gender, age, comorbidity, tumor site, lymph node

invasion, and radiation.

“After controlling for potential confounders, our conclusion still stands.

We found significantly improved overall and disease-free survival [in surgically treated patients], with the exception of stage III oropharyngeal cancer,” he said.

At the presentation, several audience members took issue with the study. Critiques included the fact that patients were not stratified according to whether or not they were surgical candidates, and no details were provided for treatments in the nonsurgery group. n

Disclosure: Dr. Cheng reported no potential conflicts of interest.

Reference 1. Cheng CT, Terng SD, Lin CY, et al: Primary surgery for advanced oropharyngeal and hypopharyngeal cancers: A nationwide study in Taiwan. 2015 European Cancer Congress. Abstract 2804. Presented September 26, 2015.

EXPERT POINT OF VIEW

A

fter presentation of the study by Cheng and colleagues at the 2015 European Cancer Congress, formal discussant Vincent Grégoire, MD, PhD, Department of Radiation Oncology, UCL St-Luc University Hospital, Brussels, Belgium, was cautious in endorsing a surgical approach for stage III and IV oropharyngeal and hypopharyngeal cancers.

This study should be hypothesis-generating.

It is interesting data, but I would be very careful about basing policy guidelines on these data, even in Taiwan.

—Vincent Grégoire, MD, PhD

“This paper shows that, in Taiwan, it is better to have oropharyngeal cancer than hypopharyngeal cancer, and it is better to have stage III disease than stage IV. This is the same all over the world, but in Taiwan, it is also better to have surgery than not. However, the environment and other considerations in Taiwan may be different,” he said.

“Patient selection and potential bias is an important issue in retrospective studies,” he continued. “We need to be sure about the methodology.

Surgical treatments were unclear in the data. Was radiation used for curative intent or palliation? Was the radiotherapy dose optimized? We can’t compare apples and oranges,” he stated.

“There is no doubt that we need to know which approach is better— surgical vs nonsurgical—and the outcomes studied should be efficacy, toxicity, and side effects, such as speech and swallowing,” he added.

Dr. Grégoire concluded, “This study should be hypothesis-generating.

It is interesting data, but I would be very careful about basing policy guidelines on these data, even in Taiwan.” n Disclosure: Dr. Grégoire reported no potential conflicts of interest.

ASCOPost.com | DECEMBER 25, 2015

PAGE 55

Announcements

ASTRO Launches Template to Help Radiation Oncologists Guide Cancer Survivors Through Ongoing Care

A

new template published by the American Society for Radiation Oncology (ASTRO) standardizes and streamlines the creation of patient-focused plans for long-term cancer survivor care following radiation therapy.

As the number of cancer patients and survivors in the United States continues to grow—the American Cancer Society predicts a 37% increase in the number

to meet new accreditation requirements set by the American College of Surgeons Commission on Cancer (CoC). In response to a 2006 recommendation from the Institutes of Medicine that cancer patients be provided with a survivorship care plan following treatment, CoC issued a mandate that cancer programs provide survivorship care plans for all curative cancer patients by 2019 to maintain accreditation.

This two-page template facilitates consistency in survivorship care plans across the discipline and also reduces the time and effort required by providers to complete each plan.

—Ronald Chen, MD, MPH

of cancer patients surviving 5 years or longer over the next decade—so does the need for greater attention to longterm survivorship care. The template and related research papers1,2 are published in Practical Radiation Oncology.

Template Creation The template was developed to coordinate post-treatment care for cancer survivors among the various contributors to their care, including primary care providers and oncology specialists (radiation, medical, and surgical), as well as patients themselves.

The framework also enables practices

The new CoC requirement may necessitate changes for the majority of radiation oncology programs, according to data from a March 2014 survey of ASTRO members, which included nearly all practicing radiation oncologists in the United States. The survey found that only 40% and 19% of respondents used survivorship care plans for curative and palliative patients, respectively. Primary barriers to implementation included cost and the lack of a standardized, comprehensive survivorship care plan framework suited to patients who received radiation.

Nearly 80% of the radiation therapy

providers who reported using survivorship care plans relied on a framework developed internally within their practice, indicating that different patients may receive different types of information depending on where they receive treatment.

“This two-page template facilitates consistency in survivorship care plans across the discipline and also reduces the time and effort required by providers to complete each individual plan,” said ­Ronald Chen, MD, MPH, Associate Professor in Radiation Oncology at the University of North Carolina at Chapel Hill. “The field of radiation oncology has a long tradition of creating treatment summaries for each patient, even before the Institute of Medicine recommended survivorship care plans in 2006. This radiation oncology–specific template will serve a dual purpose as both a traditional radiation oncology treatment summary and a plan for survivorship care that meets CoC requirements, thus reducing the burden on radiation oncologists from having to create two documents for each patient.”

Dr. Chen was the Chair of ASTRO’s Clinical, Translational, and Basic Science Advisory Committee, the group that examined current adoption levels of survivorship care plans and developed the template to standardize them in the future.

Template Content While many radiation oncologists provide their patients with follow-up material such as diagnosis and treat-

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ment summaries; contacts for ancillary services such as financial or nutritional counseling; and information on potential late treatment effects, the survivorship care plan template coordinates these components in a central document. The template includes both elements required by CoC in survivorship care plans, namely a summary of past treatment and directions for future care.

The treatment summary outlines the survivor’s diagnosis and stage information; treatment details such as the site, dosage, and schedule of radiation therapy; and contact information for providers who delivered the treatment. The plan for follow-up care covers anticipated toxicities from radiation therapy; expected course of recovery from treatment-related toxicities; possible functional and/or social limitations; recommendations for preventative measures and behaviors; cancer information resources; and referrals to supportive care providers. n References 1. Chen RC, Hoffman KE, Sher DJ, et al: Development of a standard survivorship care plan template for radiation oncologists. Pract Radiat Oncol 3:e24-e253, 2015.

2. Koontz BF, Benda R, De Los Santos J, et al: US radiation oncology practice patterns for posttreatment survivor care. Pract Radiat Oncol. October 6, 2015 (early release online).

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PAGE 58

Journal Spotlight Gastrointestinal Oncology

Phase III Trials Fail to Show Noninferiority of Surgical Outcome for Laparoscopic vs Open Resection in Rectal Cancer

By Matthew Stenger

T

wo phase III trials, reported in JAMA by James Fleshman, MD, of Baylor University Medical Center, Dallas, and colleagues1 and Andrew R. Stevenson, MBBS, FRACS, of the University of Queensland, Brisbane,

The laparoscopic and open surgery groups were generally balanced for all baseline characteristics assessed, including age, sex, race, planned procedure, tumor location, Zubrod performance score, clinical stage, and prior therapy.

Among patients with stage II or III rectal cancer, the use of laparoscopic resection compared with open resection failed to meet the criterion for noninferiority for pathologic outcomes.

—James Fleshman, MD, and colleagues

Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery.

—Andrew R. Stevenson, MBBS, FRACS, and colleagues

Australia, and colleagues,2 failed to show noninferiority of surgical outcome for laparoscopic vs open resection in patients with rectal cancer.

ACOSOG Z6051 Trial In the American College of Surgeons Oncology Group (ACOSOG) Z6051 trial, reported by Fleshman and colleagues, 486 patients with stage II or III rectal cancer within 12 cm of the anal verge from 35 institutions in the United States and Canada were randomly assigned between October 2008 and September 2013 to undergo laparoscopic resection (n = 240 evaluable patients) or open resection (n = 222 evaluable patients) by credentialed surgeons after neoadjuvant chemotherapy.

The primary outcome measure was successful resection as a composite of circumferential radial margin > 1 mm, distal margin without tumor, and completeness of total mesorectal excision.

The noninferiority margin was 6%.

Successful resection occurred in 81.7% of patients undergoing laparoscopic resection (95% confidence interval [CI] = 76.8%–86.6%) vs 86.9% of those undergoing open resection (95% CI = 82.5%–91.4%); the difference was −5.3%, with a one-sided 95% confidence interval of −10.8% to ∞ and P for noninferiority = .41. Conversion to open resection occurred in 11.3% of patients in the laparoscopic resection group.

Mean operation time was 266.2 vs 220.6 minutes (mean difference = 45.5 minutes, P < .001). There were no significant differences in length of hospital stay (mean, 7.3 vs 7.0 days), readmission within 30 days (3.3% vs 4.1%), or

severe complications (22.5% vs 22.1%).

Overall, quality of the total mesorectal excision specimen in the 462 evaluable cases was complete (77%) or nearly complete (16.5%) in 93.5% of patients (92.1% vs 95.1%, P = .20). A negative circumferential radial margin was observed in 90% of patients overall (87.9% vs 92.3%, P = .11). The distal margin result was negative in > 98% of patients irrespective of type of surgery (P = .91).

The investigators concluded: “Among patients with stage II or III rectal cancer, the use of laparoscopic resection compared with open resection failed to meet the criterion for noninferiority for pathologic outcomes. Pending clinical oncologic outcomes, the findings do not support the use of laparoscopic resection in these patients.”

ALaCaRT Trial In the Australasian Laparoscopic Cancer of the Rectum Trial ­(ALaCaRT), reported by Stevenson and colleagues, 475 patients with stage T1 to T3 rectal cancer < 15 cm from the anal verge from 24 sites in Australia and New Zealand were randomly assigned between March 2010 and November 2014 to undergo laparoscopic (n = 238) or open resection (n = 237) by credentialed surgeons.

The primary outcome measure was successful resection as a composite of complete total mesorectal excision, clear circumferential margin (≥ 1 mm), and clear distal resection margin (≥ 1 mm). The noninferiority margin was 8%.

The laparoscopic and open resection groups were generally balanced for all baseline characteristics assessed, includin age, sex, ECOG performance status, preoperative radiotherapy, planned procedure, tumor location, stage, nodal status, and distant metastasis.

Laparoscopy vs Open Surgery for Rectal Cancer ■■ The ACOSOG Z6051 trial failed to show noninferiority of surgical outcomes for laparoscopic vs open resection in stage II or III rectal cancer.

■■ The ALaCaRT trial failed to show noninferiority of surgical outcomes for laparoscopic vs open resection in stage T1 to T3 rectal cancer.

Resection was successful in 82% of the laparoscopic surgery group vs 89% of the open surgery group; the difference was −7.0%, with a 95% confidence interval of −12.4% to ∞ and P = .38 for noninferiority. Conversion to open resection occurred in 9% of the laparoscopic group.

Circumferential resection margin was clear in 93% vs 97% (difference = −3.7%, P = .06), distal margin was clear in 99% vs 99% (difference = −0.4%, P = .67), and total mesorectal excision was complete in 87% vs 92% (difference = −5.4%, P = .06).

Median operation time was 210 vs 190 minutes (P = .007). There were no significant differences between groups in length of hospital stay or rates of major complications.

The investigators concluded: “Among patients with T1-T3 rectal tumors, noninferiority of laparoscopic surgery compared with open surgery for successful resection was not established. Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery. Longer follow-up of recurrence and survival is currently being acquired.” n Disclosure: The ACOSOG Z6051 trial was supported by a grant from the National Cancer Institute, and the Covidien Company provided unrestricted research support to the ACOSOG infrastructure for the trial.

The ALaCaRT Trial was supported by grants from the Colorectal Surgical Society of Australia and New Zealand Foundation and the National Health and Medical Research Council. The American Society of Colon and Rectal Surgeons provided funding for the quality-of-life secondary endpoint evaluation during the study. For full disclosures of the study authors, visit jama.jamanetwork.com.

References 1. Fleshman J, Branda M, Sargent DJ, et al: Effect of laparoscopic-assisted resection vs open resection of stage II or III rectal cancer on pathologic outcomes: The ACOSOG Z6051 randomized clinical trial. JAMA 314:1346-1355, 2015.

2. Stevenson AR, Solomon MJ, Lumley JW, et al: Effect of laparoscopicassisted resection vs open resection on pathological outcomes in rectal cancer: The ALa­CaRT randomized clinical trial.

JAMA 314:1356-1363, 2015.

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ASCOPost.com | DECEMBER 25, 2015

PAGE 59

Perspective

Minimally Invasive Surgery for Rectal Cancer: An Evolving Issue

By Steven Nurkin, MD, MS, FACS

O

ver 10 years ago, we welcomed a new approach to cancer surgery when the 2004 COST trial demonstrated the benefits of laparoscopic compared with open surgery for colon cancer. This randomized trial of 872 patients showed improved perioperative recovery with laparoscopic colectomy without compromising long-term oncologic outcomes.1 As a result of this and other studies, oncologic surgeons have tried to push the envelope and expand the indications for minimally invasive surgery, including in rectal cancer.

long-term follow up showed no difference in long-term outcome or quality of oncologic resection (ie, circumfer-

ential radial margin, completeness of total mesorectal excision, lymph node evaluation, and complication rate).

Recently, results of the COLOR II trial were reported in The New England continued on page 60

ADVERTORIAL

Mixed Results Research to date, however, indicates that the benefits of laparoscopic over open surgery for rectal cancer remain mixed. The recently reported ACOSOG Z6051 and ALaCaRT trials,2,3 summarized in this issue of The ASCO Post, suggested laparoscopy as possibly inferior to open surgery. ACOSOG Z6051 and ALaCaRT are both well-designed studies involving highly proficient rectal cancer surgeons. Participating surgeons were very experienced in both open and laparoscopic surgery, and the study groups required specific surgeon credentialing.

In both studies, the primary outcome difference did not meet statistical significance. However, based on their predetermined statistical criteria, laparoscopy failed to show noninferiority compared with an open approach with regard to pathologic assessment.

Both studies concluded that their findings do not provide sufficient evidence to support the routine use of laparoscopic surgery.

Other similar trials, with longterm follow-up, comparing laparoscopy with open surgery have not found the same results. The COREAN trial randomized 340 neoadjuvantly treated patients to open vs laparoscopic surgery.4 Their short-term and recent Dr. Nurkin is Assistant Professor, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York.

CANCER STEM CELLS

SIGNALING PATHWAYS

REGROWTH

APOPTOSIS

Cancer Stem Cells and Their Role in Recurrence and Metastasis Despite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 Cancer stem cells are a subset of the total cancer cell population that is highly tumorigenic.2,3 Chemotherapy and radiation have been shown to affect the primary tumor, but not the cancer stem cell.4 Many patients with cancer, even though diagnosed early, succumb to the disease because of recurrence and metastasis.5,6 Cancer stem cells are thought to contribute to this recurrence and metastasis.7

Boston Biomedical is developing the next generation of cancer therapeutics with drugs designed to inhibit cancer stem cell pathways. Clinical trials are underway with the goal of reducing recurrence and metastasis.

Another characteristic of cancer stem cells is that they possess stemness. Stemness distinguishes cancer stem cells by their ability to continually self-renew, differentiate into cancer cells, migrate, and regrow the tumor.7,8 Most chemotherapeutic strategies target actively proliferating cancer cells, resulting in bulk tumor shrinkage. Cancer stem cells, however, are highly resistant to these therapies and may not be eradicated during treatment, resulting in recurrence and metastasis.4,7 Moreover, chemotherapy and radiation have the potential to induce stemness properties in non-stem cancer cells.2,9 Several signaling pathways are involved in the induction and maintenance of stemness in cancer stem cells, including JAK/ STAT, Wnt/β-catenin, Hedgehog, Notch, and Nanog.10-12 Targeting these aberrant signaling pathways may result in cancer stem cell apoptosis, while reducing the toxicity to normal tissues that is associated with chemotherapy.4

EDU-NPS-0027

8/2015

©2015 Boston Biomedical

Learn more at www.bostonbiomedical.com References: 1. Li Y, Rogoff HA, Keates S, et al. Supression of cancer relapse and metastasis by inhibiting cancer stemness.

Proc Natl Acad Sci. 2015;112(6):1839-1844. 2. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer stemness by chemotherapy.

Cell Cycle. 2012;11(14):2691-2698. 3. Clarke MF. Self-renewal and solid-tumor stem cells. Biol Blood Marrow Transplant. 2005:11(2 suppl 2):14-16. 4. Boman BM, Huang E. Human colon cancer stem cells: A new paradigm in gastrointestinal oncology. J Clin Oncol.

2008;26(17):2828-2838. 5. Ahmad A. Pathways for breast cancer recurrence. ISRN Oncol. 2013;2013:290568. doi: 10.1155/2013/290568.

6. Hung JH, Wu YC. Stage I non-small cell lung cancer: recurrence patterns, prognostic factors and survival. In: Cardoso P, ed. Topics in Thoracic Surgery. Shanghai, China: InTech; 2012:285-292. http:// www.intechopen.com/books/topics-in-thoracic-surgery/stage-inon-smallcell-lung-cancer-recurrence-patterns-prognostic-factorsand-survival. Accessed May 8, 2015. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261.

8. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 9. Ghisolfi L, Keates AC, Hu X, Lee D, Li CJ. Ionizing radiation induces stemness in cancer cells.

PLOS ONE. 2012;7(8):1-11. 10. Hoffmeyer K, Raggioli A, Rudloff S, et al. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336(6088):1549-1554. 11. Bourguignon LYW, Earle C, Wong G, Spevak CC, Krueger K. Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene. 2012;31(2):149160. 12. Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. Notch signaling: targeting cancer stem cells and epithelial-tomesenchymal transition. Onco Targets Ther. 2013;6:1249-1259.

The ASCO Post | DECEMBER 25, 2015

PAGE 60

Perspective

Steven Nurkin, MD, MS, FACS plane and are devoid of wrist motion, continued from page 59

Journal of Medicine.5 A total of 1,044 patients with rectal cancer were randomized to both surgical approaches.

At 3 years, there was no difference in locoregional recurrence, disease-free survival, or overall survival. Laparoscopy actually showed better outcomes with regard to circumferential margins in lower rectal tumors. It will be interesting to see whether failure to meet noninferiority in the ACOSOG Z6051 and ALaCaRT studies will correlate with short- and long-term differences in oncologic outcomes.

Laparoscopy vs Open Surgery Rectal cancer surgery is challenging, even when performed with traditional open methods. Both tumor and patientrelated factors can bring important technical challenges. The dark, narrow, and confined bony pelvis limits the working space for dissection and visualization.

Tumors and nodal disease may extend radially and may compromise the mesorectal envelope, placing the circumferential margin at risk. This dissection must also account for critical pelvic and sacral vessels and nerves that, if injured, can lead to significant intraoperative blood loss and permanent urinary and/or sexual dysfunction.

An intact mesorectum and a negative (circumferential) margin resection are associated with the lowest rates of locoregional recurrence and are considered important prognostic factors (and markers of surgical quality) in rectal cancer. Their importance is such that both the ALaCaRT and ACOSOG Z6051 studies used these factors to determine their primary outcomes. Notably, they may also be the factors most influenced by the limitations of laparoscopy. Standard rigid, in-line laparoscopic instruments are limited by their ergonomics within the deep pelvis; they can be restricted by the amount of traction and countertraction needed for optimal visualization of the total mesorectal excision

which would be helpful to clean the circumferential mesorectum before distal rectal transection.

Other Techniques Therefore, other techniques have been developed to try to improve on the limitations of laparoscopic total mesorectal excision. The robotic platform has gained popularity, especially in rectal cancer surgery, for these reasons. High-definition, three-dimensional optics, stable instruments, along with varying degrees of wrist motion, may make up for laparoscopic limitations. Of note, in the ACOSOG Z6051 trial, 14.2% of patients in the laparoscopic arm underwent robotic

sorectal excision from above, and a transanal approach using a minimally invasive surgery platform dissection from below, for total mesorectal excision completion. This approach allows for clear distinction of the distal margin and improved visualization of the total mesorectal excision dissection in the deep pelvis. With the results of the ACOSOG Z6051 and ALaCaRT trials, these techniques will likely be critically evaluated further as minimally invasive options.

Clinical Implications There is no question that laparoscopic total mesorectal excision is difficult to perform and comes with a steep learning curve. Both the

Laparoscopic, robotic, transanal, and open approaches may all have a place in the management of rectal cancer.

—Steven Nurkin, MD, MS, FACS

surgery; unfortunately, the outcomes of this subgroup have not been reported. Robotics was excluded in the ALaCaRT study.

Preliminary data from the ROLARR trial showed no significant difference between laparoscopic and robotic surgery regarding conversion to open and circumferential margin positivity; however, there was a trend toward improved outcomes with robotics for the most challenging patients (ie, male, obese, and those with low tumors).

Another minimally invasive procedure, transanal total mesorectal excision, is also gaining momentum in this field. Lacy and colleagues recently published their success using this technique in 140 patients.6 It involved a two-step approach: laparoscopic mobilization of the splenic flexure and start of the abdominal total me-

ACOSOG Z6051 and ALaCaRT studies increase our awareness of the complexities and technical challenges of laparoscopy for rectal cancer. Clinical trials such as these often involve academic clinicians with exceptional expertise and likely do not represent the skill set of the average general surgeon. Thus, even minor differences in outcomes between surgical approaches noted in these trials may become magnified on a national level.

However, we should pause before we conclude that laparoscopy is inferior to open surgery for all rectal cancer. As mentioned previously, studies with long-term follow-up are not in agreement with these results, and some studies actually show superiority of minimally invasive approaches in short-term and oncologic outcomes.

Some patients (and tumors) will be at

varying risk for incomplete total mesorectal excision and margin positivity.

I eagerly await a more-detailed analysis (or meta-analysis) of these studies to determine which factors or surgical approaches lead to the best outcomes. Such data may help assess patient risk and guide surgeons to offer the best procedure appropriate to the patient and the disease. Laparoscopic, robotic, transanal, and open approaches may all have a place in the management of rectal cancer. Cost, training, proficiency, and credentialing remain important aspects of surgical care, and they cannot be stressed enough for rectal cancer surgery. n

Disclosure: Dr. Nurkin reported no potential conflicts of interest.

References 1. Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350:20502059, 2004.

2. Fleshman J, Branda M, Sargent DJ, et al: Effect of laparoscopic-assisted resection vs open resection of stage II or III rectal cancer on pathologic outcomes: The ACOSOG Z6051 randomized clinical trial. JAMA 314:1346-1355, 2015.

3. Stevenson AR, Solomon MJ, Lumley JW, et al: Effect of laparoscopicassisted resection vs open resection on pathological outcomes in rectal cancer: The ALaCaRT randomized clinical trial.

JAMA 314:1356-1363, 2015.

4. Jeong SY, Park JW, Nam BH, et al: Open versus laparoscopic surgery for mid-rectal or low-rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): Survival outcomes of an open-label, non-inferiority, randomised controlled trial. Lancet Oncol 15:767-774, 2014.

5. Bonjer HJ, Deijen CL, Abis GA, et al: A randomized trial of laparoscopic versus open surgery for rectal cancer. N Engl J Med 372:1324-1332, 2015.

6. Lacy AM, Tasende MM, Delgado S, et al: Transanal total mesorectal excision for rectal cancer: Outcomes after 140 patients. J Am Coll Surg 221:415-423, 2015.

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ASCOPost.com | DECEMBER 25, 2015

PAGE 61

JCO Spotlight Breast Cancer

Surgical Excision Without Radiation Therapy in Women With Low-Risk Ductal Carcinoma in Situ

By Matthew Stenger

L

awrence J. Solin, MD, of Albert Einstein Healthcare Network, Philadelphia, and colleagues reported the 12-year results from the ECOGACRIN E5194 trial in the Journal of Clinical Oncology. Among women with ductal carcinoma in situ with low-risk clinical and pathologic characteristics,

no radiation therapy. Excision was to have a minimum negative margin width of ≥ 3 mm or no tumor on re-excision.

The primary endpoint of the study was an ipsilateral breast event, defined as the first local recurrence of ductal carcinoma in situ or invasive carcinoma in the treated breast.

Individual patients and their physicians will need to decide if these 12-year risks are acceptable and to judge whether or not to add adjuvant treatment after surgical excision.

—Lawrence J. Solin, MD

they found that surgical excision without radiation therapy was associated with ipsilateral breast invasive recurrence in 7.5% of those with low- or intermediate-grade disease and 13.4% of those with high-grade disease at 12 years. The risk increased over time, with no plateau observed.1 The clinical trial was conducted by the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOG-ACRIN).

Study Details In the nonrandomized ECOGACRIN E5194 study, women with ductal carcinoma in situ with low-risk clinical and pathologic characteristics were assigned to two cohorts between April 1997 and October 2002: Cohort 1 (n = 561) had low- (50%) or intermediategrade (50%) ductal carcinoma in situ and a tumor size ≤ 2.5 cm; cohort 2 (n = 104) had high-grade ductal carcinoma in situ and a tumor size ≤ 1 cm. Enrollment and cohort assignment were based on clinical and pathology assessment at treating institutions.

All patients underwent surgical excision (lumpectomy) of the primary ductal carcinoma in situ tumor and received

For cohorts 1 and 2, patient ages were ≤ 39 years in 2% and 4%, 40–49 in 17% and 20%, 50–59 in 30% and 29%, 60–69 in 26% and 27%, and ≥ 70 years in 25% and 20%. Most of the patients in both cohorts were white, and approximately three-quarters were postmenopausal.

The tumor size was ≤ 5 mm in 40% and 27%, 6–10 mm in 41% and 59%, and > 10 mm in 19% and 14%; the minimum negative margin width was 3 to 4.9 mm in 33% and 27%, 5–9.9 mm in 43% and 45%, and ≥ 10 mm in 21% and 24%.

In patients in cohorts 1 and 2, 31%, and 24% had received tamoxifen, and approximately 45% had received hormone replacement therapy prior to study entry.

The College of American Pathologists (CAP) grade was low, intermediate, and high in 15%, 59%, and 26% and in 2%, 24%, and 74%, respectively.

Ipsilateral Breast Events Median follow-up was 12.3 years. A total of 99 ipsilateral breast events were observed (74 in cohort 1 and 25 in cohort 2), including 51 invasive ipsilateral breast events (52%; 39 in cohort 1 and 12 in cohort 2). The 12-year rates of an ipsilateral breast event were 14.4% for cohort 1 and 24.6% for cohort 2

(P = .003), and the 12-year rates of an invasive ipsilateral breast event were 7.5% and 13.4% (P = .08). The risks of developing an ipsilateral breast event and an invasive ipsilateral breast event increased over time through 12 years, with no plateau observed. In cohort 1, the rates of developing an ipsilateral breast event and an invasive ipsilateral breast event were approximately 1.2% and 0.6% per year through year 12. At 12 years, overall survival was 84.0% and 82.8% (P = .96), and the incidence of contralateral breast cancer events was 6.7% and 12.0% (P = .16).

On multivariate analysis, the study cohort (hazard ratio [HR] = 1.84, P = .009, for cohort 2 vs 1) and tumor size (HR = 2.11, P = .03, for > 10 mm vs ≤ 5 mm) were significantly associated with the occurrence of ipsilateral breast event. Factors that were not significantly associated included age, menopausal status, minimum negative margin width, method of detection, bloody nipple discharge, tamoxifen use, and prior hormone therapy. On multivariate analysis for an invasive ipsilateral breast event, the study cohort was of borderline significance (P = .08), with no other factor being significant.

Findings With CAP Grading In a subset of 500 patients with central pathology review using current CAP guidelines for ductal carcinoma in situ, 12-year rates of an ipsilateral breast event were 12.5% for low-grade disease, 15.1% for intermediate-grade disease, and 20.6% for high-grade disease (P =

.16). The 12-year rates for an invasive ipsilateral breast event were 5.5%, 6.7%, and 11.7% (P = .19), respectively.

The investigators concluded: “[T]his study has demonstrated that the risks of developing an ipsilateral breast event and an invasive ipsilateral breast event increased over time through 12 years of follow-up, without plateau, for patients with ductal carcinoma in situ of the breast who were selected for favorable clinical and pathologic characteristics and treated with surgical excision without radiation. Individual patients and their physicians will need to decide if these 12-year risks are acceptable and to judge whether or not to add adjuvant treatment after surgical excision. Not all patients and their physicians will agree on what is considered too high a risk of developing an ipsilateral breast event or an invasive ipsilateral breast event to recommend observation after surgical excision or what risk is considered too low to justify adding radiation treatment. However, this study provides 12-year data to begin those discussions and to help inform the treatment decision-making process.” n Disclosure: The study was supported in part by the National Cancer Institute and Breast Cancer Research Foundation. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. Solin LJ, Gray R, Hughes LL, et al: Surgical excision without radiation for ductal carcinoma in situ of the breast: 12-year results from the ECOG-ACRIN E5194 study. J Clin Oncol 33:3938-3944, 2015.

Risk of Recurrence Without Radiotherapy in Ductal Carcinoma in Situ ■■ Among women with low-risk ductal carcinoma in situ treated with lumpectomy and no radiotherapy, 12-year rates of ipsilateral breast invasive recurrence were 7.5% in those with low- or intermediate-grade disease and 13.4% in those with high-disease.

■■ The risk of local recurrence of ductal carcinoma in situ or invasive carcinoma in the treated breast increased during follow-up, with no plateau observed.

More on Ductal Carcinoma in Situ Meena S. Moran, MD, of Yale University School of Medicine, comments on the study reported above by Solin et al.

See page 62 in this issue of The ASCO Post.

The ASCO Post | DECEMBER 25, 2015

PAGE 62

Perspective

Ductal Carcinoma in Situ and Relevant Endpoints for Omission of Standard Treatments: Are We There Yet?

By Meena S. Moran, MD

T

he optimal management strategy for ductal carcinoma in situ has become increasingly controversial with respect to potential overdiagnosis and overtreatment. Much of the controversy for ductal carcinoma in situ stems from its exceptional breast cancer–specific survival, which approaches close to 100% irrespective of local treatment choice. With an absence of data to demonstrate that any of our current treatment modalities for ductal carcinoma in situ directly affects survival, it is easy to argue that we may be overtreating and should consider modifying our treatment strategies.

Remaining Challenges Although most treating physicians agree that there is significant variability in the natural history of ductal carcinoma in situ, with a proportion likely remaining clinically insignificant in the absence of any treatments, precisely how to consistently identify this indolent subset remains the challenge. We have yet to scientifically establish and reliably demonstrate any subgroups of patients for whom radiation therapy has not been beneficial in decreasing invasive in-breast recurrences.1 And because invasive recurrences are associated with decreased survival,2,3 careful selection when omitting radiation therapy is warranted.

Furthermore, the optimal clinical endpoint(s) for ductal carcinoma in situ is not agreed upon. Should we adhere to survival outcomes such as breast cancer–specific survival, for which no local treatment modality (mastectomy or local excision, with or without radiation or hormone therapy) appears to have comparative benefit over another? Alternatively, should we be measuring all in-breast recurrences, since any recurrence, irrespective of whether it is invasive or in situ, is generally meaningful for the patient, provoking anxiety and mandating additional surgery? Or should we only be measuring invasive recurrences, which theoretically have the potential to metastasize and ultimately affect survival?

Dr. Moran is Professor of Therapeutic Radiology at Yale University School of Medicine, New Haven, Connecticut.

In-Breast Recurrences If all in-breast local relapses in ductal carcinoma in situ are estimated by annual risk of recurrence, it is estimated that approximately 1% to 2+% will recur per year with breast-conserving surgery alone. The addition of radiation therapy generally results in a ≥ 50% relative risk reduction for both invasive and noninvasive recurrences, diminishing the overall in-breast recurrence risk to < 1% per year.1 Five years of hormone therapy in estrogen

with local excision alone (without radiation) for “low-risk” patients, despite the variation in the definition of “lowrisk” across studies that have prospectively attempted to omit radiation.

The only prospective, randomized study is the RTOG 98-04, which randomized mammographically detected grade I/II ductal carcinoma in situ measuring < 2.5 cm with margins > 3 mm to whole-breast radiation vs observation after local excision. Of the enrolled patients, 62% received

These data should be used as a starting point to begin discussions on what risk of relapse is considered too high to recommend observation only after surgical excision and what risk might be considered too low to warrant adding radiation treatment.

—Meena S. Moran, MD

receptor–positive patients results in an additional 30% relative risk reduction, thus bringing the annual risk of in-breast recurrence to < 0.7%+/year.2 Generally speaking, radiation oncologists will use ≤ 1% per year as a rule of thumb threshold for an acceptable upper limit of in-breast recurrences with breast radiation therapy.

For example, based on disease estimates from the long-term follow-up of the four randomized ductal carcinoma in situ radiation trials, the 15-year inbreast recurrence with local excision alone across the whole spectrum of ductal carcinoma in situ ranged from 20% to 30+%.2-5 With adjuvant radiation therapy, the event rate is reduced to 10% to 15%, and with hormone therapy, a relapse rate of well under 10% is achieved at 15 years.2,5 These numbers may be an overrepresentation of the breast events experienced by these patients with ductal carcinoma in situ today, given the advances in screening/earlier detection and improvements in pathology procedures.

Nevertheless, using the estimates described above, one can roughly anticipate in-breast recurrence rates

tamoxifen. Despite being statistically underpowered because of poor accrual, with only one-third of the projected enrollment (target N = 1,800, final N = 636), the initial report at 7 years of follow-up demonstrated a significantly greater risk of in-breast recurrences for patients who did not receive radiation therapy (7% vs ≤ 1%, P < .001).

The authors concluded that radiation significantly reduced the number of in-breast events despite the low-risk characteristics and limited numbers of patients and that longer follow-up was needed because of the protracted clinical course of ductal carcinoma in situ.6 Another prospective, single-arm study enrolled patients with “low risk” ductal carcinoma in situ to receive wide local excision alone (the WEA study). Their definition of “low-risk” was mammographically detected lesions measuring < 2.5 cm with ≥ 10 mm margins and predominantly grade I/II. Tamoxifen was not delivered. This trial also closed early, after accrual of 158 patients, because of the extraordinarily high number of in-breast events that met the protocol’s stopping rules.

At 5 years, the initial cumulative

incidence of in-breast recurrence was 12%, with an annual recurrence rate of 2.4% per year,7 which was more recently updated to a 10-year cumulative incidence of 15.6%. The authors concluded that with longer follow-up, the risk of local relapse increases over time and remains substantial for favorable ductal carcinoma in situ treated with widely excised margins without radiation therapy.8 Lastly, ECOG 5194 was a prospective observational study of two separate cohorts of “low-risk” patients treated with local excision alone. The protocol mandated margins of ≥ 3 mm in all patients and required sequential sectioning and complete embedding of each specimen, which are not routine practice in many institutions. Each group was distinguished by its grade and size, with group 2 defined as high grade, smaller (≤ 1 cm) tumors and group 1 as low/intermediate grade, larger (≤ 2.5 cm) ductal carcinoma in situ. The original report of 5-year in-breast recurrences of 15.3% in group 2 and 6.1% in group 1 led the authors to conclude that the recurrence rate in group 2 was too high to consider surgery alone, but it was reasonable to consider omitting radiation for patients with pathologic characteristics of group 1.9

Starting Point to Discussions Consequently, the most recent 12year results of ECOG 5194—reported by Solin et al and summarized in this issue of The ASCO Post—are not surprising.10 In-breast recurrences steadily increased over time in both cohorts of “low-risk” patient. The 12year rate of in-breast recurrence was 24.6% in group 2 and 14.4% in group 1, of which, as expected, approximately 50% were invasive (13.4% and 7.5%, respectively). Consistent with other data, this update clearly exhibits the late but ongoing risk of recurrence in patients with ductal carcinoma in situ. Since risk of inbreast relapses increased without plateau over the 12-year follow-up period for these seemingly low-risk patients, the authors concluded that these data should be used as a startcontinued on page 69

ASCOPost.com | DECEMBER 25, 2015

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Perspective

Meena S. Moran, MD continued from page 62

ing point to begin discussions on what risk of relapse is considered too high to recommend observation (no radiation) after surgical excision and what risk might be considered too low to warrant adding radiation treatment.

Collectively, these data suggest that the longer a patient is followed, the higher the overall (absolute) risk for in-breast recurrence. The current methods being employed to stratify patients with ductal carcinoma in situ into a “low-risk” category, whether clinical-pathologic criteria or genomic testing, are not truly identifying those with indolent disease. Although they may be separating the large spectrum of ductal carcinoma in situ into a smaller group in which the absolute risk of in-breast relapse is lower, a significant proportion of these patients will develop in-breast (and invasive) recurrences—which can be reduced with radiation therapy. Which brings us to the question: How low must risk for in-breast recurrence be to be considered low enough? Potentially, a combination of clinical-pathologic features and genomic analysis will allow for accurate identification of a subset within this low-risk group with truly inconsequential disease.

Major Advances in Radiation Therapy Lastly, with regard to the omission of radiation therapy, it is important to note that our subspecialty, too, has undergone major advances over the years. Relative to the patients treated in the original ductal carcinoma in situ randomized trials that established the benefits of radiation therapy with breast conservation, major advances in treatment planning and delivery of radiation therapy have resulted in significantly diminished side effects.

There are now level 1 data demonstrating that three-dimensional and intensity-modulated radiation therapy techniques deliver a significantly more homogeneous dose, which consequently results in both decreased acute and long-term toxicities for breast treatment compared with twodimensional techniques.11,12 Additionally, technologic advances such as the use of deep inspiration breath hold, respiratory gating, and prone positioning have helped to eliminate heart and lung

exposure significantly.13 And finally, techniques that deliver treatment in a shorter amount of time, such as accelerated hypofractionated radiation and accelerated partial-breast irradiation, are being utilized to increase patient convenience.14 Hence, who is to say that 5 years of hormonal therapy (which diminishes only invasive [but not in situ] recurrences and is effective in reducing inbreast relapses only in hormone receptor–positive patients, has its own potential for serious side effects, and is predictably associated with a high noncompliance rate15), would be more appealing than a course of radiation as adjuvant treatment? Even for patients with indolent disease, the selection of the most tolerable treatment and the thresholds for “what is too low” to warrant treatment or “what is too high” to omit treatment is subjective to the individual patient.

(warranting aggressive treatment) from those of no consequence (possibly warranting less than standard therapy), we, as treating physicians, will need to incorporate multiple factors beyond risk stratification alone in our discussions. An individual patient’s risk of relapse can be roughly estimated using clinical nomograms,18 historic data,1 or more-contemporary studies of lowrisk patients.6,10 But ultimately, this risk estimation must be placed in context with the patient’s comorbidities, anticipated longevity, preferences among various management options, and relative anxiety levels pertaining to recurrence vs treatment—since such decisions can be anticipated to be more likely to impact these patients’ quality-of-life measures than breast cancer–related survival outcomes. n Disclosure: Dr. Moran reported no potential conflicts of interest.

Future Direction An alternative strategy has been proposed to manage patients with clinically indolent ductal carcinoma in situ with no treatment after biopsy alone. As such, two prospective, randomized trials are currently examining no treatment for “low-risk” ductal carcinoma in situ as their experimental arm.16,17 In these studies, asymptomatic, mammographically screen-detected, low- or intermediate-grade ductal carcinoma in situ with calcifications will be observed after biopsy alone compared with the treatment arm of surgery with or without radiation and with or without hormonal therapy.

In addition to reporting breast recurrence outcomes as their primary endpoints, these studies will importantly also include patient-reported outcomes such as anxiety, coping, and quality-of-life measures for treatment vs no treatment.17 Incorporating patient-centered endpoints into future studies of treatment omission for ductal carcinoma in situ will allow for better incorporation of these scientific data into clinical practice by providing data supporting that psychological well-being and qualityof-life measures are noninferior (not affected) when treatment is omitted for ductal carcinoma in situ.

Thus, ductal carcinoma in situ remains a complex disease entity. Until we are able to reliably distinguish lesions of true malignant potential

References 1. Early Breast Cancer Trialists’ Collaborative Group, Correa C, McGale P, et al: Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr 2010:162-177, 2010.

2. Wapnir IL, Dignam JJ, Fisher B, et al: Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst 103:478-488, 2011.

3. Donker M, Litière S, Werutsky G, et al: Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-Year recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized phase III trial. J Clin Oncol 31:4054-4059, 2013.

4. Wärnberg F, Garmo H, Emdin S, et al: Effect of radiotherapy after breastconserving surgery for ductal carcinoma in situ: 20 Years follow-up in the randomized SweDCIS trial. J Clin Oncol 32:3613-3618, 2014.

5. Cuzick J, Sestak I, Pinder SE, et al: Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: Long-term results from the UK/ANZ DCIS trial. Lancet Oncol 12:21-29, 2011.

6. McCormick B, Winter K, Hudis C, et al: RTOG 9804: A prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol 33:709715, 2015.

7. Wong JS, Kaelin CM, Troyan SL, et al: Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol 24:1031-1036, 2006.

8. Wong JS, Chen YH, Gadd MA, et al: Eight-year update of a prospective study of wide excision alone for small low- or intermediate-grade ductal carcinoma in situ (DCIS). Breast Cancer Res Treat 143:343-350, 2014.

9. Hughes LL, Wang M, Page DL, et al: Local excision alone without irradiation for ductal carcinoma in situ of the breast: A trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27:53195324, 2009.

10. Solin LJ, Gray R, Hughes LL, et al: Surgical excision without radiation for ductal carcinoma in situ of the breast: 12-Year results from the ECOG-ACRIN E5194 study. J Clin Oncol 33:39383944, 2015.

11. Donovan E, Bleakley N, Denholm E, et al: Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol 82:254-264, 2007.

12. Pignol JP, Olivotto I, Rakovitch E, et al: A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol 26:2085-2092, 2008.

13. Moran MS, Haffty BG: Radiation techniques and toxicities for locally advanced breast cancer. Semin Radiat Oncol 19:244-255, 2009.

14. Rowe B, Moran MS: Accelerated partial breast irradiation and hypofractionated whole breast radiation. US Oncol Hematol 7:31-37, 2011.

15. Livaudais JC, Hwang ES, Karliner L, et al: Adjuvant hormonal therapy use among women with ductal carcinoma in situ. J Womens Health (Larchmt) 21:3542, 2012.

16. Elshof LE, Tryfonidis K, Slaets L, et al: Feasibility of a prospective, randomised, open-label, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ—The LORD study. Eur J Cancer 51:14971510, 2015.

17. Francis A, Thomas J, Fallowfield L, et al: Addressing overtreatment of screen detected DCIS. The LORIS trial.

Eur J Cancer 51:2296-2303, 2015.

18. Rudloff U, Jacks LM, Goldberg JI, et al: Nomogram for predicting the risk of local recurrence after breast-conserving surgery for ductal carcinoma in situ. J Clin Oncol 28:3762-3769, 2010.

The ASCO Post | DECEMBER 25, 2015

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JCO Spotlight Thoracic Oncology

ASCO Endorses ACCP Guideline on Treatment of Small Cell Lung Cancer

By Matthew Stenger

A

s reported in the Journal of Clinical Oncology,1 ASCO has endorsed the current American College of Chest Physicians (ACCP) guideline on treatment of small cell lung cancer (SCLC), released in 2013.2 After review of evidence from an updated literature search covering 2011 to March 2015, an ASCO endorsement panel determined that there was no definitive evidence warranting substantive modification of the ACCP treatment recommendations.

However, the panel added qualifying statements for recommendations in several areas. The endorsement panel was co-chaired by Giuseppe Giaccone, MD, PhD, of Georgetown University, Washington DC, and Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.

The ACCP guideline sought to address the following questions: (1) What is the ability of positron emission tomography (PET) imaging to determine the stage of cancer? (2) In patients with limitedstage disease, how do the parameters of thoracic radiotherapy affect survival? (3) In patients with extensive-stage disease, what is survival after treatment with chemotherapy, including novel and targeted agents? (4) In elderly patients, what are survival and toxicity after treatment with chemotherapy or radiation therapy?

tained, bone scan may be omitted. Complete blood cell count should include differential.

In patients with clinically limitedstage SCLC, PET imaging is suggested (grade 2C). Remark: If PET is obtained, bone scan may be omitted. Qualifying statement: PET scan use is also applicable to extensive-stage SCLC. It is recommended that both the Veterans Administration system (limited-stage vs extensive-stage) and the American Joint Committee on Cancer/ International Union Against Cancer 7th edition system (TNM) should be used to classify the tumor stage (grade 1B).

In patients with clinical stage I SCLC

with platinum-based chemotherapy, is recommended (grade 1B). Qualifying statement: Comparison of accelerated hyperfractionated radiotherapy with an extended course of daily radiation therapy at standard fractionation is currently being investigated.

In patients with limited-stage or extensive-stage SCLC who achieve a complete or partial response to initial therapy, prophylactic cranial irradiation is recommended (grade 1B). Remark: The regimen of 25 Gy in 10 daily fractions has the greatest supporting data for safety and efficacy.

Qualifying statement: The panel notes that a recent Japanese study failed to demonstrate a survival advantage with prophylactic cranial

In patients with limited-stage SCLC, early chemoradiotherapy, with accelerated hyperfractionated radiation therapy (twice-daily treatment) concurrently with platinum-based chemotherapy, is recommended.

—Giuseppe Giaccone, MD, PhD, and Charles M. Rudin, MD, PhD

Key Recommendations Key recommendations are reproduced here. On the ACCP evidence grading system, retained in the endorsement, 1 = strong recommendation; 2 = weak recommendation; and A, B, and C = high-, medium-, and low-quality evidence. ASCO qualifying statements and remarks appear in italics.

In patients with proven or suspected SCLC, a staging evaluation is recommended, consisting of a medical history and physical examination, complete blood cell count and comprehensive chemistry panel with renal and hepatic function tests, computed tomography (CT) of the chest and abdomen with IV contrast or CT scan of the chest extending through the liver and adrenal glands, magnetic resonance imaging (MRI) or CT of the brain, and bone scan (grade 1B). Qualifying statement: If PET is ob-

who are being considered for curativeintent surgical resection, invasive mediastinal staging and extrathoracic imaging (head MRI/CT and PET or abdominal CT plus bone scan) are recommended (grade 1B).

In patients with clinical stage I SCLC, after a thorough evaluation for distant metastases and invasive mediastinal stage evaluation, surgical resection is suggested over nonsurgical treatment (grade 2C).

In patients with stage I SCLC who have undergone curative-intent surgical resection, platinum-based adjuvant chemotherapy is recommended (grade 1C).

In patients with limited-stage SCLC, early chemoradiotherapy, with accelerated hyperfractionated radiation therapy (twice-daily treatment) concurrently

irradiation in patients with extensive-stage SCLC. On publication of the mature data from this study, the recommendation for prophylactic cranial irradiation in extensivestage SCLC might be subject to revision.

In patients with extensive-stage SCLC who have completed chemotherapy and achieved a complete response outside the chest and a complete or partial response in the chest, a course of consolidative thoracic radiotherapy is suggested (grade 2C). Qualifying statement: Further evaluation of this question is required before a treatment recommendation can be made.

In patients with either limited-stage or extensive-stage SCLC, four to six cycles of platinum-based chemotherapy with either cisplatin or carboplatin plus either etoposide or irinotecan are recommend-

ed over other chemotherapy regimens (grade 1A). Qualifying statement: Clinical trials in the United States and Europe have not demonstrated a benefit for the irinotecan regimen over that based on etoposide. In limited-stage disease, four cycles is preferred.

In patients with relapsed or refractory SCLC, the administration of second-line, single-agent chemotherapy is recommended (grade 1B). Remark: Reinitiation of the previously administered first-line chemotherapy regimen is recommended in patients who experience relapse 6 months from completion of initial chemotherapy. Enrollment onto a clinical trial is encouraged. Qualifying statement: Singleagent topotecan has U.S. Food and Drug Administration approval in this context.

In elderly patients with limited-stage SCLC and a good performance status (Eastern Cooperative Oncology Group performance status of 0 to 2), treatment with platinum-based chemotherapy plus thoracic radiotherapy is suggested, with close attention to management of treatment-related toxicity (grade 2B).

In elderly patients with extensivestage SCLC and a good performance status, treatment with carboplatin-based chemotherapy is suggested (grade 2A).

In elderly patients with SCLC and a poor performance status, treatment with chemotherapy is suggested if the poor performance status is due to SCLC (grade 2C).

More information is available at http://www.asco.org/endorsements/ sclc and http://www.asco.org/guidelineswiki. Patient information is available at http://www.cancer.net. The ACCP guideline is available at http:// www.chestnet.org/. n

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

References 1. Rudin CM, Ismaila N, Hann CL, et al: Treatment of small-cell lung cancer: American Society of Clinical Oncology endorsement of the American College of Chest Physicians guideline. J Clin Oncol 33:4106-4111, 2015.

2. Jett JR, Schild SE, Kesler KA, et al: Treatment of small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

Chest 143(5 suppl):e400S-e419S, 2013.

More on ASCO Endorsement of ACCP Guideline Leena Gandhi, MD, PhD, of Dana-Farber discusses the JCO report summarized above. See page 72 in this issue of The ASCO Post.

ASCOPost.com | DECEMBER 25, 2015

PAGE 71

Announcements

Charles S. Abrams, MD, Named President of ASH

C

harles S. Abrams, MD, the Francis C. Wood Professor of Medicine, Pathology, and Laboratory Medicine at the Perelman School of Medicine and

Charles S. Abrams, MD

Abramson Cancer Center of the University of Pennsylvania and Director of the Blood Center for Patient Care & Discovery at Penn and The Children’s Hospital of Philadelphia, began his 1-year term as President of the American Society of Hematology (ASH) on December 8, 2015, during the organization’s 57th Annual Meeting and Exposition.

ASH is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood.

Before his term as President, Dr. Abrams served a 1-year term as Vice President, followed by a successive term as President-Elect. He also previously served a 4-year term as ASH Secretary from 2009–2012.

At Penn Medicine, Dr. Abrams also serves as Vice Chair for Research and Chief Scientific Officer of the Department of Medicine.

His clinical and research interests have focused on the role of platelets in bleeding and clotting disorders, inflammation, and metastasis formation. He is also the principal investigator of a National Institutes of Health (NIH) Program Project Grant and a K12 mentored training grant.

Dr. Abrams has been elected to the American Society of Clinical Investigation and the Association of American Physicians.

Dr. Abrams received his medical degree from Yale University School of Medicine. After an internship at Temple University Hospital, Dr. Abrams completed a residency and hematology-oncology fellowship at the Hospital of the University of Pennsylvania. n

‘Confetti Mouse’

2016 ASPIRE Breast Cancer Research Awards Pfizer is proud to announce the Advancing Science through Pfizer – Investigator Research Exchange (ASPIRE) Breast Cancer Research Awards, a competitive, peer-reviewed grants program sponsored by Pfizer for investigators in the United States

Call for Research Proposals For complete information on the scope of research, please visit ASPIRE website at www.aspireresearch.org Mission The mission of the ASPIRE Awards is to support clinical research of a Pfizer compound in advanced breast cancer through a competitive grants program to advance knowledge in the treatment and disease management of advanced breast cancer.

Awards 2016 ASPIRE Breast Cancer Research Awards program intends to fund four to six clinical studies within scope, for a total of approximately 4 million US dollars.

It is open to US investigators. Selection of research proposals will be performed by an independent external review panel of breast cancer experts.

Credit: Heinz Baumann, Sean T. Glenn, Mary Kay Ellsworth, and Kenneth W. Gross, Roswell Park Cancer Institute, Buffalo, New York.

Submissions are due March 31, 2016

Photo depicts the “confetti mouse,” a strain of mice genetically engineered so that their cells glow in various combinations of red, blue, yellow, or green markers, depending on what particular proteins those cells are producing. This color coding, demonstrated here in mouse kidney cells, can be especially useful in cancer research, shedding light on subtle molecular differences among tumors and providing clues to what may be driving the spread of cancer cells beyond the original tumor site.

This image recently earned Heinz Baumann and colleagues at the Roswell Park Cancer Institute, Buffalo, New York, a place of honor in the Federation of American Societies for Experimental Biology’s 2015 Bioart competition.

www.aspireresearch.org

The ASCO Post | DECEMBER 25, 2015

PAGE 72

Perspective

ASCO Endorsement of ACCP Guideline on Treating SCLC: Moving Forward to Better Outcomes in Oncology

By Leena Gandhi, MD, PhD

I

n the current climate of rising health-care costs, particularly in the field of oncology, clinical guidelines provide a crucial tool to guide practitioners in evidence-based care and to improve the quality and consistency of care.1 The ASCO review and endorsement of the American College of Chest Physicians (ACCP) guidelines on small cell lung cancer (SCLC)—recently reported by Rudin and colleagues2 and summarized in this issue of The ASCO Post—provide an important addition to the consistent message conveyed by both the ACCP guidelines and National Comprehensive Cancer Network (NCCN) guidelines on the management of SCLC.

Key Affirmations The ASCO review, led by Drs ­Giaccone and Rudin, endorses consideration of surgery as the modality of local therapy for stage I tumors, provided there has been rigorous clinical and pathologic staging. For these patients, as well as patients with limited-stage disease and tumors more extensive than stage I, positron-emission tomography–computed tomography (PET-CT) is recommended to exclude distant metastases. The ASCO review extended this recommendation to the staging evaluation of patients with extensive-stage disease, noting that if PET-CT is performed, a bone scan may be omitted. The use of PET-CT has also thankfully allowed for the removal of invasive bone marrow biopsy as part of staging.3 The ASCO panel also endorsed longstanding recommendations to treat elderly patients with good performance status equivalently to younger patients, with platinumbased chemotherapy and with the addition of thoracic radiation therapy in patients with limited-stage disease.

In addition, the ASCO panel affirmed the goal of treating even poor–performance status patients with chemotherapy if the poor performance status is deemed to be due to cancer.

Dr. Gandhi is a medical oncologist at the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston.

With the advent of immunotherapy showing promise in multiple tumor types including SCLC and with promising data from PARP inhibitors and other novel agents leading to more clinical trials, future guidelines will hopefully incorporate new systemic therapy options as well.

—Leena Gandhi, MD, PhD

Key Modifications The ASCO panel also made several qualifying statements to the ACCP recommendations that modified the endorsement of particular points.

Specifically, although the ACCP recommended twice-daily hyperfractionated radiation therapy as the standard for limited-stage patients (when given concurrently with chemotherapy), the ASCO review notes that there is an ongoing Radiation Therapy Oncology Group/Cancer and Leukemia Group B study comparing twice-daily hyperfractionated radiotherapy (45 Gy or 70 Gy) to a higher total dose of once-daily radiotherapy (70 Gy). This qualifier is more reflective of real-world practice, where logistics of administration often limit the use of hyperfractionated therapy.

The ASCO review also emphasizes the point that trials in the United States and Europe have not shown superiority of irinotecan over etoposide as a partner in platinum-doublet chemotherapy and that platinum plus etoposide remains the standard of care in the United States for first-line treatment of both limited- and extensive-stage disease.

With regard to systemic therapy in the second line, the ACCP focuses on retreatment with the original regimen (only beneficial with a diseasefree interval of > 6 months) or irinotecan. The ASCO review emphasizes that topotecan is the only approved second-line agent that has randomized data showing benefit. Although

amrubicin is approved in the secondline setting in Japan, it is not approved in the United States due to failure to show improvement in overall survival despite improved response rate when compared to topotecan.4

Areas of Controversy One of the most important aspects of guidelines is that they provide upto-date assessments of the field to make recommendations. In many tumor types, this can mean rapidly changing guidelines with the advent of new drug approvals, which are happening more and more quickly in oncology. In SCLC, the major advances have come not from changes in systemic therapy but in radiotherapy.

Although the ASCO review of the ACCP guidelines was released in 2015, the ACCP guidelines themselves were published in 2013.5 Since 2013, two important trials of radiotherapy were completed and presented at the 2014 ASCO meeting. The most recent of them, from Slotman and colleagues, was a randomized phase III trial of consolidation thoracic radiation therapy in patients with extensive-stage SCLC who had a good response in extrathoracic disease. This study demonstrated improved progression-free survival and significantly improved 2-year overall survival with the addition of thoracic radiation, although the primary endpoint of improved 1-year survival was not met for unclear reasons.6 This study underscored similar

findings from a randomized phase II study by Jeremic and colleagues from 1999.7 The ACCP recommended consideration of consolidation thoracic radiation based on the Jeremic et al study alone; however, although the ASCO review panel had data from the second randomized phase III study, they declined to make a recommendation, saying further study is required. The NCCN panel has also recommended cautious consideration of thoracic radiation in selected patients based on both of the above-mentioned studies, as well as a third, nonrandomized study suggesting benefit.8 Another area of treatment that remains controversial is the use of prophylactic cranial irradiation following treatment of either limited- or extensive-stage SCLC. Meta-analyses in 1999 and 2009 established the survival benefit of prophylactic cranial irradiation for limited-stage SCLC,9,10 but a randomized study from Slotman and colleagues in extensive-stage SCLC led to the widespread adoption of prophylactic cranial irradiation in patients who had a response to chemotherapy, regardless of stage.11 However, the Slotman study was flawed in an important way. No magnetic resonance imaging (MRI) scans were performed prior to randomization to prophylactic cranial irradiation or no prophylactic cranial irradiation—therefore, it is likely that there were at least some patients with asymptomatic brain metastases in the patient population who contributed to the benefit seen with “prophylactic cranial irradiation” (not really prophylactic in these cases).

A similar study from Seto and colleagues in Japan was presented at the 2014 ASCO Annual Meeting; in this study’s design, all patients underwent screening MRI to determine CNS disease-free status prior to randomization.12 In addition, patients who were not randomized to prophylactic cranial irradiation were followed with serial MRI. In this study, there was no survival benefit seen with the prophylactic technique.

ASCOPost.com | DECEMBER 25, 2015

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Perspective

Given the morbidity (cognitive and other neurotoxicity) seen with prophylactic cranial irradiation, this study has led to a more cautious approach in recommending the strategy at many centers, including our own. However, although guidelines in Japan were changed after this presentation, the study has not actually been published yet and thus has not yet changed guidelines elsewhere. However, the ASCO review does modify the ACCP recommendation for prophylactic cranial irradiation in noting that publication of the Japanese study may lead to revision of that recommendation.

Future Outlook With the advent of immunotherapy showing promise in multiple tumor types including SCLC and with promising data from PARP inhibitors and other novel agents leading to more clinical trials, future guidelines will hopefully incorporate new systemic therapy options as well. SCLC

still is largely a systemic problem that is in dire need of improved systemic strategies in addition to improved staging and radiation approaches. n

Disclosure: Dr.Gandhi potential conflicts of interest.

reported

no

References 1. Grimshaw JM, Russell IT: Effect of clinical guidelines on medical practice: A systematic review of rigorous evaluations.

Lancet 342:1317-1322, 1993.

2. Rudin CM, Ismaila N, Hann CL, et al: Treatment of small-cell lung cancer: American Society of Clinical Oncology endorsement of the American College of Chest Physicians guideline. J Clin Oncol 33:4106-4111, 2015.

3. Fischer BM, Mortensen J, Langer SW, et al: A prospective study of PET/CT in initial staging of small-cell lung cancer: Comparison with CT, bone scintigraphy and bone marrow analysis. Ann Oncol 18:338-345, 2007.

4. von Pawel J, Jotte R, Spigel DR, et al: Randomized phase III trial of amrubicin

versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol 32:4012-4019, 2014.

5. Jett JR, Schild SE, Kesler KA, et al: Treatment of small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed—American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143(suppl):e400Se400s-e419S, 2013.

6. Slotman BJ, van Tinteren H, Praag JO, et al: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: A phase 3 randomised controlled trial. Lancet 385:36-42, 2015.

7. Jeremic B, Shibamoto Y, Nikolic N, et al: Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: A randomized study. J Clin Oncol 17:20922099, 1999.

8. Yee D, Butts C, Reiman A, et al: Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 102:234-238, 2012.

9. Auperin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341:476-484, 1999.

10. Patel S, Macdonald OK, Suntharalingam M: Evaluation of the use of prophylactic cranial irradiation in small cell lung cancer. Cancer 115:842-850, 2009.

11. Slotman BJ, Mauer ME, Bottomley A, et al: Prophylactic cranial irradiation in extensive disease small-cell lung cancer: Short-term health-related quality of life and patient reported symptoms: Results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J Clin Oncol 27:78-84, 2009.

12. Seto T, Takahashi T, Yamanaka T, et al: Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III trial. 2014 ASCO Annual Meeting. Abstract 7503.

Announcements

UAMS Becomes Home to Cancer Imaging Archive for National Cancer Institute

T

he University of Arkansas for Medical Sciences (UAMS) has become home to The Cancer Imaging Archive of the National Cancer Institute (NCI), with the transfer to UAMS of more than 40 terabytes of data from the archive’s former home at Washington University in St. Louis.

Cancer researchers can use the archive’s data to develop new analysis techniques to advance scientific understanding of cancer, and educators can use it as a teaching tool to introduce students to medical imaging technology and types of cancer.

The public can access the archive and see how cancer appears in diagnostic

Fred Prior, PhD

images, as well as learn about the instruments physicians use to diagnose cancer and measure the success of treatment.

The archive moved to UAMS on October 1 with Fred Prior, PhD, when he left his previous position at

Washington University to chair the newly established Department of Biomedical Informatics in the UAMS College of Medicine.

Biomedical informatics uses computers rather than traditional laboratories to extract knowledge from large sets of data. The department develops computational tools to assess and manage medical and public health information for patient care and research programs. Research using the archive has produced about 250 academic papers in recent years.

An important area of research that makes intensive use of The Cancer Imaging Archive is computer-based im-

age analysis, or radiomics.

“For instance, we are extracting tens of thousands of data points from one computed tomography scan and then analyzing these image features to identify disease signatures,” Dr. Prior explained. “We are comparing genomic feature sets with the imaging feature sets to try to understand how to identify different disease subtypes that may require different therapies.”

That comparative analysis using biomedical informatics has the potential to greatly speed up the process of choosing the best course of treatment for someone with cancer and improving his or her prognosis. n

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twitter.com/ascopost

The ASCO Post | DECEMBER 25, 2015

PAGE 74

In the Clinic Thoracic Oncology

Necitumumab in Metastatic Squamous Non–Small Cell Lung Cancer

By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n November 24, 2015, necitumumab (Portrazza) was approved for use in combination with gemcitabine and cisplatin for first-line treatment of patients with metastatic squamous non–small cell lung cancer (NSCLC).1,2 Necitumumab is not indicated for treatment of nonsquamous NSCLC.

Supporting Efficacy Data Approval was based on improvement in overall survival in an open-label phase III trial in which 1,093 patients were randomly assigned to receive necitumumab at 800 mg via intravenous infusion on days 1 and 8, gemcitabine at 1,250 mg/ m2 on days 1 and 8, and cisplatin at 75 mg/m2 on day 1 of each 3-week cycle (n = 545) or gemcitabine/cisplatin alone (n = 548) until progression or unacceptable toxicity.2,3 Patients had a median age of 62 years, 83% were male, 84% were white, 92% were smokers, performance

OF NOTE Necitumumab binds to EGFR and blocks the binding of EGFR to its ligands, leading to antibody-dependent cellular cytotoxicity in EGFRexpressing cells.

status was 0 or 1 for 91%, and 90% had metastatic disease in at least two sites.

Median overall survival, the primary endpoint, was 11.5 months (95% confidence interval [CI] = 10.4–12.6 months) in the necitumumab group vs 9.9 months (95% CI = 8.9–11.1 months) in the control group (hazard ratio [HR] = 0.84, P = .01). Median progressionfree survival was 5.7 vs 5.5 months (HR = 0.85, P = .02). The objective response rate was 31% vs 29% (P = .40).

A lack of efficacy of necitumumab combined with pemetrexed (Alimta)/ cisplatin vs pemetrexed/cisplatin alone in metastatic nonsquamous NSCLC was shown in a phase III trial that was closed prematurely after enrollment of 633 patients due to an increased incidence of death due to any cause and thromboem-

bolic events in the necitumumab group.4 No improvement in overall survival (HR = 1.01, P = .96), progression-free survival (HR = 0.96, 95% CI = 0.8–1.16), or response rate (31% vs 32%) was observed with the addition of necitumu­ mab in this setting.

OF NOTE Necitumumab carries boxed warnings for cardiopulmonary arrest, sudden death, hypomagnesemia, and other electrolyte abnormalities when combined with gemcitabine/cisplatin.

How It Works Necitumumab is a recombinant human IgG1 monoclonal antibody that binds to epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands. Expression and activation of EGFR have been correlated with malignant progression, induction of angiogenesis, and inhibition of apoptosis.

Necitumumab binding induces EGFR internalization and degradation in vitro, as well as resulting in antibody-dependent cellular cytotoxicity in EGFR-expressing cells. In studies in mouse xenografts, including NSCLC, the addition of necitumumab to gemcitabine/cisplatin resulted in increased antitumor activity.

How It Is Used The recommended dose of necitumumab is 800 mg via intravenous infusion over 60 minutes on days 1 and 8 of each 3-week cycle prior to gemcitabine and cisplatin infusion, with treatment continued until disease progression or unacceptable toxicity.

For grade 1 infusion-related reaction, the infusion rate should be reduced by 50%. For grade 2 infusion-related reaction, the infusion should be stopped until signs and symptoms have resolved to grade 0 or 1, with necitumumab resumed at a 50% reduced rate for all subsequent infusions. Treatment should be permanently discontinued for grade 3 or 4 infusion-related reaction.

Patients who have experienced a previous grade 1 or 2 infusion-related reaction should receive premedication with diphenhydramine hydrochloride (or equivalent) prior to all subsequent infusions. Those who have a second grade 1 or 2 infusion-related reaction should receive premedication for all subsequent infusions with diphenhy­ dramine hydrochloride (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent).

Necitumumab should be withheld for grade 3 rash or acneiform rash until symptoms resolve to grade ≤ 2 and then resumed at a reduced dose of 400 mg for at least one treatment cycle. If symptoms do not worsen, the dose may be increased

to 600 mg and 800 mg in subsequent cycles. Treatment should be permanently discontinued for grade 3 rash or acneiform rash that does not resolve to grade ≤ 2 within 6 weeks, reactions that worsen or become intolerable at a dose of 400 mg, grade 3 skin induration/fibrosis, and grade 4 dermatologic toxicity. Patients should be advised to limit sun exposure.

Necitumumab carries boxed warnings for cardiopulmonary arrest, sudden death, hypomagnesemia, and other electrolyte abnormalities when used in combination with gemcitabine/cisplatin. Serum electrolytes must be closely monitored during treatment, including monitoring for hypomagnesemia, hypocalcemia, and hypokalemia prior to each dose of necitumumab and for ≥ 8 weeks following treatment completion. Aggressive electrolyte replacement should be performed when warranted during and after treatment.

Necitumumab also carries warnings/ precautions for cardiopulmonary arrest, hypomagnesemia and other electrolyte abnormalities, venous and arterial thromboembolic events, dermatologic

Necitumumab in Metastatic NSCLC ■■ Necitumumab (Portrazza) was approved for use in combination with gemcitabine and cisplatin for first-line treatment of patients with metastatic squamous non–small cell lung cancer.

■■ The recommended dose of necitumumab is 800 mg via intravenous infusion over 60 minutes on days 1 and 8 of each 3-week cycle prior to gemcitabine and cisplatin infusion, with treatment continued until disease progression or unacceptable toxicity.

Treatment should be withheld for grade 3 or 4 electrolyte abnormalities.

Subsequent cycles may be given once electrolyte abnormalities have improved to grade ≤ 2. Electrolytes should be replenished as necessary. Treatment should be discontinued for severe venous or arterial thromboembolic events.

Safety Profile In the phase III trial supporting efficacy, the most common adverse events of any grade occurring at a frequency ≥ 2% higher in the necitumumab vs control group were rash (44% vs 6%), vomiting (29% vs 25%), and diarrhea (16% vs 11%). The most common grade 3 or 4 adverse events occurring at a ≥ 2% higher rate in the necitumumab group were venous thromboembolic events (5%, including pulmonary embolism, vs 3%), rash (4% vs 0.2%), and vomiting (3% vs 0.9%). Death attributed to cardiovascular events or sudden death was reported in 3% of the necitumumab group.

Hypomagnesemia of any grade occurred in 83% vs 70% of patients. Grade 3 or 4 electrolyte abnormalities included hypomagnesemia in 20% vs 7%, hypophosphatemia in 8% vs 6%, hypocalcemia in 6% vs 2% (albumin-corrected in 4% vs 2%), and hypokalemia in 5% vs 3%.

toxicities, infusion-related reactions, increased toxicity and mortality if used in nonsquamous NSCLC, and embryofetal toxicity. Patients should not breastfeed during necitumumab treatment. n References 1. U.S. Food and Drug Administration: Necitumumab. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm474278.htm. Accessed December 14, 2015.

2. Portrazza (necitumumab) injection for intravenous use prescribing information, Eli Lilly and Company, November 2015.

Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/125547s000lbl. pdf. Accessed December 14, 2015.

3. Thatcher N, Hirsch FR, Luft AV, et al: Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as firstline therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): An open-label, randomised, controlled phase 3 trial. Lancet Oncol 16:763-774, 2015.

4. Paz-Ares L, Mezger J, Ciuleanu TE, et al: Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): An open-label, randomised, controlled phase 3 study. Lancet Oncol 16:328-337, 2015.

The ASCO Post | DECEMBER 25, 2015

PAGE 80

Announcements

St. Jude Opens First Proton Therapy Center for Children

S

t. Jude Children’s Research Hospital has opened the St. Jude Red Frog Events Proton Therapy Center, the first proton therapy center in the world dedicated solely to children with cancer.

Patients are now being treated at the center using precisely delivered, highenergy protons to kill or shrink tumors while minimizing damage to healthy tissue and organs. For patients with brain tumors and certain other cancers, research suggests proton-beam therapy may be more effective than conventional radiation at preventing the growth and spread of tumors while reducing the risk of treatment-related side effects.

Unique Features The $90 million center includes the linear accelerator, a synchrotron, a three-story rotating gantry, powerful magnets, and other equipment necessary to generate and deliver high-

energy protons to tumors using small, carefully calibrated beams. The beams, which may include protons traveling at almost two-thirds the speed of light, are measured in millimeters.

The system features advanced imaging technology, including cone-beam computed tomography (CT) to provide a three-dimensional image of the patient’s anatomy to achieve precise positioning for treatment. The depth and intensity of the proton beam are guided by advanced control systems to conform to the shape of the tumor.

The U.S. Food and Drug Administration cleared the features unique to the St. Jude proton therapy system on ­November 2, 2015.

The center also contains three proton therapy treatment rooms, treatment preparation, and recovery rooms for patients, plus a musical staircase that leads to a rain forest– inspired waiting room. The center’s multidisciplinary staff includes spe-

cialists from oncology, radiation therapy, imaging, nursing, child life, and other disciplines.

The center is located in the Kay Research and Care Center, which opened earlier this year and also houses a stateof-the-art surgery and intensive care unit, the Marlo Thomas Center for Global Education and Collaboration, and other facilities. The center is named in honor of Red Frog Events. In 2013, the company’s co-CEOs, Ryan Kunkel and Joe Reynolds, pledged to raise $25 million to bring proton-beam therapy to the hospital’s campus.

Future Plans Since 2009, St. Jude patients have traveled to Florida to receive proton therapy at the University of Florida Proton Therapy Institute in Jacksonville as part of a clinical research ­collaboration.

St. Jude officials plan to gradually increase the number of children treat-

Visit ASCOPost.com for Interviews Filmed Live During the 2015 ASH Annual Meeting The ASCO Post presents these and other important discussions: ■■ ■■ ■■ ■■ ■■

Multiple Myeloma: The Path to a Cure CLL and Venetoclax: Clinical Trial Results MDS and CMML Study Results: SWOG S1117 CLL/SLL: Results From the RESONATE-2 Trial Clofarabine for AML: Clinical Trial Results of ECOG-ACRIN and ALFA/Clara

Visit The ASCO Post online at ASCOPost.com

ed at the newly opened center. Along with brain tumors, proton therapy is used to treat Hodgkin lymphoma and solid tumors such as Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, and retinoblastoma. By 2018, officials anticipate 80% of children receiving radiation therapy at St. Jude will receive proton-beam therapy.

The remaining patients will receive photon radiation therapy, which uses x-rays rather than protons for cancer ­treatment.

St. Jude and other researchers have made significant progress in delivering photon radiation in a more targeted manner, but x-rays travel through the body, affecting healthy tissue in the path. In contrast, the high-energy particles used in proton therapy stop at the tumor. The center’s proton-beam technology features spot or pencil beam scanning that doctors can use to “paint” the radiation dose on tumors, spot by spot and layer by layer. n

ASCOPost.com | DECEMBER 25, 2015

PAGE 81

ASH Annual Meeting Hematology Highlights

Select Abstracts From 2015 ASH Annual Meeting

Focus on Therapies for Acute Leukemias and Myelodysplastic Syndromes

By Syed A. Abutalib, MD

H

ere are several abstracts selected from the proceedings of this year’s American Society of Hematology (ASH) Annual Meeting and Exposition, highlighting therapeutics in acute leukemias and myelodysplastic syndromes. For full details of these study abstracts, visit https://ash.confex.com/ ash/2015/webprogram/start.html.

Abstract 6: Results of the global international prospective randomized placebocontrolled double-blind trial CALGB 10603/RATIFY [Alliance]1 Question Asked: Would the addition of midostaurin to induction and consolidation therapies followed by 1 year of maintenance improve overall survival compared with standard chemotherapy in younger (18 to 60 years) adults with acute myeloid leukemia (excluding acute promyelocytic leukemia) harboring any type of FLT3 mutation?

Abstract Conclusion: Yes. The addition of midostaurin significantly improved event-free survival and overall survival (in both uncensored and censored for transplant analyses) in patients whose blasts had a mutation in either tyrosine kinase domain or internal tandem domain (low or high FLT3 mutation burden). It is important to note that induction therapy consisted of 7 days of continuous intravenous infusion of cytarabine (200 mg/m2/d) with 3 once-daily doses of daunorubicin (60 mg/m2).

Abstract 1: Results of the multicenter randomized Graall-R 2005 trial comparing the pediatric-inspired Graall protocol to the same regimen plus rituximab (Rituxan), in patients aged 18 to 59 with newly diagnosed CD20-positive, BCR/ ABL-negative B-cell precursor acute lymphocytic leukemia2 Question Asked: Would the addiDr. Abutalib is Assistant Director, Hematology & Bone Marrow Transplantation Service, Cancer Treatment Centers of America, Zion, Illinois.

tion of rituximab improve event-free survival of adult patients with CD20positive (defined as expression of CD20 in more than 20% of leukemia blasts), BCR/ABL-negative, B-cell precursor acute lymphocytic leukemia?

Abstract Conclusion: Yes. The addition of rituximab prolonger event-free survival in patients treated in the rituximab arm (2-year event-free survival, 65% [95% CI, 56–75] vs 52% [95% CI, 43–63] in the control arm; hazard ratio = 0.66 [0.45–0.98]; P = .038. Of note, rituximab was administered during maintenance therapy as well.

Abstract 91: Interim results on the efficacy and safety of eltrombopag (Promacta) in inducing platelets responses in patients with low- and intermediate-1 International Prognostic Scoring System (IPSS) risk (myelodysplastic syndromes with severe thrombocytopenia) in a phase II, multicenter, prospective, placebo-controlled, single-blind study3 Question Asked: Is eltrombopag safe and active in patients with myelodysplastic syndromes who have a low- and intermediate-1 IPSS risk with severe thrombocytopenia (defined in this study as platelet count of < 30,000/L)?

Abstract Conclusion: According to these preliminary data, the drug appears to be well tolerated, effective (50% platelet response rate), and not associated with bone marrow fibrosis.

Myelodysplastic syndromes disease progression occurred in 11% and 8% of the eltrombopag and placebo arms, respectively (P = not significant). Further follow-up is required to evaluate the impact on survival.

Abstract 908: Additional analyses and results of North American intergroup study SWOG S1117, a randomized phase II study in patients with higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia4 One of Three Questions Asked:

What is the benefit of adding either vorinostat (Zolinza) or lenalidomide (Revlimid) to azacitidine in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia?

Abstract Conclusion: No, for higher-risk myelodysplastic syndromes; however, yes, for chronic myelomonocytic leukemia. In higher-risk patients with myelodysplastic syndromes, overall response rate and overall survival were similar for azacitidine monotherapy compared with combination arms, whereas for patients with chronic myelomonocytic leukemia, the overall response rate was significantly higher with azacitidine plus lenalidomide (63% vs 29%, P = .04), with a trend for longer response duration for combination therapies (P = .06).

Abstract 83: Results with frontline inotuzumab ozogamicin in combination with lower-intensity chemotherapy (mini-hyperCVD [cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x four doses]) with or without rituximab for older (≥ 60 years) adults with B-cell acute lymphoblastic ­leukemia5 Question Asked: Does the addition of inotuzumab ozogamicin, targeted nonmyelosuppressive therapy, to effective low-intensity chemotherapy improve outcomes without additional toxicity in older (60–79 years of age) adults with B-cell acute lymphoblastic leukemia?

Abstract Conclusion: According to these preliminary results, with a median follow-up of 19 months, yes. The minihyper-CVD (n = 34) appears to be superior to the historical hyper-CVAD with or without rituximab (n = 46) in a similar patient population (2-year overall survival, 70% and 38%, respectively). Of note: Sinusoidal obstructive syndrome was observed in 11% of patients (n = 4) who received mini-hyper-

CVD and in three patients without a history of allogeneic transplant. n

Disclosure: Dr. Abutalid reported no potential conflicts of interest.

References 1. Stone RM, Mandrekar S, Sanford BL, et al: The multi-kinase inhibitor midostaurin prolongs survival compared with placebo in combination with daunorubicin/cytarabine induction, high-dose C consolidation, and as maintenance therapy in newly diagnosed acute myeloid leukemia patients age 18–60 with FLT3 mutations: An international prospective randomized placebo-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]).

2015 ASH Annual Meeting and Exposition.

Abstract 6. Presented December 6, 2015.

2. Maury S, Chevret S, Thomas X, et al: Addition of rituximab improves the outcome of adult patients with CD20-positive, Ph-negative, B-cell precursor acute lymphoblastic leukemia: Results of the randomized Graall-R 2005 study. 2015 ASH Annual Meeting and Exposition. Abstract 1. Presented December 6, 2015.

3. Oliva EN, Santini V, Alati C, et al: Eltrombopag for the treatment of thrombocytopenia of low and intermediate-1 IPSS risk myelodysplastic syndromes: Interim results on efficacy, safety, and quality of life of an international, multicenter prospective, randomized, trial.

2015 ASH Annual Meeting and Exposition.

Abstract 91. Presented December 5, 2015.

4. Sekeres MA, Othus M, List AF, et al: Additional analyses of a randomized phase II study of azacitidine combined with lenalidomide or with vorinostat vs. azacitidine monotherapy in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. 2015 ASH Annual Meeting and Exposition. Abstract 908. Presented December 7, 2015.

5. Jabbour E, O’Brien S, Sasaki K, et al: Frontline inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-hyper-CVD) for older patients with acute lymphoblastic leukemia. 2015 ASH Annual Meeting and Exposition. Abstract 83. Presented December 5, 2015.

More Reports From ASH Annual Meeting For more reports from the ASH Annual Meeting in this issue of The ASCO Post, see pages 6–16 and 22–25.

The ASCO Post | DECEMBER 25, 2015

PAGE 82

Hematology Expert Review

Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System Part 3: Therapeutic Considerations and Response Assessment

By Syed Abutalib, MD, and Rimas V. Lukas, MD

The ASCO Post is pleased to present Hematology Expert Review, an occasional feature that includes a case report detailing a particular hematologic condition followed by questions.

Answers to each question appear on page 84 with expert commentary.

I

n the November 10 issue of The ASCO Post, part 2 of a case report was published and focused on the disease burden and the prognosis of a patient with diffuse large B-cell lymphoma of the central nervous system (CNS). Here is part 3 of this case study, which focuses on therapeutic considerations and response assessment.

Summary of Case Study: A 70-yearold man with an otherwise unremarkable medical history returns for follow-up after having undergone a brain biopsy of a left frontal lesion revealing diffuse large B-cell lymphoma. Magnetic resonance imaging (MRI) had revealed involvement of deeper structures of the brain.

Serum studies revealed an elevated LDH at 340 U/L. Staging workup reveals the disease is limited to the CNS (refer to part 1 of this series in the October 25 issue of The ASCO Post).

Based on his age (> 50 years old) and excellent performance status, he would be class II, with a median overall survival of 2.1–3.2 years in the Memorial Sloan Kettering Cancer Center (MSKCC)

prognostic model.1 Based on his age (> 60 years old), involvement of deep brain structures, and elevated serum LDH per the International Extranodal Lymphoma Study Group (IELSG) prognostication system, he would fall into the category with a 2-year overall survival of 48% (± 7%2; refer to part 2 of this series in the November 10 issue of The ASCO Post).

GUEST EDITORS

Question 1 Based on the rationale for the current “standard of care” for primary diffuse large B-cell lymphoma of the CNS, what is the optimal induction therapy?

A. High-dose corticosteroids alone B. Radiotherapy alone C. A high-dose methotrexate–based regimen Continued Case Study: After four cycles of induction therapy, he underwent restaging. On MRI at the site of the prior biopsy, there was a trace amount of enhancement. All of the restricted diffusion on the diffusionweighted images had resolved. A small area of increased fluid-attenuated inversion recovery abnormality and a trace (~1 mm unidirectional measurement) amount of enhancement remained along the biopsy site. All other restaging studies, including cerebrospinal fluid cytology, ophthalmologic examination, and previously abnormal LDH, were unremarkable. The patient was off all steroids at the time of restaging.

Syed A. Abutalib, MD

Syed A. Abutalib, MD, Assistant Director, Hematology & Bone Marrow Transplantation Service, Cancer Treatment Centers of America, Zion, Illinois

Rimas V. Lukas, MD

Rimas V. Lukas, MD, Director of Medical Neuro-Oncology, Associate Professor, Department of Neurology, University of Chicago

Question 2

Question 3

This patient would be classified as having which of the following International Primary Central Nervous System Lymphoma Collaborative Group response criteria?

A. Partial response B. Unconfirmed complete response C. Complete response

What is the optimal consolidation therapy for this patient?

A. High-dose chemotherapy with autologous hematopoietic rescue B. Cytarabine followed by reduceddose whole-brain radiotherapy C. Evaluation in a National Cancer Institute–sponsored cooperative group phase II trial

Continued Case Study: According to the CALGB 50201 (Alliance 50202) protocol, our patient receives another cycle of high-dose methotrexate with temozolomide in preparation for consolidation therapy.

Answers to Hematology Expert Review Questions on page 84

Don’t Miss These Important Reports in This Issue of The ASCO Post Torben Plesner, MD, on Daratumumab in Multiple Myeloma see page 1

Jan A. Burger, MD, PhD, on Ibrutinib in Elderly CLL Patients see page 6

Ronald A. DePinho, MD, on HPV Vaccination see page 1

Masakazu Toi, MD, PhD, on Capecitabine and Residual Disease After Neoadjuvant Chemotherapy in Breast Cancer see page 1

Richard M. Stone, MD, on Midostaurin as Standard of Care in AML see page 7

Visit The ASCO Post online at ASCOPost.com

Elias Jabbour, MD, on Inotuzumab Ozogamicin and Deintensified Chemotherapy in Philadelphia Chromosome–Negative ALL see page 22

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The ASCO Post | DECEMBER 25, 2015

PAGE 84

Hematology Expert Review

Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System Part 3: Therapeutic Considerations and Response Assessment Question 1: Based on the rationale for the current “standard of care” for primary diffuse large B-cell lymphoma of the CNS, what is the optimal induction therapy?

Correct Answer: C. A high-dose methotrexate–based regimen.

Expert Perspective Untreated primary diffuse large Bcell lymphoma of the CNS is associated with dismal outcomes, with a median

other active agents or strategies during induction (with high-dose methotrexate) and consolidation (after high-dose methotrexate) phases of therapy.

The earliest use of a methotrexatebased regimen was intravenous methotrexate at doses of 200 mg/m2 and 1 g/m2 in conjunction with intrathecal methotrexate followed by whole-brain radiotherapy and high-dose cytarabine.8 This approach was further evaluated in a larger group of patients (n = 102) in a multicenter trial

Table 1: Survival Outcomes in Primary Diffuse Large B-Cell Lymphoma of the CNS Intervention

Median survival

Surgery (not indicated) alone

2–3 months

Conventional whole-brain radiotherapy

11–18 months

High-dose methotrexate ± conventional whole-brain radiotherapy

40–60 months

Polychemoimmunotherapy with high-dose methotrexate 1) MT-R→EA11

Median survival not reached, with a median follow-up of 4.9 years

2) R-MPV→rdWBRT→cytarabine12

Median survival not reached, with a median follow-up of 5.9 years

MT-R = methotrexate, temozolomide, rituximab; EA = etoposide plus cytarabine; R-MPV = rituximab, methotrexate, procarbazine, and vincristine; rdWBRT = reduced-dose whole-brain radiotherapy.

survival of 2–3 months.1-3 Corticosteroids can provide both rapid clinical and radiographic improvement when used alone, but they rarely lead to a sustained response. Steroids are included as a component of a number of polychemotherapy regimens for primary diffuse large B-cell lymphoma of the CNS. Radiation alone is associated with high response rates, but 66% of patients recur within the tumor bed; this results in disappointing progression-free survival rates and a median overall survival in the range of 11–18 months, leaving few (1%–2%) long-term survivors.4,5 However, wholebrain radiotherapy alone remains a viable option in patients deemed too weak to tolerate high-dose methotrexate.

In a multivariate analysis, high-dose methotrexate has been shown to be the only treatment-related factor independently associated with improvement in survival (P = .01)6; however; singleagent high-dose methotrexate alone is not a sufficient induction approach in otherwise “fit” patients with diffuse large B-cell lymphoma of the CNS.7 Therefore, efforts have been focused on further increasing treatment efficacy by adding

(RTOG 9310), where high-dose methotrexate (2.5 g/m2) in conjunction with intrathecal methotrexate, vincristine, and oral procarbazine were followed by wholebrain radiotherapy and cytarabine.9

The overall survival and progressionfree survival were 36.9 and 24.0 months, respectively. A total of 58% of patients experienced complete response, with an additional 36% of patients experiencing partial responses, prior to delivery of whole-brain radiotherapy. Older age and intervention with whole-brain radiotherapy, even at a lower dose of 36 Gy (decreased from the original 45 Gy dose in this trial), did not prevent treatmentrelated deleterious neurotoxicity. Approximately 24% of patients treated with combined chemoradiotherapy for diffuse large B-cell lymphoma of the CNS developed serious neurotoxicity, which increased over time.10 Thus, optimal treatment for patients with diffuse large B-cell lymphoma is poorly defined, due to a lack of randomized phase III trials.

Furthermore, a direct comparison between the specific components of highdose methotrexate–based regimens studied in different trials is not possible. For example, many of the regimens included whole-brain radiotherapy consolidation or utilized intrathecal chemotherapy during induction. However, despite these limitations in data, a number of recent phase II clinical trials have documented continued improved outcomes with highdose methotrexate–based regimen(s), establishing high-dose methotrexate as a “standard part of induction therapy.”

Our patient started induction therapy as outlined in the CALGB 50202 (Alliance 50202) trial. This induction regimen (which included high-dose meth-

otrexate, leucovorin, rituximab, and temozolomide) has proved to be effective and well tolerated in adults up to age 74.11 Following induction therapy, the disease is re-assessed, and in this particular protocol, consolidation therapy with cytarabine and etoposide is delivered to patients who achieve complete response or unconfirmed complete response.

The CALGB 50201 (Alliance 50202) protocol successfully eliminated the risk of radiation-induced neurotoxicity by omitting consolidative whole-brain radiotherapy without jeopardizing outcomes (Table 1). Wholebrain radiotherapy still may have an important therapeutic position, albeit at a lower dose than 30 Gy when combined with polychemoimmunotherapy.

For example, a multicenter phase II study administered rituximab, methotrexate, procarbazine, and vincristine followed by consolidation with reduced-dose wholebrain radiotherapy (23.4 Gy) and cytarabine. This regimen resulted in encouraging outcomes with minimal neurotoxicity.12 However, on this protocol, older (> 60 years) adults had inferior progression-free survival compared to younger adults.

Question 2: This patient would be classified as having which of the following International Primary Central Nervous System Lymphoma Collaborative Group response criteria?

Correct Answer: B. Unconfirmed complete response. continued on page 85

Table 2: International Primary Central Nervous System Lymphoma Collaborative Group Response Criteria Response

Brain MRI with gadolinium*

Ophthalmology exam

CSF cytology

Steroid dose

Complete response

No enhancing lesion

Normal

Negative

None

Unconfirmed CR

Minimal abnormality

Minor retinal pigment epithelium abnormality

Negative

Any (patient continues to require steroids)

Negative

N/A

No contrast enhancement Partial response

50% decrease in enhancement of tumor No contrast enhancement 25% increase in lesion

Progressive disease

New site of disease; CNS or systemic

Stable disease

All scenarios not covered by responses above

CSF = cerebrospinal fluid; N/A = not applicable.

Adapted from Abrey LE, et al: J Clin Oncol 23:5034-5043, 2005.

Normal Minor retinal pigment epithelium abnormality or normal Decrease in vitreous cells or retinal infiltrate Recurrent or new ocular lesion

Persistent or suspicious

Recurrent or positive

N/A

ASCOPost.com | DECEMBER 25, 2015

PAGE 85

Expert’s Corner Immunotherapy

The Promise of Immune Checkpoint Blockade in Cancer Therapy A Conversation With James P. Allison, PhD

By Ronald Piana

James P. Allison, PhD

T

he concept of using activation of the innate immune system and an inflammatory response against a bacterial component to instigate an antitumor response was studied in the 1960s, which led to the development of intravesical bacillus Calmette-Guérin, now used in the treatment of superficial

bladder cancer. Over the following decades, the promise of immunotherapy ebbed and flowed until a couple of decades ago, when researchers saw promise in T-cell activation, paving the way for a revival of immunotherapy. Today, one of the most exciting areas in immunotherapy is checkpoint blockade.

The ASCO Post recently spoke with James P. Allison, PhD, who received the 2015 Lasker-DeBakey Clinical Medical Research Award for his pioneering work in enabling T cells to attack cancer cells by removing “checkpoints” that normally inhibit T-cell activity.

A Career-Changing Period Please tell the readers a bit about your career and your current position.

I came from a small town in south Texas and received both my bachelor

Raising the tail of the survival curve, which is our slogan for getting durable responses and perhaps cures in the largest fraction of our patients, is possible. It’s a huge challenge, but I’m confident it is within reach.

—James P. Allison, PhD

degree and PhD at the University of Texas in Austin. I then did postdoctoral training at the Scripps Clinic in La Jolla, California. I returned to Texas and took my first faculty position at the University of Texas Science Park, which was part of MD Anderson Cancer Center. I stayed there about 8 years. I was actually trained in biochemistry but became interested in immunology—specifically T cells and the complex activation processes—and switched fields.

In 1984, I moved to the University

of California, Berkeley, where I became Head of the Immunology Program and Director of the Cancer Research Lab. I continued my work in T cells, and during that work, I began wondering whether T cells could be manipulated in a way to fight cancer cells. It turned out to be a career-changing period.

Although Berkeley was a fantastic place, it didn’t have a clinic, so in 2004, I moved to Sloan Kettering Cancer Center in New York and was there for almost 10 years.

the CALGB 51101 trial, but he elected to be treated off trial on the CALGB 50201 (Alliance 50202) protocol. After completing consolidation therapy with etoposide plus cytarabine, he remains in remission and is scheduled for a clinic visit soon. n

Clin Oncol 16:864-871, 1998.

7. Batchelor T, Carson K, O’Neill A, et al: Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy. J Clin Oncol 21:1044-1049, 2003.

8. DeAngelis LM, Yahalom J, Heinemann MH, et al: Primary CNS lymphoma. Neurology 40:80-86, 1990.

9. DeAngelis LM, Seiferheld W, Schold SC, et al: Combination chemotherapy and radiotherapy for primary central nervous system lymphoma. J Clin Oncol 20:4643-4648, 2002.

10. Omuro AM, Ben-Porat LS, Panageas KS, et al: Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 62:1595-1600, 2005.

11. Rubenstein JL, Hsi ED, Johnson JL, et al: Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma. J Clin Oncol 31:3061-3068, 2013.

12. Morris PG, Correa DD, Yahalom J, et al: Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma. J Clin Oncol 31:3971-3979, 2013.

13. Küker W, Nagele T, Thiel E, et al: Primary central nervous system lymphomas.

Neurology 65:1129-1131, 2005.

14. Abrey LE, Batchelor TT, Ferreri AJ, et al: Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034-5043, 2005.

continued on page 92

Hematology Expert Review continued from page 84

Expert Perspective

The patient has demonstrated a near resolution of all radiographic abnormalities. The response noted on his scan is greater than the ≥ 50% reduction in the cross-sectional area of enhancing tumor necessary for a partial response. A complete response would require a complete resolution of the enhancement in addition to negative cerebrospinal fluid cytology (if previously positive) and negative ophthalmologic slit lamp examination— all while the patient is not on steroids for at least 2 weeks. Due to the small amount of residual enhancement likely representative of gliosis at the biopsy site, our patient is categorized as having an unconfirmed complete response13,14 (Table 2).

Question 3: What is the optimal consolidation therapy?

Correct Answer: C. Evaluation in a National Cancer Institute–sponsored cooperative group phase II trial.

Expert Perspective There remain many unanswered questions in the management of primary diffuse large B-cell lymphoma of the CNS. This question highlights controversies related to consolidation therapy in patients with this type of lymphoma. At present, the optimal consolidation therapy for patients with primary diffuse large B-cell lymphoma of the CNS is not clear. As previously stated,

high-dose methotrexate–based regimens have utilized both chemotherapy and whole-brain radiotherapy as part of consolidation therapy, with favorable outcomes (Table 1). However, in older adults (particularly those ≥ age 60), there are substantial concerns of deleterious neurotoxicity with whole-brain radiotherapy.10 In addition, consolidation with polychemotherapy (ie, etoposide plus cytarabine) in older adults did not adversely affect outcomes.11 For these multiple reasons, we utilized the CALGB 50201 (Alliance 50202) protocol for our patient outside of a clinical trial. Other viable options exist as well for this patient population.

There are two ongoing phase II National Cancer Institute–sponsored cooperative group studies evaluating the role of different treatment modalities for consolidation after predefined induction chemoimmunotherapies.

1) CALGB 51101 (NCT01511562): MT-R followed by consolidative EA vs high-dose chemotherapy using carmustine and thiotepa with autologous cell rescue for patient between the ages of 18 and 75.

2) RTOG 1114 (NCT01399372): R-MPV followed by cytarabine consolidation vs the same regimen with the addition of rdWBRT (of 23.4 Gy) in 13 fractions prior to cytarabine for patients older than age 18.

Our patient was offered the choice of

Disclosure: Drs. Abutalib and Lukas reported no potential conflicts of interest.

References 1. Abrey LE, Ben-Porat L, Panageas KS, et al: Primary central nervous system lymphoma. J Clin Oncol 24:5711-5715, 2006.

2. Ferreri AJ, Blay JY, Reni M, et al: Prognostic scoring system for primary CNS lymphomas. J Clin Oncol 21:266-272, 2003.

3. Ney DE, Deangelis LM: Management of CNS lymphoma, in Armitage JO, Mauch PM, Harris NL, et al (eds): NonHodgkin Lymphomas, 2nd ed, ch 36, pp 527-539. Philadelphia, Lippincott Williams & Wilkins, 2014.

4. Nelson DF, Martz KL, Bonner H, et al: Non-Hodgkin’s lymphoma of the brain: Can high dose, large volume radiation therapy improve survival? Int J Radiat Oncol Biol Phys 23:9-17, 1992.

5. Shibamoto Y, Ogino H, Hasegawa M, et al: Results of radiation monotherapy for primary central nervous system lymphoma in the 1990s. Int J Radiat Oncol Biol Phys 62:809-813, 2005.

6. Blay JY, Conroy T, Chevreau C, et al: High-dose methotrexate for the treatment of primary cerebral lymphomas. J

OVERALL SURVIVAL AT 5 YEARS IN DLBCL IS

1

Could a better understanding of this disease be on the horizon?

60%

Š 2015 Genentech USA, Inc. All rights reserved. HEM/062915/0014a Printed in USA.

DLBCL is an aggressive disease2 Remarkably, more than half of patients are able to survive diffuse large B-cell lymphoma (DLBCL) for 5 years or longer.1,3

Although strides have been made in the science of DLBCL, we are determined to further our knowledge of this aggressive disease

To learn more, visit BCellResearch.com

References: 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2012. National Cancer Institute website. http://seer.cancer.gov/csr/1975_2012/results_single/sect_19_table.29_2pgs.pdf. Updated April 23, 2015.

Accessed June 15, 2015. 2. Jaffe ES, Harris NL, Stein H, Campo E, Pileri SA, Swerdlow SH. Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008:158-166.

3. Larouche J-F, Berger F, Chassagne-ClĂŠment C, et al. Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. J Clin Oncol. 2010;28(12):2094-2100.

The ASCO Post | DECEMBER 25, 2015

PAGE 88

Direct From ASCO

Researcher Spotlight: Conquering Cancer With Dr. Heske

S

ometimes, cancer treatments that initially appear promising begin to lose their effectiveness. This is due to the ability diseases like cancer have to develop resistance to treatments over time and, essentially, outsmart them.

But what if there were ways to ensure this didn’t happen? What if doctors could guarantee promising new treatments stayed promising and led to better outcomes for their patients?

Christine Heske, MD, Clinical Fellow at the National Cancer In-

stitute, is tackling this question as it relates to rhabdomyosarcoma, a tumor that strikes young children and adolescents. Rhabdomyosarcoma is a type of soft-tissue sarcoma that affects muscle tissue, and for patients with metastatic or recurrent disease, treatment options are extremely limited.

One class of drugs called IGF-1 receptor antibodies has caused tumors to shrink in some patients with rhabdomyosarcoma, but ultimately, the tumors develop resistance to the drug.

Thanks to her 2014 Conquer Cancer Foundation of ASCO Young Investigator Award, Dr. Heske has been examining strategies to counteract this. “I have been looking at ways to overcome that resistance so that we can potentially use combination drug therapy,” said Dr. Heske. “That means using the IGF-1 receptor inhibitor plus another agent to keep the tumors responding in this group of patients.”

Dr. Heske’s study is still in process, but the preliminary findings are encouraging. She and her team have identified something some of the resistant tumors share: activity of a receptor called PDGFR-beta. The activity of this receptor could be important to the tumors’ resilience. With this knowledge, they are now investigating ways to suppress PDGFR-beta and keep the tumors responding to treatment.

If Dr. Heske’s team is successful, their results could mean more effective treatment and increased survival

rates for patients with rhabdomyo­ sarcoma.

“The work that I’ve been doing is very translational,” said Dr. Heske.

“Uncovering science in the lab that can help us to better treat patients is so rewarding; finding discoveries that are immediately applicable to the care of patients is what keeps me going.”

Dr. Heske notes the pivotal role her grant has played in her career development: “Having the funding from this grant has been a really amazing opportunity,” said Dr. Heske.

“I think I’m probably among many young investigators who feel that this grant has made an enormous impact on our ability to stay in the field.” n Dr. Heske’s Conquer Cancer Foundation of ASCO Young Investigator Award was supported by the WWWW Foundation, Inc. (QuadW). © 2015. American Society of Clinical Oncology. All rights reserved.

ASCO Guides Members Through MACRA Implementation With a Robust Set of New Resources

T

he Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), passed earlier this year, repealed the fundamentally flawed Sustainable Growth Rate formula and introduced significant changes in how Medicare will pay oncologists for the care they provide in the coming years.

The new law will be fully implemented by 2019 and will profoundly impact reimbursement and care delivery for oncology practices throughout the United States—and now is the time to understand and prepare for these changes.

MACRA will require all oncology practices to transform in two major

ways: (1) how they conduct Medicare reporting requirements, and (2) how they are paid for the services provided to Medicare beneficiaries. The ultimate goal of these changes is to move toward a value-based practice environment that ensures high-quality, affordable health care. ASCO has long embraced this goal and has dedicated significant resources that will provide oncologists with the foundation needed to move into the MACRA era.

Guided by a committed group of volunteers, ASCO will be a partner to oncologists in MACRA implementation and will provide a wide range of

resources and tools that are designed to help adapt to and satisfy MACRA requirements. ASCO will also aggressively advocate that provisions in the law are implemented in a manner that reflects the current realities of cancer care enabling oncologists to provide the full range of services and high-quality care, which patients with cancer need to fight their disease.

Please visit ASCO’s new website at www.asco.org/macra to learn more about MACRA and its impact on oncology care and to see to a number of educational and practical resources from ASCO in the coming months. This site

will be continually updated with new information, so please bookmark this page and visit often to get the latest updates, new materials, and dates for upcoming webinars.

Read the ASCO in Action MACRA brief at http://www.asco.org/advocacy/ asco-action-brief-macra for a high-level overview of the new legislation and its impact on practices, and be sure to follow ASCO in Action at http://www .asco.org/advocacy/news for the latest cancer policy news. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | DECEMBER 25, 2015

PAGE 89

Direct From ASCO

2015–2016 Leadership Development Program Participants Examine Genomics, Data Collection, Team-Based Cancer Care, and Meeting Experience

A

SCO’s Leadership Development Program (LDP) offers mid-career oncologists the opportunity to learn valuable leadership skills from ASCO’s exceptional leaders and participate in networking and mentoring opportunities. Participants work on strategy development, interpersonal effectiveness and teamwork, media communication, and conflict management so that they can become future leaders in their institutions, professional associations, and organizations such as ASCO. In 2015, LDP was expanded to include more participants than ever before due to the demand for more leadership skills training and the high quality of applications. Participants are currently engaged in the following projects that explore important oncology and ASCO-related issues:

Genomics in Clinical Practice This project seeks to better understand the application of genomics in clinical settings at community-based practices. Participants will use ­ASCO’S Targeted Agent and Profiling Utilization Registry (TAPUR) Study and will also look at the genomic-related challenges currently faced by practices and how they are being resolved. The project goal is to identify existing gaps in this arena and to recommend how ASCO can further help practices improve.

Collection and Use of Oncology Clinical Data LDP participants are examining the current state of the collection and use of oncology clinical data in the practice setting. The goal of this project is to better understand how data are being used at practices and how such collections can help improve cancer care.

Team-Based Cancer Care Multidisciplinary, team-based cancer care remains an ongoing area of interest and need in oncology. The LDP project goal is to help inform the cancer community about ways to enhance and build multidisciplinary teams. Participants will also provide ASCO with guidance on other types of activities and initiatives that should be developed to foster team-based care in oncology.

Live Meeting Experience With attendance at ASCO’s meetings continuing to grow, participants

will explore new educational formats, collaboration and networking opportunities, technology enhancements, and other innovations to enhance the on-site experience for

future attendees, both international and domestic. n Originally printed in ASCO Connection. © American Society of Clinical Oncology.

“2015–2016 Leadership Development Program Participants Examine Genomics, Data Collection, Team-Based Cancer Care, and Meeting Experience” connection.asco. org 26 August 2015. All rights reserved.

In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 CASES OF PROGRESSION WITH FIRSTGENERATION EGFR TKIs ARE RELATED TO THE T790M MUTATION1,2 Lung cancer is the leading cause of cancer-related deaths both in the US and worldwide.3,4 For NSCLC EGFRm+ patients, the recommended frst-line treatment is EGFR tyrosine kinase inhibitors (TKIs).5

The majority of tumors will acquire EGFR TKI–resistance mutations Despite initial high response rates with frst-generation EGFR TKIs, many tumors will develop new mutations and become resistant.6,7 A major barrier to disease control is resistance to treatment. Resistance to frst-generation therapy will develop in most patients with EGFRm+ advanced NSCLC on a currently approved EGFR TKI.7 After disease progression, clinical guidelines recommend subsequent treatments including either continuing with an EGFR TKI therapy or beginning platinum-based chemotherapy.5

Nearly 2 out of 3 cases of progression with first-generation EGFR TKIs are related to the T790M mutation In patients with NSCLC who are EGFRm+, T790M is an acquired mutation and has been identifed as the most common mechanism of acquired resistance in nearly 2 out of 3 patients.1,2 Development of T790M mutation may confer resistance through several potential mechanisms, which may include8,9: - Steric hindrance, which reduces receptor binding of reversible EGFR TKIs - Increased binding affnity of EGFR for ATP, resulting in reduced TKI potency

T790M Is the Most Common Mechanism of Acquired Resistance to First-Generation EGFR TKI Therapy1

63%

T790M (98/155)

CI, (9555 –70 ) %

%

MET amplifcation (4/75)

5% (95% CI, 1%–13%)

HER2 amplifcation (3/24)

NEARLY 2 OUT OF 3

%

13% (95% CI, 3%–32%)

0%

10% 20% 30% 40% 50% 60% 70%

Study of 155 patients with radiographic progression following a response or durable stable disease with frst-generation EGFR TKI therapy.

CASES ARE RELATED TO T790M

Other rare mechanisms of acquired resistance may include BRAF, FGFR, and PIK3CA mutations, and transformation to small-cell histology.10,11

Discovering the cause of resistance Patients should be monitored for radiologic or clinical progression. Tumors can also be assessed for molecular progression to uncover additional acquired mutations.1,12-16 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).5

AstraZeneca is a leader in lung cancer research AstraZeneca is conducting ongoing research to understand the science of the T790M mutation as a driver of resistance.

Find out more at EGFRevolution.com.

References: 1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247. 2. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 3. American Cancer Society.

Cancer Facts & Figures 2015. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed March 17, 2015. 4. GLOBOCAN 2012. http://globocan.iarc.fr. Accessed February 9, 2015. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Mok TS, Wu YL, Thongprasert S, et al. Geftinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957. 7. Sequist LV, Yang JCH, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334. 8. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to geftinib. N Engl J Med. 2005;352:786-792. 9. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affnity for ATP. Proc Natl Acad Sci U S A. 2008;105:2070-2075. 10. Cheng L, Alexander RE, MacLennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25:347-369. 11. Ware KE, Marshall ME, Heasley LY, et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One. 2010;5:e14117. doi:10.1371/journal.pone.0014117.12. Johnson KR, Ringland C, Stokes BJ, et al. Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis. Lancet. 2006;7:741-746. 13. Lussier YA, Khodarev NN, Regan K, et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specifc microRNAs. PLoS One. 2012;7:e50141. doi:10.1371/journal.pone.0050141. 14. Jackman DM, Miller VA, Cioffredi, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non–small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009;15:5267-5273. 15. Noronha V, Joshi A, Gokarn A, et al. The importance of brain metastasis in EGFR mutation positive NSCLC patients. Chemother Res Pract. doi:10.1155/2014/856156. 16. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. ©2015 AstraZeneca. All rights reserved. 3140404 6/15

The ASCO Post | DECEMBER 25, 2015

PAGE 90

Direct From ASCO

Opening Doors: ASCO Aims to Increase Workforce Diversity Through Physician Mentoring Program

O

lumide Gbolahan, MD, faced a familiar dilemma among aspiring oncologists. Dr. Gbolahan, an internal medicine resident of the Morehouse School of Medicine, wanted extra time and experience in an oncologic elective summer rotation to ease his transition from internal medicine to oncology.

Unsure of the best strategy, he sought out a mentor through the ASCO Diversity Mentoring Program.

Taofeek K. Owonikoko, MD, PhD, of the Department of Hematology and Medical Oncology and the Winship Cancer Institute of Emory University, began mentoring Dr. Gbolahan in early 2014 through the ASCO Diversity Mentoring Program. The ASCO Diversity Mentoring Program fosters relationships between physicians-in-training and experienced oncology professionals in an effort to recruit and retain individuals from populations underrepresented in medicine to careers in oncology.

Dr. Owonikoko, Associate Director of the Hematology/Oncology Fellowship Training Program at Winship, evaluates the applications of Emory’s hematology and oncology fellowship candidates.

He knew what type of elective program

would most likely benefit his mentee.

The elective outside rotation Dr. Gbolahan initially considered, Dr. Owonikoko said, was not the right fit.

“I said if the goal is to get into a fellowship, a 1-month elective rotation in a basic science laboratory is probably

Taofeek K. Owonikoko, MD, PhD

not going to help you so much at this stage of your career. You need to do something different,” Dr. Owonikoko said.

Armed with that advice, Dr. ­Gbolahan applied and was accepted for another program that better fit his career goals.

“As a junior person in the profession, you don’t know how to navigate your way,” Dr. Gbolahan said. “If you are lucky or if you are hardworking, maybe

things will open up for you. But if you have somebody who is holding your hand, the doors will open more easily.”

A Need to Diversify the Oncology Workforce Oncology, like many other fields of medicine, has statistically fewer physicians who are African American, Hispanic, or female than white male physicians. ASCO recognizes that diversifying the health professional workforce is a key strategy to addressing disparities in health-care outcomes.

A sample of 4,000 oncologic physicians indicated 59% of the workforce is white, according to a 2007 Association of American Medical Colleges report.1 That total is compounded by a lack of minority candidates entering the field of oncology.

Only 2.3% of practicing oncologists are African American, according to the 2015 ASCO report The State of Cancer Care in America.2 In training programs, only 4% of oncology fellows are African American. Similarly, only 3% of practicing oncologists and 5.8% of oncology fellows are Hispanic.

Women also make up a smaller per-

centage of active oncologic physicians; 30.2% of the 13,755 active hematology and oncology physicians in 2013 were women, according to a report from the Association of American Medical Colleges.3 A lack of workforce diversity among physicians can negatively affect the quality of care of minority patients, according to the 2004 Sullivan Commission report Missing Persons: Minorities in the Health Professions.4 According to the report, “Studies suggest that increasing the diversity of the health workforce can improve patient access, patient satisfaction, and quality of care for all patients.”

A diverse physician workforce brings increased cultural competency and engenders trust and comfort in patients.

Providing increased and improved clinical oncology care to underserved communities calls for the recruitment of oncologists from diverse backgrounds.

The Benefits of a Mentor– Mentee Relationship The ASCO Diversity Mentoring Program seeks to educate medical students and residents about rewarding cacontinued on page 91

MAKE SOMEONE’S NEW YEAR A LITTLE BRIGHTER—DONATE TO THE CONQUER CANCER FOUNDATION TODAY! There’s still time to make your 2015 tax-deductible charitable donation before the clock strikes midnight.

Donate at conquercancerfoundation.org/tap.

ASCOPost.com | DECEMBER 25, 2015

PAGE 91

Direct From ASCO Physician Mentoring Program continued from page 90

reers in oncology by pairing them with established oncology professionals.

Nearly 80 mentees and mentors have been paired since 2014.

“For an [early-career] oncologist, mentors can offer guidance for personal, research, and professional development,” said Sandra Wong, MD, MS, FACS, of Dartmouth-Hitchcock and the Geisel School of Medicine and Immediate Past Chair of the ASCO’s Health Disparities

eral Hospital Cancer Center, helped launch the ASCO Diversity Mentoring Program in 2013. Dr. Winkfield, a member of ASCO’s Health Disparities Committee and Chair of its Workforce Development Work Group, said one of the program’s goals in future years is increasing participation among mentors.

Overall, more than 100 medical students and residents applied to the ASCO Diversity Mentoring Program, yet there were not enough volunteers who met the needs of what some applicants were

Just having someone who is fascinating, someone who you can look up to, that sometimes in and of itself can encourage a medical student to go into oncology.

—Karen M. Winkfield, MD, PhD

Committee. “Facilitating opportunities for a mentor–mentee relationship is a win-win. By connecting students and physicians-in-training with experienced cancer care providers, the hope is that more prospective oncologists, especially those from underrepresented populations, will choose to pursue oncology as a career.”

The ASCO Diversity Mentoring Program requires a 1-year commitment from mentors and mentees. Participants are encouraged to communicate remotely by various sources of technology, including email, phone, instant message, and videoconference.

Mentors must be ASCO members who are residents of the United States.

Those participating in the ASCO Diversity Mentoring Program can be found at the Annual Meeting wearing a purple ribbon.

Mentees must be students enrolled in a DO or MD medical school in the United States or residents enrolled in an ACGME-accredited residency program.

Karen M. Winkfield, MD, PhD, Director of Hematologic Radiation Oncology of the Massachusetts Gen-

looking for in a mentor. For example, there was a high demand among applicants to be matched with pediatric oncologists, yet a limited number of pediatric oncologists volunteered.

Increasing mentorship will not only benefit the ASCO Diversity Mentoring Program, but also the field of oncology overall, Dr. Winkfield said.

“Students oftentimes will gravitate to topics that interest them,” Dr. ­Winkfield said. “Just having someone who is fascinating, someone who you can look up to, that sometimes in and of itself can encourage a medical student to go into oncology.”

Although primarily designed for medical students and residents underrepresented in medicine, the ASCO Diversity Mentoring Program is open to any medical student or resident interested in learning more about the field of oncology. For more information, please visit asco.org/diversity. n

Sandra Wong, MD, MS, FACS

Demand for Oncologists: A Report to the American Society of Clinical Oncology (ASCO) from the AAMC Center for Workforce Studies. Available at American Society of Clinical Oncology website. asco.org/sites/default/files/oncology_workforce_report_final.pdf. Accessed March 2, 2015.

2. American Society of Clinical Oncology: The State of Cancer Care in America. Available at American Society of Clinical Oncology website. asco.org/

practice-research/cancer-care-america.

Accessed March 2, 2015.

3. Association of American Medical Colleges: 2014 Physician Specialty Data Book. Available at Association of American Medical Colleges website. members. aamc.org/eweb/upload/14-086%20Specialty%20Databook%202014_711.pdf. Accessed March 2, 2015.

4. The Sullivan Commission: Missing Persons: Minorities in the Health Professions. Available at American Association of Colleges of Nursing website. aacn.nche. edu/media-relations/SullivanReport.pdf Accessed March 2, 2015.

Originally printed in the ASCO Daily News. © American Society of Clinical Oncology.

“Opening Doors: ASCO Aims to Increase Workforce Diversity Through Physician Mentoring Program” am.asco.org 30 May 2015. All rights reserved.

Updated: ASCO Answers Guide to Colorectal Cancer

T

he recently updated ASCO Answers: Guide to Colorectal Cancer helps people who are newly diagnosed

References 1. Association of American Medical Colleges: Forecasting the Supply of and

better understand the disease and their treatment options. This informationpacked guide includes treatment information; an emphasis on palliative care; an expanded follow-up care section; questions patients can ask their health care team; space to write down answers and make other notes; and check boxes to help patients keep track of the tests, procedures, and treatments they will be receiving.

This guide is available as a free printable PDF at www.cancer.net/ colorectalguide or at the ASCO University Bookstore at www.cancer.net/ estore. ASCO members receive a 20% discount. n © 2015. American Society of Clinical Oncology. All rights reserved.

Save the Date Genitourinary Cancers Symposium

Cancer Survivorship Symposium

ASCO Quality Care Symposium

January 7–9, 2016

January 15–16, 2016

February 26-27, 2016

Moscone West Building

San Francisco Marriott Marquis

JW Marriott Phoenix Desert Ridge

San Francisco, California

San Francisco, California

Phoenix, Arizona

The ASCO Post | DECEMBER 25, 2015

PAGE 92

Expert’s Corner James P. Allison, PhD continued from page 85

About 3 years ago, I returned to MD Anderson Cancer Center, where I am now Chair of the Immunology Program and Director of the Immunotherapy Platform.

Immunosurveillance The concept of immunosurveillance was proposed back in the 1950s. What did we learn from this approach that helped move the field forward?

From its inception, the idea of immunosurveillance was quite controversial. It regained favor in the 1960s and then lost support for awhile. The theory suggested that tumors are constantly developing, but they are detected by immune system cells, which can eradicate them; the cancer only recurs when this immune surveillance fails. And now we’ve reached a point where we recognize that the immune system can detect tumors, and we are using this knowledge to further the field.

Please discuss the initial investigations on T-cell activation and how they paved the way for the renewed interest in ­immunotherapy.

During my first faculty job, I became very interested in T cells, which could cruise around your body with about 100 million different specific receptors. When a T cell encounters a foreign antigen, it results in T-cell activation, rapid proliferation, and development of the functional capacity to directly kill or make cytokines to help kill the offending cell.

Moreover, we thought that immunotherapy using T cells could cure the problem without killing you in the process.

That said, cell communication is a very complicated process, and my first accomplishment was defining the structure of the T-cell antigen receptor at the protein level.

It became clear very quickly in work from many labs that the antigen receptor signal by itself was not sufficient to “turn on” a naive T cell. It’s necessary but not sufficient.

Several labs demonstrated that costimulatory factors could only be provided by dendritic cell signals, which were unique in providing that second signal. The question remained: What is that signal? We showed that the receptor on the T cell was a molecule called CD28. Turning it on required both the Tcell antigen-receptor signal and CD-28 costimulatory signal, at pretty much the same time. Subsequently, other researchers showed that a molecule called B7 was the CD-28 ligand on antigen-presenting cells. Given this finding, it seemed that one of the reasons that tumor cells are virtually invisible is because solid tumors do not provide the costimulatory signal.

There was also a molecule called CTLA-4 with a DNA sequence very homologous to CD-28, but nobody knew what it did, except that it only expressed itself after activation. There was a vigorous race to figure it out. The group that got there first showed that it bound to the same molecule that CD-28 bound to.

The first studies demonstrated that CTLA-4 could not costimulate on itself; however, it could synergize with CD-28 and sustain costimulation to keep the T cells activated. My lab and that of Jeff Bluestone came to the conclusion that the prevailing notion, which was already in textbooks, was

backward. Actually the CTLA-4 antibodies were removing the negative signal, resulting in an increase in activity, not providing another positive signal.

This finding kicked up some heated negative and positive debates at conferences. It was a lot of fun.

When we got the results, I started thinking about it in the context of tumors, which was a change of focus for me, because I didn’t originally get into this work in cancer therapies; I wanted to know how T cells worked. So, we then knew that tumors didn’t have the second costimulatory ligand, making them essentially invisible to the immune system.

So the tumors just kept growing. But by then, we realized that when a T cell gets a costimulatory signal, it initiates its natural propensity to kill things. However, at the same time, the costimulatory signal turns on the CTLA-4 gene, which basically initiates an off switch (or inhibitory program), which will eventually stop the T-cell response and let the tumor continue to grow unmolested by the immune system.

After a lot of thinking on this, I realized that since the tumor has had a head start, maybe the CTLA-4–driven program stops the T cell before it can respond effectively with the tumor.

Therefore, setting up a blockade of the CTLA-4 expression, or checkpoint, enhances antitumor T-cell responses and the tumor-rejection process.

Creation of Immune Checkpoint Therapy How did this concept of checkpoint blockade relate to cancer therapy?

Actually it did so in two ways. First,

using a monoclonal antibody therapy doesn’t target the tumor cell specifically but engages a target on the patient’s immune system, giving it the opportunity to have benefit in a wide variety of ­tumors.

Second, this action of not targeting a specific tumor unleashes the immune system by removing the inhibitory pathways. And clinical trials with anti–CTLA-4 showed tumor regression in patients with a host of different tumors, and based largely on this work, the field of immune checkpoint therapy was created.

Raising the Tail of the Survival Curve Do you have any last thoughts on this exciting line of research?

In melanoma, 22% of patients given ipilimumab (Yervoy) are still alive after 10 years, but what about the other 78% of melanoma patients? And what about patients with other tumors?

These are the challenges we are wrestling with daily in the lab. Raising the tail of the survival curve, which is our slogan for getting durable responses and perhaps cures in the largest fraction of our patients, is possible. It’s a huge challenge, but I’m confident it is within reach. n Disclosure: Dr. Allison is a licensor of intellectual property and receives royalties from Bristol Myers-Squibb; is founder, a licensor of intellectual property, and scientific advisory board member of Jounce Therapeutics; is a licensor of intellectual property and receives royalties from Merck; is a founder and scientific advisory board member of Neon Therapeutics; and a scentific advisory board member of Kite Pharmaceuticals.

Don’t Miss These Important Reports in This Issue of The ASCO Post Daniel DeAngelo, MD, PhD, on Pediatric Chemotherapy in Young Adults With ALL see page 24

Lawrence D. Kaplan, MD, on Treatment of HIV-Associated Lymphoma see page 31

Kathleen E. Bickel, MD, MPhil, on ASCO and AAPHM’s Standardization of Primary Palliative Care in Oncology see page 26

William J. Gradishar, MD, on Partnering Endocrine Therapy and Targeted Agents in Estrogen Receptor–Positive Breast Cancer see page 36

Visit The ASCO Post online at ASCOPost.com

Rachelle E. Bernacki, MD, MS, on Goals-of-Care Conversations at the End of Life see page 27

Harold J. Burstein, MD, PhD, on Follow-Up Testing in Breast Cancer Survivors see page 38

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The ASCO Post | DECEMBER 25, 2015

PAGE 94

Book Review

A Primary Care Doctor’s Tough-Love Medicare Fix

By Ronald Piana

“S

everal years ago I decided to write a book about geriatric health-care delivery from the perspective of a practicing (author’s emphasis) primary care physician…. I am a down and dirty doctor living in the trenches; I see patients 5 days a week, often 10 hours a day; while I am on call 24/7 365 days a year, I’m answering messages continuously throughout the day, including immediately before turning off my lights and immediately after turning them on in the morning,” writes Andy Lazris, MD, in the foreword of his self-published book, Curing Medicare: One Doctor’s View of How Our Health Care System Is Failing the Elderly and How to Fix It. Adding to that mind-boggling schedule, the author lets the readers know that he is also medical director for a few longterm care facilities; runs a busy practice; is on his computer day and night and through the weekend, whether preparing weekly talks to nurses and patients or deciphering new Medicare rules, completing notes, or putting his practice’s financial

behavior or sentiment to the ubiquitous “we,” you need data to back up the claim.

Academic quibbling aside, the book’s title, Curing Medicare, lays down a very large gauntlet. Medicare is ailing, but it is here to stay—unless it goes belly-up, as some conservatives predict—and, since it is the single largest payer for cancer patients, all things that might cure Medicare are of interest to the oncology community.

Bookmark

Quality Measures and Guidelines

Publication date: September 13, 2014

Dr. Lazris uses a confrontational style, backed by anecdotal and empirical data, and in his first chapter, “Defining Quality,” he tackles a subject much discussed in the oncology community. The author gives a well-balanced overview of how certain quality-measuring metrics are not generalizable to a heterogeneous elderly population. The ASCO Post readers will find his discussion on clinical guidelines interesting as well as his observations about the value of prostate-specific antigen tests, mammograms, and colonoscopy. And

A large proportion of Medicare patients who undergo screening colonoscopy do so more frequently than recommended. Current Medicare regulations intending to limit reimbursement for screening colonoscopy to every 10 years would not appear to be effective.

—Andy Lazris, MD

house in order. Which begs the question: How did Dr. Lazris squeeze in the time to write and self-publish this book?

Dr. Lazris’ first tried the traditional publishing route, and even though an editor at a major publishing house was interested, before biting she needed an academic reviewer to give the manuscript a read. One did, and then another; both slammed the book, calling it “crass, abrasive, unprofessional, and offensive, the very antithesis of a good academic book…. It reads primarily as a denunciation of the care of the elderly in America.”

That’s subjective criticism leveled by academics, and the problem with the critique of the academics is that Curing Medicare is not an academic book, which is one of its strengths. Here’s an example of what irked his reviewers: Dr. Lazris writes: “This is a book reflective of the brewing anger among us who actually practice geriatric care, those of us who have been trampled on and muffled…perhaps this book is a bit crass, perhaps it may offend.”

Dr. Lazris should know that if you ascribe

while he backs the philosophy behind quality measures and guidelines, he is quick to point out a qualm that is probably shared by doctors across all disciplines.

He writes: “Quality indicators and our fixation with number measurement and number fixing through medicines has led us down a very precarious path…. Once we believe an older person’s health status can be equated to a number, we then assume that the health problems associated with aging can be solved by a guideline, which erodes the art of practicing medicine.”

On Medicare-reimbursed screening, he cites current data, such as on colonoscopy, that find: “A large proportion of Medicare patients who undergo screening colonoscopy do so more frequently than recommended. Current Medicare regulations intending to limit reimbursement for screening colonoscopy to every 10 years would not appear to be effective.”

To his credit, Dr. Lazris acknowledges the merit of government oversight entities, such as the U.S. Preventive Services Task

Title: Curing Medicare: One Doctor’s View of How Our Health Care System Is Failing the Elderly and How to Fix It Author: Andy Lazris, MD Publisher: CreateSpace

Price: $13.75; paperback, 290 pages Force, a committee that comes under constant fire from advocacy groups as well as medical organizations for its conservative outlook on screening services.

Overhospitalization Another subject he takes head on is overhospitalization, driven by our misuse of Medicare’s Part A. Here again is a subject that the oncology community will find interesting. He wades into a thorny political area when he connects the dots between overhospitalization and profit-driven hospitals.

“Studies have found regional variation of care within Medicare populations, in which regions of the country with increased numbers of hospital beds and higher specialist concentrations are more likely to hospitalize the elderly….

These high-spending hospitals will cost Medicare more money per patient without a commensurate benefit in health outcomes,” he writes.

Although it’s an important observation for those concerned about overspending and overutilization of Medicare services, it is not a news flash. It was pointed out more eloquently years ago by the Dartmouth Atlas Project and others.

Fiscal Problems and Solutions Many of Dr. Lazris’ discussions in the first five chapters read like an introduction to the meat of his book, which is the closing chapter, aptly called “Curing Medicare.” The author begins the chapter with a laundry list of Medicare’s profligate spending habits on services that, many times, are unnecessary. There are no missteps in his analysis; however, he doesn’t offer any new revelations that might add deeper insight into Medicare’s fiscal problems.

When he tries to boil a very complex issue down to one culprit of overspend-

ing, it comes off a bit lame. “Currently much of Medicare’s dollars go to the sickest and oldest of our patients, without any proof that such money improves quality or length of life…. Much is spent on endof-life care, where huge expenditures are squandered in situations with tragic outcomes. Why is not the bulk of that reform effort not aimed at reducing that number?”

Herein lies a central problem of this ambitious book. In using phrases like “without any proof,” he will be eviscerated by doctor-reviewers. Moreover, the author does not quantify “that number,” nor does he offer any alternatives to the status quo he’s railing at until chapter six, the denouement of the book.

And there, in some respects, he moves out of the box, offering innovative solutions. He describes a way to decentralize the role of hospitals and specialists, reform malpractice law, enact stricter regulatory oversight, and create strategies to increase the number of primary care doctors. He also scores high marks on his reform plan for the hugely wasteful Medicare Part D drug benefit.

These are all good strategies, but he does go off the rails a bit when he makes a threadbare case for physician-assisted suicide. His most compelling argument is his bid to unify Medicare into a single program. It is a political third rail, but it is worth considering, and Dr. Lazris makes a bold argument for a single-payer system.

Curing Medicare is a flawed book on several levels. For one, the writing needed a good edit, and the tone, at times, is histrionic. That said, Dr. Lazris is a passionate advocate for patients and the system that provides their care. Readers of The ASCO Post should skim through the first five chapters and take a hard look at chapter six. The author doesn’t cure Medicare, but he offers a lot more fixes than most. n

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR TREANDA® (bendamustine hydrochloride) injection, for intravenous use TREANDA® (bendamustine hydrochloride) for injection, for intravenous use 1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

2 DOSAGE AND ADMINISTRATION 2.1 Selection of TREANDA Formulation to Administer TREANDA is available in two formulations, a solution (TREANDA Injection) and a lyophilized powder (TREANDA for Injection).

Do not use TREANDA Injection if you intend to use closed system transfer devices (CSTDs), adapters and syringes containing polycarbonate or acrylonitrilebutadiene-styrene (ABS) prior to dilution in the infusion bag [see Dosage and Administration (2.4)].

If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a polypropylene syringe with a metal needle and polypropylene hub to withdraw and transfer TREANDA Injection into the infusion bag. Polypropylene syringes are translucent in appearance.

TREANDA Injection and the reconstituted TREANDA for Injection have different concentrations of bendamustine hydrochloride. The concentration of bendamustine hydrochloride in the solution is 90 mg/mL and the concentration of bendamustine hydrochloride in the reconstituted solution of lyophilized powder is 5 mg/mL. Do not mix or combine the two formulations.

TREANDA Injection must be withdrawn and transferred for dilution in a biosafety cabinet (BSC) or containment isolator using a polypropylene syringe with a metal needle and a polypropylene hub.

If a CSTD or adapter that contains polycarbonate or ABS is used as supplemental protection prior to dilution, only use TREANDA for Injection, the lyophilized powder formulation [see How Supplied/Storage and Handling (16.1)].

2.2 Dosing Instructions for CLL Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.

Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [see Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle.

Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle.

Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.

2.4 Preparation for Intravenous Administration TREANDA is a cytotoxic drug. Follow applicable special handling and disposal procedures.

TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) TREANDA Injection must be diluted in a biosafety cabinet (BSC) or containment isolator.

• When preparing and transferring the concentrated TREANDA Injection solution into the infusion bag, do not use devices that contain polycarbonate or ABS. However, after dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used. TREANDA Injection contains N,N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices, including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA which is present in the product. This incompatibility leads to device failure (e.g., leaking, breaking, or operational failure of CSTD components), possible product contamination, and potential serious adverse

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

health consequences to the practitioner, including skin reactions; or to the patient, including but not limited to, the risk of small blood vessel blockage if they receive product contaminated with dissolved ABS or polycarbonate. Devices that are compatible for use in dilution of TREANDA Injection are available.

• If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a polypropylene syringe with a metal needle and a polypropylene hub to withdraw and transfer TREANDA Injection into the infusion bag.

• Each vial of TREANDA Injection is intended for single dose only.

• Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution using a polypropylene syringe with a metal needle and a polypropylene hub.

• Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.7 mg/mL. • After dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used.

• Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear colorless to yellow solution.

Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.

TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder) If a closed system transfer device or adapter that contains polycarbonate or ABS is to be used as supplemental protection during preparation, only use TREANDA for Injection, the lyophilized formulation.

• Each vial of TREANDA for Injection is intended for single dose only.

• Aseptically reconstitute each TREANDA for Injection vial as follows: ◦ 25 mg TREANDA for Injection vial: Add 5 mL of only Sterile Water for Injection, USP. ◦ 100 mg TREANDA for Injection vial: Add 20 mL of only Sterile Water for Injection, USP. • Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. If particulate matter is observed, the reconstituted product should not be used.

• Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag.

• Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear and colorless to slightly yellow solution.

Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.

General Information Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.

2.5 Admixture Stability TREANDA Injection and TREANDA for Injection contain no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.

TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature (15°-30°C or 59°86°F) and room light. Administration of diluted TREANDA Injection must be completed within this period.

TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder) Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (3647°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of reconstituted and diluted TREANDA for Injection must be completed within this period.

4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [see Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4).

Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [see Dosage and Administration (2. 2)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.

5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].

5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports,

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents.

In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes.

The relationship to TREANDA cannot be determined.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.

5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Chronic Lymphocytic Leukemia The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days.

Adverse reactions were reported according to NCI CTC v.2.0. Non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).

Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis.

Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved.

The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%).

Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class All Grade All Grade Preferred term Grades 3/4 Grades 3/4 Total number of 121 (79) 52 (34) 96 (67) 25 (17) patients with at least 1 adverse reaction Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class All Grade All Grade Preferred term Grades 3/4 Grades 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study Laboratory TREANDA Chlorambucil Abnormality N=150 N=141 All Grade All Grade Grades 3/4 Grades 3/4 n (%) n (%) n (%) n (%) Hemoglobin 134 (89) 20 (13) 115 (82) 12 (9) Decreased Platelets 116 (77) 16 (11) 110 (78) 14 (10) Decreased Leukocytes 92 (61) 42 (28) 26 (18) 4 (3) Decreased Lymphocytes 102 (68) 70 (47) 27 (19) 6 (4) Decreased Neutrophils 113 (75) 65 (43) 86 (61) 30 (21) Decreased In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis.

Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [see Warnings and Precautions (5.5)]

7 DRUG INTERACTIONS No formal clinical assessments of pharmacokinetic drug-drug interactions between TREANDA and other drugs have been conducted.

Bendamustine’s active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma concentrations of bendamustine and decrease plasma concentrations of active metabolites.

Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites. Caution should be used, or alternative treatments considered if concomitant treatment with CYP1A2 inhibitors or inducers is needed.

The role of active transport systems in bendamustine distribution has not been fully evaluated. In vitro data suggest that P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may have a role in bendamustine transport.

Based on in vitro data, bendamustine is not likely to inhibit metabolism via human CYP isoenzymes CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or to induce metabolism of substrates of cytochrome P450 enzymes.

8.6 Renal Impairment No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild or moderate renal impairment. TREANDA should not be used in patients with CrCL < 40 mL/min.

8.7 Hepatic Impairment No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild hepatic impairment. TREANDA should not be used in patients with moderate (AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 X ULN) or severe (total bilirubin > 3 X ULN) hepatic impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal TREANDA is a cytotoxic drug. Follow applicable special handling and disposal procedures. Care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection and TREANDA for Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If gloves come in contact with TREANDA Injection prior to dilution, remove gloves and follow disposal procedures. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water.

16.3 Storage TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) TREANDA Injection must be stored refrigerated between 2°-8°C (36°-46°F). Retain in original package until time of use to protect from light.

TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder) TREANDA for Injection may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2015 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates.

All rights reserved.

Brief Summary of TREANDA Prescribing Information TRE-011

TRE-40554

The ASCO Post | DECEMBER 25, 2015

PAGE 98

Expert’s Corner Hematology

Acute Myeloid Leukemia in the Elderly: Trial Data Stir Hope for the Transplant Option

By Caroline McNeil

O

lder patients with acute myeloid leukemia (AML) have high relapse rates after induction chemotherapy, low survival rates, and fewer treatment options compared with younger patients. One of the options for both younger and older patients is hematopoietic cell transplantation, but relatively few older patients undergo this potentially curative treatment for a variety of reasons.

Now, the first prospective, multicenter trial of transplants in selected older AML patients may prompt more consideration of this option. The trial has supported the findings of smaller, retrospective studies showing that a modified, less aggressive transplant regimen in the elderly appears to significantly improve survival. Two

the modified transplant regimen for those who are eligible, either on or off trial.

“I still don’t know which is better, but the data are intriguing and changing in favor for transplant,” said Syed A. Abutalib, MD, Assistant Director, Stem Cell Transplant & Cell Therapy, at the Midwestern Regional Medical Center, Cancer Treatment Centers of America, commenting on the cooperative group study. “Transplant is a solid option.”

In younger patients with AML, transplant involves high-dose chemotherapy to condition the bone marrow, ie, eradicate leukemia cells, before infusing the body with healthy donor stem cells. In younger patients, these stem cells can be autolo-

—Steven M. Devine, MD

gous, derived from the patient’s own marrow, or allogeneic, ie, from healthy donor stem cells. Both the high-dose conditioning regimen and the allotransplant procedure are risky for patients aged 60 years and older. But starting in the early 2000s, small studies began to suggest that with reduced-intensity conditioning and allogeneic donors, fit older patients could tolerate and benefit from transplants. Based on those findings, the clinical guidelines of the National Comprehensive Cancer Network now recommend that patients aged 60 and older, “who are deemed strong candidates for stem cell transplant and have an available donor should be transplanted in first remission.”2 Oncologists and their older patients have not flocked to the transplant option, however. The potential toxicity of even reduced-intensity conditioning and the difficulty of knowing which patients are “strong candidates” for transplant are two related and important reasons. Other factors—medical, logistical, financial, and social—also come into play.

“It’s a difficult discussion,” said Harry P. Erba, MD, PhD, Professor of Medicine and Director of the Hematologic

kemia-free survival rate at 8 years was 32% on the transplant arm compared to 13% on the chemotherapy arm.

Other transplant trials in older AML patients, listed in the National Institutes of Health database, clinicaltrials.gov, are underway in the United States and Europe.

Issues in Decision-Making

Slow Increase in Use

We need to understand more about how the mutational status of a patient with AML determines response to various therapies including transplantation.

years after first complete remission in this nonrandomized phase II trial, survival rates were over 40%—twice as high as expected based on historical data.

We have shown this to be “an effective strategy for suitable older patients with an available matched donor,” concluded the authors, led by Steven M. Devine, MD, who directs the Blood and Marrow Transplant Program at the James Comprehensive Cancer Center, The Ohio State University. Carried out jointly by the Blood and Marrow Transplant Clinical Trials Network and the Transplant Committee of the Cancer and Leukemia Group B (CALGB)—now the Alliance for Clinical Trials in Oncology—the study was recently published in the Journal of Clinical Oncology.1 The new data could play a role in the crucial decision-making process that comes in AML once the patient has had induction therapy and reached first complete remission. At this point, physicians and their older AML patients have several general options to consider, including standard consolidation chemotherapy; a trial of one of the many new and combination chemotherapies under study; or

Malignancy Program at the University of Alabama, Birmingham (UAB). “There are many factors to consider other than outcomes data from clinical trials.”

Syed A. Abutalib, MD

Possibly because of these uncertainties and concerns, relatively few transplants take place in older AML patients.

The number has risen somewhat since 2000, according to data from the Center for International Blood and Marrow Transplant Research. But it has been estimated that only an estimated 6% of the elderly patients diagnosed with AML each year undergo transplants.3

Transplant Trials The CALGB trial enrolled 114 patients between the ages of 60 and 74 years with a median age of 65. All patients were in first complete remission after induction therapy, and all received reduced-intensity conditioning (fludarabine followed by busulfan [Busulfex]), at half the strength used in younger patients. The transplanted hematopoietic cells were from HLA-matched related or unrelated donors. Patients also took tacrolimus and methotrexate to help reduce the risk of graft-vs-host disease.

Two years after transplant, 42% of patients were cancer-free, an apparent improvement compared to only about 20% of similar patients who had received consolidation chemotherapy in prior CALGB trials.

The trial’s results are bolstered by preliminary findings from a larger, randomized trial, the AML 2004 East German Study Group (OSHO) trial, presented in abstract form⁴ at the 2014 American Society of Hematology Annual Meeting and Exhibition by Dietger Niederwieser, MD, of the University of Leipzig. In that phase III trial, the relapse rate at 2 years was 79% in older AML patients who received consolidation chemotherapy vs 40% in those who received a transplant after first complete remission. The leu-

While clinicians and their older AML patients now have more data to use when considering a transplant, issues remain.

“When I talk to my patients, I tell them that the chance of relapse appears to be lower with transplant than with any other postremission option,” said Dr. Erba. “But it is also clear that the magnitude of the benefit is greatest in specific subsets of patients. So we look at other factors.”

One of those factors is age. A key message from the CALGB trial is that physiologic age is more important than chronologic age when deciding about transplant, Dr. Devine said. “We consider patients for transplant even in their 70s if they have a reasonable performance status and are reasonably fit,” he said.

But how to determine reasonable fitness is still a gray area. A high ECOG performance score is often used along with an assessment of comorbidities. Some programs are exploring supplementary methods, such as frailty assessments and/ or using surveys done in the clinic during appointments, Dr. Devine said.

None of these approaches is completely reliable, however, and patient selection is “always a big issue,” he said. “In future trials,” he added, “we need to look at how to do a better job of assessing fitness.”

Prognostic Markers Also important in selecting patients for transplant are prognostic biomarkers. Patients with core binding factor (CBF) translocations, for instance, are at lower risk for relapse and therefore

Dietger Niederwieser, MD

ASCOPost.com | DECEMBER 25, 2015

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Expert’s Corner

may not need a transplant in first remission. This is particularly true if they also do not have the molecular markers that have been associated with a worse prognosis, such as the FLT3 or KIT mutation. Furthermore, patients with translocation 8;21 and inversion 16 are particularly sensitive to chemotherapy and often respond to salvage therapy at the time of relapse.

“The leukemia doctor will consider such prognostic biomarkers, assessing the patient’s chances of a cure with chemotherapy or the need for a transplant,” said Dr. Erba.

These and other biomarkers are expected to play an increasingly larger role. “We need to understand more about how the mutational status of a patient with AML determines response to various therapies including transplantation,” said Dr. Devine. “That is, certain patients may do better with transplant vs conventional therapy, and certain patients may not even do well with transplant and require novel approaches.”

identification of donors—can stretch over several months. Ideally, the search for a donor should begin early, while induction therapy is still underway, say experts.

“A strong message from [the CALGB study] is that patients should be considered for transplant early in the course of the disease to determine if they are potential candidates,” said Dr. Devine.

And transplant and leukemia doctors should cooperate early in that process, Dr. Abutalib said.

That is less an issue in large medical centers with active transplant programs, such as UAB. “When we admit a patient who is a potential transplant recipient,”

When I talk to my patients, I tell them that the chance of relapse appears to be lower with transplant than with any other postremission option. But it is also clear that the magnitude of the benefit is greatest in specific subsets of patients. So we look at other factors.

Logistics Other issues that can affect the choice of transplantation are logistical. One of them is the need to find a matched, allogeneic donor. The ­CALGB study originally was limited to sibling donors, but the protocol was changed as it became clear that among elderly patients, sibling donors were often not available. Accrual rates rose when the protocol was amended to allow unrelated donors, and in the final results, there were no significant differences in outcomes between patients with related and unrelated donors.

The transplant field has recently developed alternative sources, including cord blood and haploidentical donors. As a result, said Dr. Erba, “a suitable donor can be found for most AML patients.”

But it still takes time, and the entire process—initiation of HLA typing and

At UAB, for instance, there are many uninsured patients, Dr. Erba said. “We scramble to get them Medicaid or charity care, but it takes time, and time is of the essence.”

Perhaps even more difficult for some potential transplant patients is the requirement that they have a caregiver at home, 24 hours a day, 7 days a week, for at least 3 months after coming home from the hospital.

Transplant patients are at high risk for graft-vs-host disease, and opportunistic infections during this period have to be monitored closely. But many elderly patients live alone or with a

—Harry P. Erba, MD, PhD

said Dr. Erba, “we do HLA typing and have them seen by the transplant team.

If I have a patient who is a potential candidate for transplant, I get the transplant team involved as soon as possible.”

But in community cancer centers, the patient may not be referred to a transplant center for evaluation until after remission. This delay can reduce the chances of finding a donor in time, since remissions after induction therapy are often brief, especially in older patients.

Social Issues There are also a variety of social issues that potential transplant patients, along with families and physicians, have to consider. One of these is insurance.

partner with other health problems; their families may be geographically scattered. Without a suitable caregiver, transplant is not an option.

“Finally, quality-of-life issues should always be part of these discussions with patients,” Dr. Erba said. “I tell my fellows that they should understand the goals of their patients for this time of their lives.” Patients who are deciding between chemotherapy and transplant have to weigh the chance of cure vs the impact of treatment in terms of their own goals. “If they want to live to see a baby born, due in 6 months, then chemotherapy might be the best choice. If it’s most important to them to see a grandson graduate from col-

lege 6 years from now, they might opt for the transplant.”

Despite the numerous factors that make the decision a complex one, researchers are buoyed by the new data and the prospect of more.

Looking forward, one important area of research is maintenance of remission, Dr. Devine said. Although consolidation chemotherapies and transplants prolong remission, most patients relapse eventually. So development of candidate maintenance therapies is an urgent need.

“One of my hopes is that we can work collaboratively with our leukemia colleagues on a trial of strategies to further reduce relapse rates,” he said. n

Disclosure: Dr. Devine has received research funding from Genzyme. Drs. Abutalib, Erba, and Niederwieser reported no potential conflicts of interest.

References 1. Devine SM, Owzar K, Blum W, et al: Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen. J Clin Oncol 33:4167-4175, 2015.

2. National Comprehensive Cancer Network: Acute myeloid leukemia, version 1.2015. Available at www.nccn.org. Accessed December 11, 2015.

3. Ustun C, Lazarus HM, Weisdorf D: To transplant or not: A dilemma for treatment of elderly AML patients in the twenty-first century. Bone Marrow Transplant 48:1497-1505, 2013.

4. Niederwieser D, Al-Ali HK, Krahl R, et al: Higher leukemia free survival after post-induction hematopoietic cell transplantation compared to consolidation therapy in patients >60 years with acute myelogenous leukemia (AML): Report from the AML 2004 East German Study Group (OSHO). 2014 ASH Annual Meeting. Abstract 280. Presented December 8, 2014.

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The ASCO Post | DECEMBER 25, 2015

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Announcements

2015 NCI Outstanding Investigator Award Recipients

T

he first class of National Cancer Institute (NCI) Outstanding Investigator Award recipients showcases the cutting edge of oncologic research and the 43 investigators behind it.

NCI’s Outstanding Investigator Award supports accomplished leaders in cancer research, who are providing significant contributions toward understanding cancer and developing applications that may lead to a breakthrough in biomedical, behavioral, or clinical cancer research. The Award provides up to $600,000 in direct costs per year for 7 years, allowing substantial time for funded investigators to take greater risks and be more adventurous in their research.

Below is the complete list of 2015 recipients:

tional programs critical for p53-mediated suppression of pancreatic cancer.

erogeneity drives tumor progression and emergence of drug resistance.

Michael Fiore, MD, PhD, MPH, MBA

Darrell Bigner, MD, PhD

Simon R. Cherry, PhD

Michael Fiore, MD, PhD, MPH, MBA

Darrell Bigner, MD, PhD

Simon R. Cherry, PhD

Director, The Preston Robert Tisch Brain Tumor Center at Duke University Research focus: Oncolytic polovirus, immunotoxin, and checkpoint inhibitor therapy of gliomas. Intended outcome will represent paradigm shifts in glioblastoma multiforme cells, with treatment resulting in significant increases in high quality of life and overall survival.

Distinguished Professor, Departments of Biomedical Engineering and Radiology, University of California, Davis Research focus: Discovering new opportunities for cancer imaging and cancer therapy based on radiation and photonics.

Professor of Medicine, University of Wisconsin-Madison Research focus: electronic health records and using groundbreaking research methods to reengineer healthcare delivery systems to efficiently organize and deliver state-of-the-art treatment to smokers visiting primary care settings.

Craig Crews, PhD

Levi Garraway, MD, PhD

Steven Artandi, MD, PhD

Steven Artandi, MD, PhD Professor of Medicine (Hematology) and Biochemistry, Stanford University Research focus: Addressing the target cell populations from which cancers emerge—the cell of origin—and determining how these early beginnings are linked to one of the most fundamental properties of cancer cells: the acquisition of immortal proliferative properties.

John C. Byrd, MD

John C. Byrd, MD Professor of Medicine and D. Warren Brown Chair of Leukemia Research, The Ohio State University Research focus: Exploring basic and translational biologic questions to develop novel immunologic and targeted therapies for acute myeloid leukemia and chronic lymphocytic leukemia.

Craig Crews, PhD

Levi Garraway, MD, PhD

Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology, Yale University Research focus: Contributing toward developing the new field of “controlled proteostasis” and helping to develop the Proteolysis Targeting Chimerae (PROTACs) technology further to target truly undruggable proteins that are key oncogenic drivers.

Associate Professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute Research focus: Researching the spectrum of resistance mechanisms for any given cancer therapeutic modality, which could coalesce onto a much smaller set of critical downstream effects or “nodes.” Focus on discerning the mechanisms operating within these “points of coalescence” to yield new insights into oncogenic dependencies and illuminate guiding principles for the design of novel therapeutic combinations.

Laura D. Attardi, PhD

Laura D. Attardi, PhD Professor, Departments of Radiation Oncology and Genetics, Stanford University School of Medicine Research focus: Deconstructing the transcriptional programs through which wild-type p53 suppresses cancer and through which missense mutant p53 exerts gain of function effects to promote cancer; and using integrated genetic, genomic, cell biologic, and biochemical approaches to define the p53 transcrip-

Carlo Croce, MD Andrea Califano, PhD

Andrea Califano, PhD Clyde and Helen Wu Professor of Chemical Systems Biology, Columbia University Medical Center Research focus: Developing a novel methodologic framework integrating both experimental and computational approaches to systematically elucidate the mechanisms by which tumor het-

Carlo Croce, MD Chair of the Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Medical Center Research focus: Identifying genetic and genomic alterations that cause human cancer in order to develop novel targeted treatments for different human tumors.

Jean Gautier, PhD

Jean Gautier, PhD Professor of Genetics and Development, Columbia University Medical Center Research focus: Building a map of protein-protein interactions for repair factors common to multiple repair

ASCOPost.com | DECEMBER 25, 2015

PAGE 105

Announcements

pathways and identifying protein-protein interactions that are specifically enhanced or reduced following treatment.

molecular biology in partnership with strong translational collaborations to identify new biomarkers, developing effective interventions to break obesitycancer links, and reducing the burden of obesity-associated cancer.

mutational mechanisms and new genes in extended kindreds severely affected by breast or ovarian cancer with normal sequences of all known breast and ovarian cancer genes.

western University Feinberg School of Medicine Research focus: Therapeutic targeting of malignant glioma stem cells, guided by the hypothesis that novel nonviral gene therapies can be designed to arrest these cells’ fate in gliomas by suppressing the master neurodevelopmental transcriptional factors that control these cells’ phenotypes.

Amato Giaccia, PhD

Amato Giaccia, PhD Professor of Radiation Oncology, Stanford University Research focus: Exploring the molecular mechanisms governing lipid homeostasis in cancer, characterizing their contribution to tumorigenesis, and identifying ways that they can be therapeutically targeted in solid tumors.

Hartmut Land, PhD Rakesh K. Jain, PhD

Rakesh K. Jain, PhD A.W. Cook Professor of Tumor Biology (Radiation Oncology) and Director, Edwin L. Steele Laboratory for Tumor Biology, Massachusetts General Hospital and Harvard Medical School Research focus: Dissecting the microenvironment of pediatric brain tumors with the goal of improving existing therapies and developing new ones, using powerful, noninvasive, high-resolution imaging technologies.

Hartmut Land, PhD Chairman of the Department of Biomedical Genetics, Director of Research, and Codirector of the Wilmot Cancer Institute, University of Rochester Medical Center Research focus: Exploring the hypothesis that cooperation response genes are critical to sustaining core features of a malignant phenotype shared between diverse cancers and identifying key regulatory pathways and circuits related to the activity of these genes that control cancer cell homeostasis.

Kun-Liang Guan, PhD

Kun-Liang Guan, PhD Distinguished Professor in the Department of Pharmacology, University of California, San Diego Research focus: Obtaining a comprehensive molecular understanding of the mTORC1 and Hippo pathways under normal physiologic conditions and elucidating how dysregulation of these pathways contributes to tumorigenesis.

Timothy Ley, MD Lewis T. and Rosalind B. Apple Professor of Oncology in the Department of Medicine, Washington University in St. Louis Research focus: Exploring the hypothesis that a complete understanding of the consequences of initiating mutations is required to fully understand acute myeloid leukemia (AML) pathogenesis and focusing on the therapeutic approaches against initiating mutations with the potential of providing long-term benefits for patients with AML.

Thomas Kensler, PhD

Thomas Kensler, PhD Professor in the Department of Pharmacology and Chemical Biology, University of Pittsburgh Research focus: Chemoprevention, which may offer practical opportunities to reduce risks associated with “unavoidable” or largely intractable exposures, using natural products that target the Nrf2 cytoprotective pathway.

Caryn Lerman, PhD

Caryn Lerman, PhD Mary W. Calkins Professor of Psychiatry, Deputy Director of the Abramson Cancer Center, University of Pennsylvania Research focus: Merging concepts and tools from the fields of cognitive neuroscience and behavioral science to develop and evaluate novel neuroscience-based interventions to promote sustainable behavior change for cancer prevention.

Stephen Hursting, PhD, MPH

Stephen Hursting, PhD, MPH Professor in the Department of Nutrition and Nutrition Research Institute; Director of the Division of Nutritional Biochemistry; member of the UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill Research focus: Utilizing a transdisciplinary approach combining wellcharacterized preclinical models with expertise in nutrition, metabolism, and

Timothy Ley, MD

Mary-Claire King, PhD

Mary-Claire King, PhD Professor of Genome Sciences and of Medicine (Medical Genetics), University of Washington Research focus: Discovering new

Maciej Lesniak, MD

Maciej Lesniak, MD Professor and Chair of the Department of Neurological Surgery, North-

Xihong Lin, PhD

Xihong Lin, PhD Chair and Henry Pickering Walcott Professor of Biostatistics and Professor of Statistics, Harvard T.H. Chan School of Public Health and Harvard Faculty of Arts and Sciences Research focus: Developing and applying statistical and computational methods for analysis of whole-genome sequencing association studies; investigation of gene-environment interactions; integrative analysis; risk prediction using genetic, genomic, and environmental data; and analysis of large administrative databases, to advance genetic and genomic epidemiology, precision prevention, and precision medicine for cancer. continued on page 106

The ASCO Post | DECEMBER 25, 2015

PAGE 106

Announcements NCI Award Recipients continued from page 105

signaling network (the PI3K-mTOR network), focusing on the critical role of this network in influencing the sensitivity and resistance of tumors to targeted cancer therapies and in tumor cell metabolism.

Research focus: Developing strategies to enhance the antitumor activity of endogenous natural killer cells in patients with solid tumor malignancies and developing off-the-shelf reagents to activate these cells, overcome inhibitory receptor signaling, and target them to specific tumor ­antigens.

Marcus Peter, PhD

Marcus Peter, PhD Ian Macara, PhD

Ian Macara, PhD Chair of the Cell & Developmental Biology Department, Vanderbilt University Research focus: Understanding how cell context determines phenotype, and determining the roles of mitotic spindle misorientation in cancer initiation, tumor suppression by myoepithelial cells, and subversion of mechanical tension signaling by breast cancer cells.

Joshua Mendell, MD, PhD

Joshua Mendell, MD, PhD Professor in the Molecular Biology Department, University of Texas Southwestern Medical Center Research focus: Analyzing miRNA functions in normal physiology and cancer in vivo; investigating the regulation of miRNA processing in normal development and tumorigenesis; elucidating lncRNA functions in normal physiology and cancer; and application of CRISPR-based genomic editing to illuminate noncoding RNA functions in cells and animals and to discover and validate novel regulators of malignancy-associated phenotypes.

Jeanne Mandelblatt, MD, MPH

Jeanne Mandelblatt, MD, MPH Associate Director for Population Sciences at the Lombardi Comprehensive Cancer Center, Georgetown University Research focus: Using a biobehavioral framework to conduct population sciences research at the intersection of cancer and aging. Focus on shifting the paradigms of research and care for the growing older population; determining whether biologic age markers can identify survivors at greatest risk for functional declines; informing future intervention trials; and expanding the limited number of cancer and aging researchers.

Professor of Genetics and Complex Diseases, Harvard School of Public Health Research focus: Defining the wiring and functions of a nutrient-sensing

Shuji Ogino, MD, PhD, MS Professor of Pathology and Professor in the Department of Epidemiology, DanaFarber Cancer Institute Research focus: Conducting molecular pathologic epidemiology (MPE) research on colorectal cancer omics, intratumor heterogeneity, and immunity, to gain insights on roles of environmental, diet, lifestyle, and genetic factors; grow the International MPE Meeting Series with a goal of making “the STROBE-MPE guideline”; and build new integrative interdisciplinary models including causal inference-MPE, immuno-MPE, socialMPE, and MPE-health communication research.

Kornelia Polyak, MD, PhD

Kornelia Polyak, MD, PhD Professor of Medicine and Medical Oncology, Dana-Farber Cancer Institute Research focus: Exploring the hypothesis that clonal heterogeneity within tumors drives metastatic progression and therapeutic resistance, which could improve the clinical management of patients with breast cancer.

Matthew Meyerson, MD, PhD

Matthew Meyerson, MD, PhD Professor of Pathology, Dana-Farber Cancer Institute Research focus: Understanding the mechanism of how significant alterations in the DNA of lung cancers— such as loss or gain of chromosomes, genetic mutations, and genomic amplification—cause the disease.

Brendan D. Manning, PhD

Brendan D. Manning, PhD

Shuji Ogino, MD, PhD, MS

Professor in Medicine-Hematology/ Oncology, Northwestern University Feinberg School of Medicine Research focus: Researching death induced by CD95R/L elimination, its mechanisms, related mechanisms, and the development of a novel form of cancer therapy that is based on targeting tumor suppressors rather than oncogenes.

Jeffrey Miller, MD

Paolo Pier Pandolfi, MD, PhD

Paolo Pier Pandolfi, MD, PhD Director of the Cancer Center and Cancer Research Institute, Beth Israel Deaconess Medical Center Research focus: Contributing to the study of critical cancer genes as paradigms for tumor suppression, through the development of a second generation of models and tools in order to explore how they function in leukemia and other cancers and to develop and test new cancer therapies.

Tannishtha Reya, PhD

Tannishtha Reya, PhD Professor in the Departments of Pharmacology and Medicine, University of California, San Diego Research focus: Combining strategies for the design of early detection tools with an understanding of cancer progression from benign lesions to a malignant state, enabling development of new therapies that can be delivered early in disease.

Jeffrey Miller, MD Deputy Director, Masonic Cancer Center, University of Minnesota

continued on page 111

Image not intended to depict total daily dose. Number of tablets may vary depending on prescribed dose. Tablets shown are not actual size.

Introducing

NOW APPROVED Please see Important Safety Information and brief summary of Prescribing Information on the following pages.

The ASCO Post | DECEMBER 25, 2015

PAGE 108

Announcements LARGE TRIM: 8.125” BLEED:8.5”

ASH Honors Baseball Hall of Famer With Outstanding Service Award SMALL TRIM:7.875”

T

he American Society of Hematology (ASH) recognized Rod Carew, Baseball Hall of Famer and Advocate for the National Marrow Donor Program (NMDP)/Be the Match, at the 57th ASH Annual Meeting and Exposition in Orlando, Flori-

SAFETY:6.875”

da, for his outstanding support of biomedical research and the practice of hematology.

Rod Carew received the 2015 ASH Outstanding Service Award, an honor recognizing effective “behindthe-scenes” leadership in areas rele-

Rod Carew

vant to the mission of the Society, for his efforts to raise public awareness about the need for volunteer bone marrow donors.

After his daughter was diagnosed with acute myeloid leukemia in 1995 at the age of 17, Mr. Carew began

NOW APPROVED Indication LONSURF® (trifluridine and tipiracil) is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild type, an anti-EGFR therapy.

Important Safety Information WARNINGS AND PRECAUTIONS Severe Myelosuppression: In Study 1, LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%), and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF-treated patients received granulocyte-colony stimulating factors.

Obtain complete blood counts prior to and on day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery, resume LONSURF at a reduced dose.

Embryo-Fetal Toxicity: LONSURF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. USE IN SPECIFIC POPULATIONS Lactation: It is not known whether LONSURF or its metabolites are present in human milk. There are no data to assess the effects of LONSURF or its metabolites on the breast-fed infant or the effects on milk production. Because of the potential for serious adverse reactions in breast-fed infants, advise women not to breast-feed during treatment with LONSURF and for 1 day following the final dose.

Male Contraception: Advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose.

Geriatric Use: Grade 3 or 4 neutropenia and thrombocytopenia and Grade 3 anemia occurred more commonly in patients 65 years or older who received LONSURF. Renal Impairment: Patients with moderate renal impairment may require dose modifications for increased toxicity. No patients with severe renal impairment were enrolled in Study 1.

Hepatic Impairment: Patients with moderate or severe hepatic impairment were not enrolled in Study 1.

ADVERSE REACTIONS Most Common Adverse Drug Reactions in Patients Treated With LONSURF (≥5%): The most common adverse drug reactions in LONSURF-treated patients vs placebo-treated patients with refractory mCRC, respectively, were asthenia/fatigue (52% vs 35%), nausea (48% vs 24%), decreased appetite (39% vs 29%), diarrhea (32% vs 12%), vomiting (28% vs 14%), abdominal pain (21% vs 18%), pyrexia (19% vs 14%), stomatitis (8% vs 6%), dysgeusia (7% vs 2%), and alopecia (7% vs 1%).

Additional Important Adverse Drug Reactions: The following occurred more frequently in LONSURF-treated patients compared to placebo: infections (27% vs 15%) and pulmonary emboli (2% vs 0%).

Interstitial lung disease (0.2%), including fatalities, has been reported in clinical studies and clinical practice settings in Asia.

Laboratory Test Abnormalities in Patients Treated With LONSURF: Laboratory test abnormalities in LONSURF-treated patients vs placebo-treated patients with refractory mCRC, respectively, were anemia (77% vs 33%), neutropenia (67% vs 1%), and thrombocytopenia (42% vs 8%).

Please see brief summary of Prescribing Information on the following pages.

Learn more at LONSURFhcp.com/new

© TAIHO ONCOLOGY, INC.

09/2015

All rights reserved.

LON-PM-US-0035

ASCOPost.com | DECEMBER 25, 2015

PAGE 109

Announcements LARGE TRIM: 8.125” BLEED:8.5”

to work tirelessly to find a matched donor for his daughter so she could receive a potentially curative bone marrow transplant. In doing so, he raised national awareness about the need for marrow donors. Since then, Mr. Carew’s work with NMDP/Be the Match and Be the Match Foundation has inspired hundreds of thou-

SMALL TRIM:7.875” people to join

sands of the registry SAFETY:6.875” and increased minority enrollment.

Mr. Carew has also helped to raise millions of dollars to support the Pediatric Research Foundation over the past 20 years through the Rod Carew Children’s Cancer Golf Classic as well as other fundraising efforts. n

LONSURF (trifluridine and tipiracil) tablets, for oral use Initial U.S. Approval: 2015 Brief Summary of Prescribing Information For complete Prescribing Information, consult official package insert.

The ASCO Post Wants to Hear From You

LONSURF (N=533)

Adverse Reactions

All Grades

Placebo (N=265)

Grades 3-4* All Grades

Gastrointestinal disorders

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Severe Myelosuppression In Study 1, LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%) and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF-treated patients received granulocyte-colony stimulating factors.

General disorders and administration site conditions

5.2 Embryo-Fetal Toxicity Based on animal studies and its mechanism of action, LONSURF can cause fetal harm when administered to a pregnant woman. Trifluridine/tipiracil caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when orally administered during gestation at dose levels resulting in exposures lower than those achieved at the recommended dose of 35 mg/m2 twice daily.

In Study 1, 3.6% of patients discontinued LONSURF for an adverse event and 13.7% of patients required a dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.

2%

24%

1%

32%

3%

12%

<1%

Vomiting

28%

2%

14%

<1%

Abdominal pain

21%

2%

18%

4%

Stomatitis

8%

<1%

6%

0%

Asthenia/fatigue

52%

7%

35%

9%

Pyrexia

19%

1%

14%

<1%

4%

29%

5%

0%

2%

0%

1%

0%

Metabolism and nutrition disorders Decreased appetite

39%

Nervous system disorders Dysgeusia

7%

Skin and subcutaneous tissue disorders Alopecia

7%

0%

*No Grade 4 definition for nausea, abdominal pain, or fatigue in National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.

Table 2 Laboratory Test Abnormalities LONSURF (N=533*) Laboratory Parameter

Placebo (N=265*)

Grade† All %

3 %

Grade† 4 %

All %

3 %

4 % N/A

Blood and lymphatic system disorders Anemia‡

77

18

N/A#

33

3

Neutropenia

67

27

11

1

0

0

Thrombocytopenia

42

5

1

8

<1

<1

*% based on number of patients with post-baseline samples, which may be less than 533 (LONSURF) or 265 (placebo) Terminology Criteria for Adverse Events (CTCAE), v4.03 ‡ Anemia: No Grade 4 definition for these laboratory parameters in CTCAE, v4.03 # One Grade 4 anemia adverse reaction based on clinical criteria was reported † Common

In Study 1, infections occurred more frequently in LONSURF-treated patients (27%) compared to those receiving placebo (15%). The most commonly reported infections which occurred more frequently in LONSURF-treated patients were nasopharyngitis (4% versus 2%), and urinary tract infections (4% versus 2%).

In Study 1, pulmonary emboli occurred more frequently in LONSURFtreatment patients (2%) compared to no patients on placebo.

Additional Clinical Experience Interstitial lung disease was reported in fifteen (0.2%) patients, three of which were fatal, among approximately 7,000 patients exposed to LONSURF in clinical studies and clinical practice settings in Asia.

7 DRUG INTERACTIONS No pharmacokinetic drug-drug interaction studies have been conducted with LONSURF. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, LONSURF can cause fetal harm. LONSURF caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when given during gestation at doses resulting in exposures lower than or similar to exposures at the recommended dose in humans. [see Data] There are no available data on LONSURF exposure in pregnant women. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

LARGE TRIM: 10.875”

The most common adverse drug reactions or laboratory abnormalities (all Grades and greater than or equal to 10% in incidence) in patients treated with LONSURF at a rate that exceeds the rate in patients receiving placebo were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.

48%

Diarrhea

BLEED:11.25”

The data described below are from Study 1, a randomized (2:1), doubleblind, placebo-controlled trial in which 533 patients (median age 63 years; 61% men; 57% White, 35% Asian, 1% Black) with previously treated metastatic colorectal cancer received LONSURF as a single agent at a dose of 35 mg/m2/dose administered twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. The mean duration of LONSURF therapy was 12.7 weeks.

Nausea

SAFETY:9.5”

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Grades 3-4*

SMALL TRIM:10.5”

LARGE TRIM: 10.875”

BLEED:11.25”

SAFETY:9.5”

SMALL TRIM:10.5”

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1) in the full Prescribing Information]

Write to The ASCO Post at editor@ASCOPost.com

Table 1 Per Patient Incidence of Adverse Drug Reactions (≥5%) in Study 1 Occurring More Commonly (>2%) than in Patients Receiving Placebo.

1 INDICATIONS AND USAGE LONSURF is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

Obtain complete blood counts prior to and on Day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery resume LONSURF at a reduced dose. [see Dosage and Administration (2.2) in the full Prescribing Information]

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

The ASCO Post | DECEMBER 25, 2015

PAGE 110

Announcements LARGE TRIM: 8.125” BLEED:8.5”

ASH Awards Inaugural Giuseppe Bigi Memorial Award in Hematopoiesis and Stem Cells to Marilena Ciciarello, PhD SMALL TRIM:7.875” SAFETY:6.875”

T

he American Society of Hematology (ASH) named Marilena Ciciarello, PhD, of the University of Bologna, the inaugural recipient of the ASH Giuseppe Bigi Memorial Award

for Achievement in Hematopoiesis and Stem Cells for her research on the role of stem cells in leukemia initiation and progression. This award is the result of a new partnership between ASH and the

8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of LONSURF. In Study 1, patients with moderate renal impairment (CLcr = 30 to 59 mL/min, n= 47) had a higher incidence (difference of at least 5%) of ≥ Grade 3 adverse events, serious adverse events, and dose delays and reductions compared to patients with normal renal function (CLcr ≥ 90 mL/min, n= 306) or patients with mild renal impairment (CLcr = 60 to 89 mL/min, n= 178).

No dose adjustment to the starting dose of LONSURF is recommended in patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min); however patients with moderate renal impairment may require dose modification for increased toxicity. No patients with severe renal impairment (CLcr < 30 mL/min) were enrolled in Study 1. [ see Clinical Pharmacology (12.3) in the full Prescribing Information] 8.8 Ethnicity There were no clinically meaningful differences in Study 1 between Western and Asian subgroups with respect to overall incidence of adverse events or ≥ Grade 3 adverse events in either the LONSURF or placebo groups.

10 OVERDOSAGE The highest dose of LONSURF administered in clinical studies was 180 mg/m2 per day.

There is no known antidote for LONSURF overdosage.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Severe Myelosuppression: Advise the patient to immediately contact their healthcare provider if they experience signs or symptoms of infection and advise patients to keep all appointments for blood tests. [see Warnings and Precautions (5.1)]

Advise the patient that anyone else who handles their medication should wear gloves. [see References (15) in the full Prescribing Information] Embryo-Fetal Toxicity: Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. [see Warnings and Precautions (5.2) and Use in Specific Populations (8.3)] Lactation: Advise women not to breastfeed during treatment with LONSURF and for one day following the final dose. [see Use in Specific Populations (8.2)] © TAIHO ONCOLOGY, INC. 09/2015

About the Awardee Dr. Ciciarello is a postdoctoral trainee at the University of Bologna, where she studies mechanisms of cross talk between mesenchymal stromal cells and the leukemic microenvironment with the aim of determining their role in the induction and advancement of acute myeloid leukemia. She is being honored for her abstract, Upregulation of Indoleamine 2,3-Dioxygenase Enzymes in Leukemic Mesenchymal Stromal Cells (MSCs) Can Influence MSC/Acute Myeloid Leukemia Cell Cross Talk (Abstract 1191). To search for her abstract online, or any abstract presented at the 2015 ASH Annual Meeting, please visit https://ash.confex.com/ash/2015/ webprogram/start.html. n

LARGE TRIM: 10.875”

Advise the patient to take LONSURF within 1 hour after eating their morning and evening meals. [see Dosage and Administration (2.1) in the full Prescribing Information]

This annual award is made possible by a grant from the Giuseppe Bigi Association, named for the late Giuseppe Bigi, MD, a well-known Italian scientist.

Dr. Bigi served as Associate Professor of Clinical Immunology at the University of Milan from 1985 until his death in 2002 and was one of the first researchers to predict the presence of stem cells in the peripheral blood. Support for the 2015 award was also provided by the IRCCS Ca’ Granda Ospedale Maggiore Policlinico Foundation.

“ASH is grateful for the generosity of the Giuseppe Bigi Association and its dedication to supporting researchers like Dr. Ciciarello who are completing high-caliber work in the area of stem cell biology and regenerative medicine,” said 2015 ASH President David A. Williams, MD, President of DanaFarber/Boston Children’s Cancer and Blood Disorders Center and Leland Fikes Professor of Pediatrics at Harvard Medical School. “ASH looks forward to working with the Giuseppe Bigi Association in the years to come to advance hematology research and patient care on an international scale.”

BLEED:11.25”

Administration Instructions: Advise the patient that LONSURF is available in two strengths and they may receive both strength tablets to provide the prescribed dose. Advise the patient of the importance of reading prescription labels carefully and taking the appropriate number of tablets.

About the Award

SAFETY:9.5”

Gastrointestinal toxicity: Advise patients to contact their healthcare provider for severe or persistent nausea, vomiting, diarrhea, or abdominal pain. [see Adverse Reactions (6.1)]

topoiesis and Stem Cells recognizes an Italian trainee (undergraduate, medical, or graduate student, resident physician, or postdoctoral fellow) based at an Italian institution who has the highestscoring abstract submitted to the ASH Annual Meeting in the field of hematopoiesis and stem cells. The recipient receives a $4,000 honorarium and $1,000 travel allowance to attend the ASH Annual Meeting and Exposition.

SMALL TRIM:10.5”

Data Animal Data Trifluridine/tipiracil was administered orally once daily to female rats during organogenesis at dose levels of 15, 50, and 150 mg/kg [trifluridine (FTD) equivalent]. Decreased fetal weight was observed at FTD doses greater than or equal to 50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 twice daily). At the FTD dose of 150 mg/kg (approximately 0.92 times the FTD exposure at the clinical dose of 35 mg/m2 twice daily) embryolethality and structural anomalies (kinked tail, cleft palate, ectrodactyly, anasarca, alterations in great vessels, and skeletal anomalies) were observed.

8.2 Lactation Risk Summary It is not known whether LONSURF or its metabolites are present in human milk. In nursing rats, trifluridine and tipiracil or their metabolites were present in breast milk. There are no data to assess the effects of LONSURF or its metabolites on the breastfed infant or the effects on milk production.

Because of the potential for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LONSURF and for one day following the final dose.

Data Radioactivity was excreted in the milk of nursing rats dosed with trifluridine/ tipiracil containing 14C-FTD or 14C-tipiracil (TPI). Levels of FTD-derived radioactivity were as high as approximately 50% of the exposure in maternal plasma an hour after dosing with trifluridine/tipiracil and were approximately the same as those in maternal plasma for up to 12 hours following dosing. Exposure to TPI-derived radioactivity was higher in milk than in maternal plasma beginning 2 hours after dosing and continuing for at least 12 hours following administration of trifuridine/tipiracil.

8.3 Females and Males of Reproductive Potential Contraception Females LONSURF can cause fetal harm when administered to a pregnant woman. [see Use in Specific Populations (8.1)] Advise females of reproductive potential to use effective contraception during treatment.

Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose. [see Nonclinical Toxicology (13.1) in the full Prescribing Information] 8.4 Pediatric Use Safety and effectiveness of LONSURF in pediatric patients have not been established.

Animal Data Dental toxicity including whitening, breakage, and malocclusion (degeneration and disarrangement in the ameloblasts, papillary layer cells and odontoblasts) were observed in rats treated with trifluridine/tipiracil at doses greater than or equal to 50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 twice daily).

8.5 Geriatric Use In Study 1, 533 patients received LONSURF; 44% were 65 years of age or over, while 7% were 75 and over. No overall differences in effectiveness were observed in patients 65 or older versus younger patients, and no adjustment is recommended for the starting dose of LONSURF based on age.

Patients 65 years of age or older who received LONSURF had a higher incidence of the following compared to patients younger than 65 years: Grade 3 or 4 neutropenia (48% vs 30%), Grade 3 anemia (26% vs 12%), and Grade 3 or 4 thrombocytopenia (9% vs 2%).

8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of LONSURF. No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin (TB) less than or equal to the upper limit of normal (ULN) and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST). Patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 times ULN and any AST) hepatic impairment were not enrolled in Study 1. [see Clinical Pharmacology (12.3) in the full Prescribing Information]

Giuseppe Bigi Association to fund Italian trainees in the area of hematopoiesis and stem cells.

Established in 2015, the ASH Giuseppe Bigi Memorial Award in Hema-

ASCOPost.com | DECEMBER 25, 2015

PAGE 111

Expert’s Corner NCI Award Recipients

Medical School, Beth Israel Deaconess Medical Center Research focus: Exploring novel areas of RNA biology and investigating their role in cancer, as well as potential development of more specific therapeutic modalities, using acute myeloid leukemia as a model disease.

continued from page 106

Ali Shilatifard, PhD

Antoni Ribas, MD, PhD

Antoni Ribas, MD, PhD Professor of Medicine, HematologyOncology, University of California, Los Angeles Research focus: Tumor immunotherapy for melanoma using checkpoint blockade alone or in combination with BRAF inhibitors and gene-engineered adoptive cell transfer therapy.

H3K4 methylases in the regulation of gene expression and during development, and determining how their mutations contribute to the pathogenesis of a large number of human cancers, including solid tumors and hematologic malignancies.

Geoffrey Wahl, PhD

Geoffrey Wahl, PhD

Paul Sondel, MD, PhD

Paul Sondel, MD, PhD

Jeremy Rich, MD

Jeremy Rich, MD Chairman in the Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute Research focus: Investigating the role of mitochondrial dynamics and metabolic control in the maintenance of brain tumor stem cells, regulating the epigenetic stem cell state and as a therapeutic modality; and providing an enhanced model of glioma hierarchy and informing the development of novel clinical trials.

Reed and Carolee Walker Professor of Pediatrics, Human Oncology, and Genetics, University of Wisconsin-Madison Research focus: Developing preclinical and clinical regimens that combine tumor-reactive monoclonal antibody–based therapeutics and other off-the-shelf agents along with genetic evaluation of innate immune function in order to decrease the morbidity and mortality of cancer worldwide.

Ali Shilatifard, PhD Chair of the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine Research focus: Full molecular and biochemical characterization of the COMPASS family of histone

approaches to define the conformational activation and homo-oligomerization mechanism(s) of BAX and BAK; characterizing a novel mechanism for BAX and BAK suppression by the BH4 domains of antiapoptotic BCL-2 proteins; and investigating a new allosteric mechanism that controls the apoptotic functionalities of BCL-2 proteins.

Daniel G. Tenen, MD

Daniel G. Tenen, MD Professor of Medicine, Harvard

Professor, Salk Institute for Biological Studies Research focus: Determining the molecular programs that drive embryonic mammary cells into the stem cell state and using gene-editing technologies to generate a new mouse model that will enable the lab to identify fMaSCs in real time based on the cytokeratins they express.

Loren D. Walensky, MD, PhD

Michael A. White, PhD

Michael A. White, PhD Professor in the Department of Cell Biology, University of Texas Southwestern Medical Center Research focus: Investigating conditional vulnerabilities that arise as a consequence of oncogene expression and tumor evolution.

Jin Zhang, PhD

Loren D. Walensky, MD, PhD

Jin Zhang, PhD

Associate Professor of Pediatrics and Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston Children’s Hospital, Harvard Medical School Research focus: Elucidating the fundamental interaction mechanisms of BCL-2 family apoptotic proteins to advance new therapeutic strategies for reactivating cell death in human cancer; applying multidisciplinary

Professor in the Department of Pharmacology, University of California, San Diego Research focus: Developing enabling technologies to probe the active molecules in their native environment and characterizing how these active molecules change in cancer, to lead to new ways of studying dysregulated molecular machinery in cancer. n

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The ASCO Post | DECEMBER 25, 2015

PAGE 112

AACI Annual Meeting Future of Oncology

Are Academic Cancer Centers a National Treasure?

By Kirsten Boyd Goldberg

T

he Association of American Cancer Institutes (AACI) is developing a marketing campaign to highlight the value of academic cancer centers to their communities and the nation.

Called “The Academic Difference,” the 2-year campaign is the initiative of AACI President George J. Weiner, MD, Director of the Holden Comprehensive Cancer Center at the University of Iowa, Iowa City. In the first phase of the project, AACI is gathering information from its member institutes to demonstrate the many accomplishments of the centers, Dr. Weiner said in his presidential address at the AACI Annual Meeting in Washington, DC, in November.

“Academic cancer centers have a major and unique role to play in enhancing cancer science, cancer care, and cancer education. This role will increase in value as our understanding of the complexity of cancer grows and is applied to care of patients,” Dr. Weiner said. “Accelerating progress in cancer medicine will remain dependent on the success of academic cancer centers and development of new models of collaboration between academic cancer centers and community oncology. To ensure academic cancer centers are able to thrive well into the future, we need to do a bet-

To ensure academic cancer centers are able to thrive well into the future, we need to do a better job of explaining the unique role they play to the broad range of constituents, including patients, payers, policy makers, university leadership, community oncology partners, and the general public.

—George J. Weiner, MD

ter job of explaining the unique role they play to the broad range of constituents, including patients, payers, policy makers, university leadership, community oncology partners, and the general public.”

Project Phases The AACI project identified four areas in which academic cancer centers play a unique role in their communities, their states, and the nation, Dr. Weiner said: cancer research, clinical care, medical education, and economic impact.

The first phase of the project entails gathering and sharing the accomplishments that AACI and its members can

Cancer Survivor Suleika Jaouad Opens AACI/CCAF Annual Meeting, Susan Dentzer Moderates Discussion

S

uleika Jaouad was diagnosed with myelodysplastic syndrome and acute myeloid leukemia at age 22, shortly after her graduation from Princeton University. She is a columnist for The New York Times Well blog, “Life Interrupted,” which chronicles her journey as a young woman living with cancer.

tion of American Cancer Institutes (AACI) and Cancer Center Administrators Forum (CCAF), held earlier this year in Washington, DC.

Susan Dentzer

Suleika Jaouad

Ms. Jaouad shared her story in the opening keynote presentation at the Annual Meeting of the Associa-

Susan Dentzer, Senior Policy Adviser to the Robert Wood Johnson Foundation, moderated the talk. Ms. Dentzer is an on-air analyst on health issues with the PBS NewsHour and a regular commentator on health policy for National Public Radio, Al Jazeera America, and other media networks. n

use in advocating for support at the local and national levels, Dr. Weiner said.

The project will not ask AACI member centers to generate new data or share confidential information, and nor will it conduct an extensive survey, he added.

In the second phase of the project, AACI plans to enlist the help of cancer center directors, public relations and government relations staff from cancer centers, and marketing professionals to develop messaging and materials. Marketing would be targeted to the public and patients, university and cancer center boards, payers, political leaders, corporations, and Chambers of Commerce.

Dr. Weiner listed some of the examples that AACI members have submitted for the project. He invited centers to continue to send these types of accomplishments to the AACI office.

Cancer Research • At the University of California Davis Comprehensive Cancer Center, researchers have filed for 172 patents from 2011–2014.

• Researchers at the University of Utah established the Utah Population Database, which has been managed by Huntsman Cancer Institute for over 20 years. This database has led to evidence of familial risk for dozens of diseases.

• Roswell Park Cancer Institute has delivered more high-dose interleukin 2 therapy for metastatic renal cell carcinoma than any other U.S. center.

• The Ohio State University Comprehensive Cancer Center and Moffitt Cancer Center were founding partners in the Oncology Research Information Exchange Network.

Clinical Care • Sidney Kimmel Cancer Center at Thomas Jefferson University conducted a long-term study on multi-

disciplinary care for prostate cancer, which showed enhanced outcomes and decreased treatment regret.

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University showed, “Specialist collaboration is associated with lower mortality without increased cost among patients with stage III colon cancer.”

• Holden Comprehensive Cancer Center published a paper stating, “Those treated at hospitals with a National Cancer Institute designation, residency program, or medical school affiliation received more guideline-concordant care.”

• Moffitt Cancer Center was involved with the U.S. Food and Drug Administration’s approval of a new combination treatment for melanoma, the first major melanoma advancement in 30 years.

• George Washington Cancer Institute offers free training to all patient navigators in the United States.

• The University of Alabama at Birmingham Comprehensive Cancer Center offers patient navigators to patients over the age of 65.

• Huntsman Cancer Institute developed the Native American Outreach Program, to provide culturally sensitive education about cancer.

Medical Education • Sidney Kimmel Cancer Center at Thomas Jefferson University trains a total of 29 fellows each year in 7 programs.

• The University of Texas MD Anderson Cancer Center is home to the only oncology postgraduate clinical training program for physician assistants in the country.

• From 2009–2014, The University of Texas MD Anderson Cancer Center has had an 8% growth in clinical trainees.

• In the past year, Georgetown Lombardi Comprehensive Cancer Center has hosted 20 multidisciplinary conferences.

• The Cancer Biology PhD program at Barbara Ann Karmanos Cancer Institute combines an interdisciplinary graduate curriculum and interaction with clinicians to educate the next generation of researchers.

• The University of California at San Diego Moores Cancer Center (MCC) offers services to the community such as the MCC-funded Healthy Foods Kitchen, which offers culinary classes with a focus on nutrition for patients with cancer and a seminar series informing the public on research advances. continued on page 118

FOR UNRESECTABLE OR METASTATIC LIPOSARCOMA OR LEIOMYOSARCOMA AFTER ANTHRACYCLINE

THERE IS A NEW OPTION

INDICATIONS

YONDELIS速 (trabectedin) is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS

YONDELIS速 is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin.

Please see the following pages for additional Important Safety Information and a Brief Summary of the full Prescribing Information.

NOW APPROVED

PROPEL TREATMENT FORWARD WITH 45%

REDUCTION OF RISK vs dacarbazine

YONDELIS® ( trabectedin) SIGNIFICANTLY IMPROVED PROGRESSION-FREE SURVIVAL (PFS) YONDELIS® resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine in a phase 3, open-label study • YONDELIS® improved median PFS* vs dacarbazine: 4.2 months with YONDELIS® vs 1.5 months for dacarbazine (hazard ratio [HR]†=0.55; 95% CI: 0.44, 0.70; P<0.001‡)

Kaplan-Meier Curve of PFS 100

Dacarbazine YONDELIS® Censored in dacarbazine Censored in YONDELIS®

90 80

Subjects, %

70 60 50 40 30 20 10 0 0

3

6

9

12

15

18

21

0 5

1

0

Progression-Free Survival, Months NUMBER OF SUBJECTS AT RISK: Dacarbazine YONDELIS®

173 345

35 133

10 71

2 29

1 10

*An exploratory analysis of independent radiology committee–determined PFS, in a subgroup consisting of approximately 60% of the total population, provided similar results to the investigator-determined PFS. †HR is estimated using Cox proportional hazards model with treatment group as the only covariate. ‡P value is based on unstratified log-rank test.

Study Design YONDELIS® was studied in a phase 3 randomized, open-label, active-controlled, multicenter trial of patients with unresectable, locally advanced or metastatic leiomyosarcomas (73%) or liposarcomas (27%).

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS

Neutropenic sepsis, including fatal cases, can occur. In Trial 1, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, was 43% (161/378). Median time to the first occurrence of Grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months). Median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18 patients (5%). Ten patients (2.6%) experienced neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4 patients (1.1%). Assess neutrophil count prior to administration of each dose of YONDELIS® and periodically throughout the treatment cycle. Withhold YONDELIS® for neutrophil counts of less than 1500 cells/microliter on the day of dosing. Permanently reduce the dose of YONDELIS® for life-threatening or prolonged, severe neutropenia in the preceding cycle.

Rhabdomyolysis—YONDELIS® can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving YONDELIS®, including Grade 3 or 4 CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation.

Among the 24 patients receiving YONDELIS® with Grade 3 or 4 CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in 4 of these 11 patients (1.1%). Median time to first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5 months).

Please see the following pages for additional Important Safety Information and a Brief Summary of the full Prescribing Information.

YONDELIS®

13.7 months

The median overall survival was 13.7 months for patients treated with YONDELIS® vs 13.1 months for patients treated with dacarbazine in the pivotal trial (HR=0.93; 95% CI: 0.75, 1.15; P=0.49)

S:13 IN

T:14 IN

B:14.25 IN

2.7 months

Median duration of response was 2.7 months longer for YONDELIS® vs dacarbazine (6.9 months vs 4.2 months, respectively)

13 weeks

The median duration of treatment with YONDELIS® was 13 weeks (range, 1 to 127 weeks), with 30% of patients treated for more than 6 months and 7% for more than 1 year Liposarcoma and leiomyosarcoma are two of the most common subtypes of soft tissue sarcomas.1,2 References: 1. Blay J-Y, Sleijfer S, Schöffski P, et al. International expert opinion on patient-tailored management of soft tissue sarcomas.

Eur J Cancer. 2014;50(4):679-689. 2. Ducimetière F, Lurkin A, Ranchère-Vince D, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294.

Median time to complete resolution was 14 days (range: 5 days to 1 month). Assess CPK levels prior to each administration of YONDELIS®. Withhold YONDELIS® for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue YONDELIS® for rhabdomyolysis.

Hepatotoxicity, including hepatic failure, can occur. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels > 2.5 x ULN were not enrolled in Trial 1. In Trial 1, the incidence of Grade 3-4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378). Median time to development of Grade 3-4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3 to 4 elevations in LFTs, 114 (85%) experienced complete resolution with the median time to complete resolution of 13 days (range: 4 days to 4.4 months).

In Trial 1, the incidence of drug-induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378). ALT or AST elevation greater than eight times the ULN occurred in 18% (67/378) of patients. Assess LFTs prior to each administration of YONDELIS®.

Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation NOW APPROVED based on severity and duration of LFT abnormality.

IMPORTANT SAFETY INFORMATION Cardiomyopathy, including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur. In Trial 1, patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial 1, cardiomyopathy occurred in 23 patients (6%) receiving YONDELIS® and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS® and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving YONDELIS® and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving YONDELIS® was 5.3 months (range: 26 days to 15.3 months). Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before initiation of YONDELIS® and at 2- to 3-month intervals thereafter until YONDELIS® is discontinued. Withhold YONDELIS® for LVEF below lower limit of normal. Permanently discontinue YONDELIS® for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks.

Extravasation Resulting in Tissue Necrosis—Extravasation of YONDELIS®, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of YONDELIS®. Administer YONDELIS® through a central venous line.

Embryofetal Toxicity—Based on its mechanism of action, YONDELIS® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of YONDELIS®. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of YONDELIS®.

Adverse Reactions—The most common (≥20%) adverse reactions were nausea (75%), fatigue (69%), vomiting (46%), constipation (37%), decreased appetite (37%), diarrhea (35%), peripheral edema (28%), dyspnea (25%), and headache (25%).

The most common (≥5%) grades 3-4 laboratory abnormalities are: neutropenia (43%), increased ALT (31%), thrombocytopenia (21%), anemia (19%), increased AST (17%), and increased creatine phosphokinase (6.4%).

Effect of Cytochrome CYP3A Inhibitors—Avoid use of strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS®. Avoid taking grapefruit or grapefruit juice. If a strong CYP3A inhibitor for short-term use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the YONDELIS® infusion, and discontinue it the day prior to the next YONDELIS® infusion.

Effect of Cytochrome CYP3A Inducers—Avoid administering strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) to patients who are taking YONDELIS®.

Please see the following pages for Brief Summary of the full Prescribing Information.

© Janssen Products, LP 2015 10/15 Printed in USA 042302-151023

NOW APPROVED

040598-150918

DRUG INTERACTIONS

YONDELIS (trabectedin) for injection, for intravenous use Brief Summary of Full Prescribing Information INDICATIONS AND USAGE YONDELIS® is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen [see Clinical Studies (14) in Full Prescribing Information].

CONTRAINDICATIONS YONDELIS is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin.

WARNINGS AND PRECAUTIONS Neutropenic Sepsis: Neutropenic sepsis, including fatal cases, can occur with YONDELIS. In Trial 1, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, in patients receiving YONDELIS was 43% (161/378). The median time to the first occurrence of Grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months); the median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18 patients (5%) treated with YONDELIS. Ten patients (2.6%) experienced neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4 patients (1.1%).

Assess neutrophil count prior to administration of each dose of YONDELIS and periodically throughout the treatment cycle. Withhold YONDELIS for neutrophil counts of less than 1500 cells/microliter on the day of dosing. Permanently reduce the dose of YONDELIS for life-threatening or prolonged, severe neutropenia in the preceding cycle [see Dosage and Administration (2.3) in Full Prescribing Information].

Rhabdomyolysis: YONDELIS can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients receiving YONDELIS. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving YONDELIS, including Grade 3 or 4 CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation. Among the 24 patients receiving YONDELIS with Grade 3 or 4 CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in 4 of these 11 patients (1.1%). The median time to first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5 months).

The median time to complete resolution was 14 days (range: 5 days to 1 month).

Assess CPK levels prior to each administration of YONDELIS. Withhold YONDELIS for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue YONDELIS for rhabdomyolysis [see Dosage and Administration (2.3) in Full Prescribing Information].

Hepatotoxicity: Hepatotoxicity, including hepatic failure, can occur with YONDELIS. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels >2.5 x ULN were not enrolled in Trial 1.

In Trial 1, the incidence of Grade 3-4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378) in patients receiving YONDELIS. The median time to development of Grade 3-4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3-4 elevations in LFTs, 114 (85%) experienced complete resolution with the median time to complete resolution of 13 days (range: 4 days to 4.4 months).

In Trial 1, the incidence of drug-induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378) in patients receiving YONDELIS. ALT or AST elevation greater than eight times the ULN occurred in 18% (67/378) of patients receiving YONDELIS. Assess LFTs prior to each administration of YONDELIS. Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation based on severity and duration of LFT abnormality [see Dosage and Administration (2.3) in Full Prescribing Information].

Cardiomyopathy: Cardiomyopathy including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur with YONDELIS. In Trial 1, patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial 1, cardiomyopathy occurred in 23 patients (6%) receiving YONDELIS and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving YONDELIS and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving YONDELIS was 5.3 months (range: 26 days to 15.3 months).

Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before initiation of YONDELIS and at 2- to 3-month intervals thereafter until YONDELIS is discontinued.

Withhold YONDELIS for LVEF below lower limit of normal. Permanently discontinue YONDELIS for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks [see Dosage and Administration (2.3) in Full Prescribing Information].

Extravasation Resulting in Tissue Necrosis: Extravasation of YONDELIS, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of YONDELIS. Administer YONDELIS through a central venous line [see Dosage and Administration (2.5) in Full Prescribing Information].

Embryofetal Toxicity: Based on its mechanism of action, YONDELIS can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of YONDELIS. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of YONDELIS [see Use in Specific Populations].

YONDELIS® (trabectedin) for injection intravenous infusion over 20 to 120 minutes once every 3 weeks (n=172) [see Clinical Studies (14) in Full Prescribing Information]. All patients treated with YONDELIS were required to receive dexamethasone 20 mg intravenous injection 30 minutes prior to start of the YONDELIS infusion.

In Trial 1, patients had been previously treated with an anthracycline- and ifosfamide-containing regimen or with an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen.

The trial excluded patients with known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, such as cirrhosis or active hepatitis, and history of myocardial infarction within 6 months, history of New York Heart Association Class II to IV heart failure, or abnormal left ventricular ejection fraction at baseline. The median age of patients in Trial 1 was 57 years (range: 17 to 81 years), with 69% female, 77% White, 12% Black or African American, 4% Asian, and <1% American Indian or Alaska Native. The median duration of exposure to trabectedin was 13 weeks (range: 1 to 127 weeks) with 30% of patients exposed to YONDELIS for greater than 6 months and 7% of patients exposed to YONDELIS for greater than 1 year.

In Trial 1, adverse reactions resulting in permanent discontinuation of YONDELIS occurred in 26% (98/378) of patients; the most common were increased liver tests (defined as ALT, AST, alkaline phosphatase, bilirubin) (5.6%), thrombocytopenia (3.4%), fatigue (1.6%), increased creatine phosphokinase (1.1%), and decreased ejection fraction (1.1%). Adverse reactions that led to dose reductions occurred in 42% (158/378) of patients treated with YONDELIS; the most common were increased liver tests (24%), neutropenia (including febrile neutropenia) (8%), thrombocytopenia (4.2%), fatigue (3.7%), increased creatine phosphokinase (2.4%), nausea (1.1%), and vomiting (1.1%). Adverse reactions led to dose interruptions in 52% (198/378) of patients treated with YONDELIS; the most common were neutropenia (31%), thrombocytopenia (15%), increased liver tests (6%), fatigue (2.9%), anemia (2.6%), increased creatinine (1.1%), and nausea (1.1%).

The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. The most common laboratory abnormalities (≥20%) were increases in AST or ALT, increased alkaline phosphatase, hypoalbuminemia, increased creatinine, increased creatine phosphokinase, anemia, neutropenia, and thrombocytopenia.

Table 1: Selected Adverse Reactionsa occurring in ≥10% of Patients receiving YONDELIS and at a higher incidence than in the Control Arm - Trial 1 System Organ Class Adverse Reaction

Gastrointestinal disorders Nausea 75 Vomiting 46 Constipation 37 Diarrhea 35 General disorders and administration site conditions 69 Fatiguec Peripheral edema 28 Metabolism and nutrition disorders Decreased appetite 37 Respiratory, thoracic and mediastinal disorders Dyspnea 25 Nervous system disorders Headache 25 Musculoskeletal and connective tissue disorders Arthralgia 15 Myalgia 12 Psychiatric disorders Insomnia 15 a

b c

Dacarbazine (N=172) All Grades Grades 3-4 (%) (%)

7 6 0.8 1.6

50 22 31 23

1.7 1.2 0.6 0

8 0.8

52 13

1.7 0.6

1.9

21

0.6

4.2

20

1.2

0.3

19

0

0 0

8 6

1.2 0

0.3

9

0

Limited to adverse reactions at a rate of ≥10% in the trabectedin arm and at a rate higher in the trabectedin arm compared with dacarbazine arm by ≥5% in overall incidence or by ≥2% for Grade 3-4 adverse reactions.

Toxicity grade is based on NCI common toxicity criteria, version 4.0.

Fatigue is a composite of the following adverse event terms: fatigue, asthenia, and malaise.

Other clinically important adverse reactions observed in <10% of patients (N=755) with soft tissue sarcoma receiving YONDELIS were: Nervous system disorders: peripheral neuropathy, paresthesia, hypoesthesia.

Respiratory, thoracic, and mediastinal disorders: pulmonary embolism.

Table 2: Incidence of Selected Treatment-Emergent Laboratory Abnormalitiesa - Trial 1 Laboratory Abnormalities Chemistry Increased ALT Increased AST Increased alkaline phosphatase Hypoalbuminemia Increased creatinine Increased creatine phosphokinase Hyperbilirubinemia Hematology Anemia Neutropenia Thrombocytopenia

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Anaphylaxis [see Contraindications] • Neutropenic Sepsis [see Warnings and Precautions] • Rhabdomyolysis [see Warnings and Precautions] • Hepatotoxicity [see Warnings and Precautions] • Cardiomyopathy [see Warnings and Precautions] • Extravasation Resulting in Tissue Necrosis [see Warnings and Precautions] Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to YONDELIS in 755 patients with soft tissue sarcoma including 197 (26%) patients exposed to YONDELIS for greater than or equal to 6 months and 57 (8%) patients exposed to YONDELIS for greater than or equal to 1 year. The safety of YONDELIS was evaluated in six open-label, single-arm trials, in which 377 patients received YONDELIS and one open-label, randomized, active-controlled clinical trial in which 378 patients received YONDELIS (Trial 1). All patients received YONDELIS at the recommended dosing regimen of 1.5 mg/m2 administered as an intravenous infusion over 24 hours once every 3 weeks (q3wk, 24-h). The median age was 54 years (range: 18 to 81 years), 63% were female, and all patients had metastatic soft tissue sarcoma.

Tables 1 and 2 present selected adverse reactions and laboratory abnormalities, respectively, observed in Trial 1, an open-label, randomized (2:1), active-controlled trial in which 550 patients with previously treated leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) received YONDELIS 1.5 mg/m2 intravenous infusion over 24 hours once every 3 weeks (n=378) or dacarbazine 1000 mg/m2

YONDELIS (N=378) Grades 3-4 All Gradesb (%) (%)

YONDELIS All Grades Grades 3-4 (%) (%)

Dacarbazine All Grades Grades 3-4 (%) (%)

90 84 70 63 46 33 13

31 17 1.6 3.7 4.2 6.4 1.9

33 32 60 51 29 9 5

0.6 1.2 0.6 3.0 1.2 0.6 0.6

96 66 59

19 43 21

79 47 57

12 26 20

Treatment-emergent laboratory abnormalities including those higher in the trabectedin arm compared with the dacarbazine arm by ≥5% (all Grades) or by ≥2% (Grade 3-4). Incidence based on number of patients who had both baseline and at least one on-study laboratory measurement YONDELIS group (range: 373 to 377 patients) and dacarbazine group (range: 166 to 168 patients). a

DRUG INTERACTIONS Effect of Cytochrome CYP3A Inhibitors: Coadministration of YONDELIS with ketoconazole, a strong CYP3A inhibitor, increases systemic exposure of trabectedin by 66%. Avoid use of strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS. Avoid taking grapefruit or grapefruit juice during YONDELIS treatment. If a strong CYP3A

YONDELIS® (trabectedin) for injection inhibitor for short-term use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the YONDELIS infusion, and discontinue it the day prior to the next YONDELIS infusion [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Effect of Cytochrome CYP3A Inducers: Coadministration of YONDELIS with rifampin, a strong CYP3A inducer, decreased systemic exposure of trabectedin by 31%. Avoid administering strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) to patients who are taking YONDELIS [see Clinical Pharmacology (12.3) in Full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Risk Summary: Based on its mechanism of action, trabectedin can cause fetal harm when administered during pregnancy [see Clinical Pharmacology (12.1) in Full Prescribing Information].

There are no available data with the use of YONDELIS during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted with trabectedin; however, placental transfer of trabectedin was demonstrated in pregnant rats. Advise pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population are unknown; however, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Lactation: Risk Summary: There are no data on the presence of trabectedin in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions from YONDELIS in breastfed infants, advise a nursing woman to discontinue nursing during treatment with YONDELIS. Females and Males of Reproductive Potential: Contraception: Females: Advise female patients of reproductive potential to use effective contraception during and for 2 months after the last dose of YONDELIS [see Use in Specific Populations]. Males: YONDELIS may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for 5 months after the last dose of YONDELIS [see Nonclinical Toxicology (13.1) in Full Prescribing Information]. Infertility: YONDELIS may result in decreased fertility in males and females [see Nonclinical Toxicology (13.1) in Full Prescribing Information].

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Clinical studies of YONDELIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Hepatic Impairment: The pharmacokinetics of trabectedin has not been evaluated in patients with a total bilirubin greater than the upper limit of normal [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Renal Impairment: No dose adjustment is recommended in patients with mild [creatinine clearance (CLcr) 60-89 mL/min] or moderate (CLcr of 30-59 mL/min) renal impairment.

The pharmacokinetics of trabectedin has not been evaluated in patients with severe renal impairment (CLcr <30 mL/min) or end stage renal disease [see Clinical Pharmacology (12.3) in Full Prescribing Information].

OVERDOSAGE There is no specific antidote for YONDELIS. Hemodialysis is not expected to enhance the elimination of YONDELIS because trabectedin is highly bound to plasma proteins (97%) and not significantly renally excreted.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Myelosuppression: Inform patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider for fever or unusual bruising, bleeding, tiredness, or paleness.

Rhabdomyolysis: Advise patients to contact their healthcare provider if they experience severe muscle pain or weakness.

Hepatotoxicity: Advise patients to contact their healthcare provider immediately for yellowing of skin and eyes (jaundice), pain in the upper right quadrant, severe nausea or vomiting, difficulty in concentrating, disorientation, or confusion.

Cardiomyopathy: Advise patients to contact their healthcare provider for new onset chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations.

Hypersensitivity: Advise patients to seek immediate medical attention for symptoms of allergic reactions including difficulty breathing, chest tightness, wheezing, severe dizziness or lightheadedness, swelling of the lips or skin rash.

Extravasation: Inform patients of the risks of extravasation and to notify their healthcare provider for redness, swelling, itchiness and discomfort or leakage at the injection site.

Embryofetal toxicity: Advise pregnant women of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with YONDELIS [see Warnings and Precautions and Use in Specific Populations].

Females and males of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with YONDELIS and for at least 2 months after last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with YONDELIS and for at least 5 months after the last dose [see Warnings and Precautions and Use in Specific Populations].

Lactation: Advise females not to breastfeed during treatment with YONDELIS [see Use in Specific Populations].

PAGE 118

The ASCO Post | DECEMBER 25, 2015

AACI Annual Meeting Academic Cancer Centers continued from page 112

Economic Impact • Moffitt Cancer Center employs 4,300 people, with an average salary of $79,000, which leads to $1.6 billion in direct economic output. In the past 3 years, Moffitt Cancer Center has treated 3,074 new patients from outside of Florida.

• The University of Kansas Cancer Center estimates a $750 million investment from 2014–2018 will drive another 1,584 new jobs: 841 at the University of Kansas and 743 regionally.

• Knight Cancer Institute estimates that its current plan will create 380 permanent full-time jobs, 6,800 construction jobs in 2 years, $35 million in state and local taxes annually during the life of construction, and $5.6 million in state income taxes annually when operational.

• For every dollar appropriated by the state of New Jersey, Rutgers Cancer Institute of New Jersey returned $13.01 to the state in economic impact.

• Since 2009, researchers from the Purdue Center for Cancer Research have initiated 12 startup companies.

042354-151026

At the Annual Meeting, AACI presented the 2015 AACI Distinguished Scientist Award to Lewis C. Cantley, PhD, a cell biologist and biochemist who serves as The Margaret and Herman Sokol Professor in Oncology Research and Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College. Dr. Cantley’s research has resulted in revolutionary treatments for cancer, diabetes, and ­autoimmune diseases.

Sen. Patty Murray (D–WA) and Rep. Kevin Yoder (R–KS) received the 2015 AACI Public Service Award.

Reps. Fred Upton (R–MI) and Diana ­DeGette (D–CO) received the 2015 AACI Champion for Cures Award in recognition of their work on H.R. 6—21st Century Cures Act—which prescribes mandatory funding of $8.75 billion for the National Institutes of Health and $550 million for the U.S. Food and Drug Administration over the next 5 years. n

Disclosure: Drs. Weiner and Cantley reported no potential conflicts of interest.

Announcements

Joseph Smith, Jr, MD, Awarded Huggins Medal

T

he Society of Urologic Oncology (SUO) recognized Joseph Smith, Jr, MD, William L. Bray Professor of Urologic Surgery at Vanderbilt University School of Medicine, with the Huggins Medal, its highest honor. Dr. Smith

Manufactured by: Baxter Oncology GmbH Halle/Westfalen Germany Manufactured for: Janssen Products, LP Horsham, PA © Janssen Products, LP. 2015 Under license from Pharma Mar, S.A.

AACI Awards for Science, Public Service

Joseph Smith, Jr, MD

was chosen for his lifetime contributions to the progress in treatment for patients with genitourinary neoplasms.

The Huggins Medal is named after Charles B. Huggins, MD, who was awarded the Nobel Prize for Physiology or Medicine in 1966 in recognition of his work on the hormonal treatment of prostate cancer.

Dr. Smith received the medal and presented the corresponding Huggins

lecture at SUO’s 2015 Annual Winter Meeting, held December 2–4 in Washington, DC. “I remember as an intern choosing to go into urologic surgery and to pursue urologic oncology because I wanted to do what looked to be the most challenging operations. The Society of Urologic Oncology has been my most coveted peer group, so to be recognized in this manner is an enormous honor,” Dr. Smith said.

Dr. Smith was recently named the next editor of The Journal of Urology. He performed Vanderbilt’s first robotic surgery in 2003 and has completed more than 7,000 prostatectomies since that time, along with radical cystectomies, partial nephrectomies, and bladder ­suspensions.

The Society of Urologic Oncology was created in 1984 to enable qualified members primarily interested in the care of patients with malignant genitourinary diseases to meet for the purpose of discussion, development, and implementation of ideas to improve care. n

ASCOPost.com | DECEMBER 25, 2015

PAGE 119

Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Pancreatic Cancer Compiled by Liz Janetschek

T

he information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with pancreatic cancer. The trials are investigating preoperative rehabilitation; chimeric antigen receptors; T-cell transplants; combination chemotherapy; chemoradiotherapy; imaging-guided dose escalation; neoadjuvant therapies; stereotactic body radiotherapy; and more. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

PILOT Study Type: Pilot/interventional/ single-group assignment Study Title: Preoperative Rehabilitation During Neoadjuvant Therapy for Pancreatic Cancer: A Pilot Study Study Sponsor and Collaborators: MD Anderson Cancer Center Purpose: To learn if it is possible to start a home-based exercise and nutrition program for patients with pancreatic cancer or who may have pancreatic cancer before surgery (preoperative rehabilitation, also known as prehabilitation) Primary Outcome Measures: Feasibility of prehabilitation program among patients [time frame: 6 weeks] Principal Investigator: Matthew H. Katz, MD, MD Anderson Cancer Center; 713-794-4660 For more information: Use ClinicalTrials.gov Identifier NCT02295956

PHASE I Study Type: Phase I/interventional/ single-group assignment Study Title: Pilot Study of Autologous T Cells Redirected to Mesothelin and CD19 With a Chimeric Antigen Receptor in Patients With Metastatic Pancreatic Cancer Study Sponsor and Collaborators: University of Pennsylvania, University of California, San Francisco Purpose: To learn if the combination therapy of CART-meso cells and CART19 cells administered at 3 days after one dose of cyclophosphamide may prolong the duration of CART-meso cells in the body

Primary Outcome Measures: Safety of IV administration of CART-meso-19 with cyclophosphamide as lymphodepleting chemotherapy in patients with pancreatic cancer using the NCI CTCAE v4.03 criteria [time frame: 24 months] Principal Investigator: Andrew Ko, MD, University of California, San Francisco; contact Elizabeth Dito, RN, 415-353-7244, elizabeth.dito@ucsf.edu For more information: Use ClinicalTrials.gov Identifier NCT02465983 Study Type: Phase I/interventional/ single-group assignment Study Title: A Phase I Study of BKM120 With mFOLFOX6 in Patients With Advanced Solid Tumors With Expansion Cohort in Metastatic Pancreatic Cancers Study Sponsor and Collaborators: UNC Lineberger Comprehensive Cancer Center Purpose: To establish the safety and tolerability of BKM120 when combined with mFOLFOX6 and to define the maximum tolerated dose of BKM120 in this combination in advanced solid tumors including metastatic pancreatic cancer Primary Outcome Measures: Dose-limiting toxicity [time frame: 3 years]; maximum tolerated dose [time frame: 3 years] Principal Investigator: Autumn McRee, MD, UNC Lineberger Comprehensive Cancer Center; contact Julie White, RN, 919-966-7112, julie_ white@med.unc.edu For more information: Use ClinicalTrials.gov Identifier NCT01571024

PHASE II Study Type: Phase II/interventional/ Parallel Assignment Study Title: Phase II Study of Preoperative FOLFIRINOX vs Gemcitabine/Nab-Paclitaxel in Patients With Resectable Pancreatic Cancer Study Sponsor and Collaborators: Massachusetts General Hospital Purpose: To evaluate a combination of drugs, FOLFIRINOX and gemcitabine/nab-paclitaxel, in the management of participants with resectable pancreatic cancer prior to surgery Primary Outcome Measures: Sur-

vival rate at 18 months [time frame: 18 months] Principal Investigator: David Patrick Ryan, MD, Massachusetts General Hospital; 617-724-4000, dpryan@ partners.org For more information: Use ClinicalTrials.gov Identifier NCT02243007 Study Type: Phase II/interventional/ single-group assignment Study Title: MR-Guided Phase II Radiotherapy Dose Escalation in Unresectable Nonmetastatic Pancreatic Cancer Study Sponsor and Collaborators: Medical College of Wisconsin Purpose: To evaluate if an imagingguided dose of escalated radiotherapy and concurrent chemotherapy in unresectable pancreatic cancer can control the spread of disease Primary Outcome Measures: To evaluate the efficacy of dose escalation to an MR-defined GTV of up to 69.75 Gy at 2.25 Gy per fraction for unresectable pancreatic cancer [time frame: 1 year from the start of treatment ] Principal Investigator: Beth Erickson, MD, Froedtert & The Medical College of Wisconsin; contact Cancer Center Clinical Trials Office, 1-800680-0505 ext 8900, ccto@mcw.edu For more information: Use ClinicalTrials.gov Identifier NCT01972919

PHASE II/III Study Type: Phase II/III/interventional/parallel assignment Study Title: Phase II Study: Neoadjuvant Gemcitabine, Docetaxel and Capecitabine Followed by Neoadjuvant Radiation Therapy With Gemcitabine and Capecitabine in the Treatment of Stage II and III Pancreatic Adenocarcinoma Study Sponsor and Collaborators: Columbia University Purpose: To assess the safety and benefit of six 3-week cycles of chemotherapy treatment consisting of gemcitabine, capecitabine and docetaxel (GTX) Primary Outcome Measures: To determine the effect of neoadjuvant regimen of GTX on the 2-year diseasefree survival rate [time frame: 2 years] Principal Investigator: William Sherman, MD, Columbia University; contact Kyung Chu, RN, 212-305-

9467, kc2113@columbia.edu For more information: Use ClinicalTrials.gov Identifier NCT01065870

PHASE III Study Type: Phase III/interventional/parallel assignment Study Title: A Randomized Phase III Study Evaluating Modified FOLFIRINOX (mFFX) With or Without Stereotactic Body Radiotherapy (SBRT) in the Treatment of Locally Advanced Pancreatic Cancer Study Sponsor and Collaborators: Stanford University Purpose: To determine the safety and efficacy of a chemotherapy regimen known as mFFX alone or with the addition of SBRT. Primary Outcome Measures: Difference in progression-free survival between mFOLFIRINOX alone vs mFOLFIRINOX and SBRT [time frame: 1 year] Principal Investigator: Albert Koong, PhD, Stanford University; contact Rachel Freiberg, PhD, 650-7250438, rachelf@stanford.edu For more information: Use ClinicalTrials.gov Identifier NCT01926197

PHASE IV Study Type: Phase IV/interventional/parallel assignment Study Title: Comparison Study in Pancreatic Fiducial Placement Study Sponsor and Collaborators: Parkview Health Purpose: To compare 19-gauge EUS FNA BNX needle vs 22-gauge EUS FNA BNX needle in pancreatic fiducial placement to treat pancreatic cancer Primary Outcome Measures: Total cost comparison [time frame: duration of fiducial placement procedure; approximately 30 minutes]; total time comparison [time frame: duration of fiducial placement procedure; up to 30 minutes] Principal Investigator: Neil ­Sharma, MD, Parkview Health; 260266-5230, neil.sharma@parview.com For more information: Use ClinicalTrials.gov Identifier NCT02376543 Editor’s Note: The clinical trials presented here do not represent all the trials listed on ClinicalTrials.gov. For the complete list, go to ClinicalTrials.gov. n

The ASCO Post | DECEMBER 25, 2015

PAGE 120

Geriatrics for the Oncologist

SIOG Annual Conference Explores Global Perspectives on Geriatric Oncology and Supportive Care

By Stuart M. Lichtman, MD

T

he 15th Annual Conference of the International Society of Geriatric Oncology (SIOG) took place in Prague, Czech Republic, over 3 days (November 12–14, 2015). At the heart of the meeting were presentations on supportive care, comprehensive geriatric assessment and treatment—so that we fully understand the complex problems faced by an elderly patient—and the multidisciplinary cooperation required to address the needs of this population.

With a theme of Geriatric Oncology & Supportive Care: A Global Approach to Advance the Science, there were more than 90 oral presentations spread across 25 scientific sessions and 115 posters.

SIOG 2015 was attended by 410 delegates—15% more than at last year’s annual meeting in Lisbon—who came from 40 countries. The plenary session focused on surgery, geriatrics, medical oncology, radiotherapy, and supportive care, and the meeting was opened by the Society President, Etienne Brain, MD, of the Department of Medical Oncology, Institut Curie–Hôpital René Huguenin, Saint-Cloud, France.

Growing Burden of Cancer Due to the aging population in the United States, 70% of the 2.3 million cancers that arise in 2030 will be in people aged 65 years and older. But the growing burden of cancer in aging populations is also a pressing problem in low- and middle-income nations and has led to urgent calls to action.

By 2020, 70% of cancers will occur in developing nations. Gouri ­Shankar Bhattacharyya, MD, PhD, DNB, MRCP, of the Fortis Hospital, Kolkata, India, expanded on this issue. Global attention has been focused on maternal and child health, with little attention paid to the elderly and palliative care.

This problem is compounded by the fact that cancer is still a stigma, by fatalism, by belief in traditional medicine and, for doctors, by lack of reimbursement.

For the entire population of India (1.2 billion), there are 165 qualified and

trained specialists in palliative care. However, even given sociocultural and financial constraints, much could be done relatively easily. This is exemplified in India and Africa by the legal restrictions on the medical use of opiates. One goal of SIOG is to help educate physicians in these countries about caring for older patients and to raise awareness about the appropriate use of opiates.

Surgery The surgical session was presented by Michael T. Jaklitsch, MD, of the DanaFarber/Harvard Cancer Center, Boston.

Supportive and perioperative care is making it possible for more elderly patients to undergo surgery with good outcomes. The 30-day operative mortality following open techniques in the elderly has been reduced to 3%. The mortality problem has largely been solved, but morbidity has not.

According to Dr. Jaklitsch, there is now far more assessment of elderly patients, both before surgery (eg, using the Frailty Index and comprehensive care plans) and after surgery. Both “prehabilitation” and rehabilitation are needed. Physical exercise programs in prehab decrease the risk of pulmonary complications and atelectasis; physical exercise post surgery maintains quality of life. Delirium in the postoperative period is a particular problem.

This disorder is present in 35% to 80% of surgical patients in intensive care and relates to complications, long-term cognitive dysfunction, and mortality.

An important recent development should further improve prospects for the elderly cancer patient undergoing surgery: In July 2015, the American College of Surgeons received a 4-year grant to develop and implement a Geriatric Surgery Verification and Quality Improvement Program.

Geriatrics Geriatrics was presented by Holly M. Holmes, MD, of The University of Texas Health Science Center, Houston.

The presentation focused on new data regarding optimum blood pressure man-

2016 MILAN

ITALY 17-19 NOV.

agement in the elderly, which is a controversial area. The recent SPRINT trial showed that targeting a systolic blood pressure of 120 mm Hg or less reduced mortality.1 About 28% of patients enrolled were aged 75 or older, but those with diabetes were excluded. Even so, the fact that the hazard ratio of 0.67 demonstrated significant benefit in the elderly subgroup will probably encourage more aggressive treatment of blood pressure, with additional drugs being prescribed.

Complications related to polypharmacy are a concern. The PARTAGE study of nursing home residents aged over 80 years found higher 2-year allcause mortality in people with a systolic blood pressure < 130 mm Hg on combination antihypertensive medication, compared with controls.2 Hence, a target of 120 or 130 mm Hg may be appropriate for robust elderly patients but harmful for the “old old” and frail, especially since there is some evidence of better cognition at higher blood pressures.

Dr. Holmes also discussed dementia, where there has been little by way of recent advance. In addition, she addressed the role of new vaccines for pneumonia and herpes zoster.

Medical Oncology Ravindran Kanesvaran, MD, of the National Cancer Centre, Singapore, discussed medical oncology. Developments likely to have a positive impact on the treatment of cancer in the elderly were presented using three recent SIOG position papers as examples.

Chemotherapy with single oral agents (principally capecitabine and vinorelbine) may be somewhat less active than intravenous formulations, but it is better tolerated. For example, vinorelbine is associated with a low rate of febrile neutropenia seen with intravenous agents. The same is true for metronomic chemotherapy.3 Dr. Kanesvaran also addressed improvements in the treatment of diffuse large B-cell lymphoma and the development of new treatment guidelines.4 As

GUEST EDITOR

Stuart M. Lichtman, MD

G

eriatrics for the Oncologist is guest edited by Stuart M. Lichtman, MD, and developed in collaboration with the International Society of Geriatric Oncology (SIOG). Dr. Lichtman is an Attending Physician at Memorial Sloan Kettering Cancer Center, Commack, New York, and Professor of Medicine, Weill Cornell Medical College, New York. He is also President Elect of the International Society of Geriatric Oncology (www.siog.org). in younger patients, studies have shown overall and progression-free survival benefits from R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in elderly patients. But we now have alternative regimens, for example, for patients with cardiovascular morbidity or for those who request less toxic treatment.

In colorectal cancer, new data have shown that the addition of oral capecitabine to FOLFIRI (leucovorin, fluorouracil [5-FU], and irinotecan) does not bring further benefit.5 The ELDA trial—conducted in older breast cancer patients—showed that weekly docetaxel is not more effective than CMF (cyclophosphamide, methotrexate, and 5-FU) and is more toxic.

The novel checkpoint inhibitors have made a significant impact in melanoma. They are less toxic and more effective compared with chemotherapy, which may give them a greater role in

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Geriatrics for the Oncologist

older patients. About 15% to 40% of patients enrolled in checkpoint inhibitor trials have been elderly. This has prompted debate on whether we should still be promoting elderly-specific trials or at least the “geriatricizing” of allcomer trials, or whether the advent of better-tolerated agents will naturally lead to an increase in the proportion of elderly patients in pivotal studies.

Radiotherapy The radiotherapy session was presented by Lorenzo Livi, MD, of the Careggi Hospital, Florence, Italy. New technology allows better identification of targeted volume, avoiding organs at risk and maintaining quality of life, and use of a reduced number of radiation fractions. For example, with short-course radiotherapy for glioblastoma multiforme, 5 fractions resulted in overall and progression-free survival rates similar to rates associated with 15 fractions.6 Dr. Livi also noted that stereotactic body radiation therapy improved overall survival relative to no radiotherapy in patients aged 70 or over with early-stage but medically inoperable non–small cell lung cancer.7 And in breast cancer, he said, it may be possible to reduce the use of whole-breast irradiation in some elderly women (aged 65 and older) who undergo breast-conserving surgery and adjuvant endocrine treatment and are at low risk of local recurrence. Such a strategy produced a low rate of ipsilateral breast cancer at 5 years in the PRIME II study.8

Supportive Care Christopher B. Steer, MBBS, FRACP, of Border Medical Oncology, Wodonga, Victoria, Australia, presented supportive care issues. According to Dr. Steer, the goal of supportive care is to ease the cancer journey during diagnosis, treatment, and either end-of-life care or survivorship. Adequate assessment yields appropriate treatment, he noted. Cancer-related disability is not an acute event but results from an accumulation of events over time. Hence, assessments need to be repeated.

Recent examples of the need for a range of support include a study showing that in the year after cancer diagnosis, elderly patients had increasing levels of depression and cognitive impairment.9 A study based on a single-institution registry found that the risk of functional deficit increases with age, comorbidities, and a lower level of education.10 Among the 65% of patients with a potentially modifiable functional deficit, only 9% were referred for occupational or physical therapy within 12 months.

Polypharmacy Issues Polypharmacy is another significant problem for older patients. One responsibility of those in supportive care is to ensure that patients are not taking unnecessary and potentially harmful drugs.

A comprehensive medication assessment that aims to include all prescription drugs, together with all complementary and alternative medicine products used, is an important part of a geriatric assessment.

Among 234 elderly cancer patients (mean age, 79) assessed at the Jefferson School of Pharmacy in Philadelphia, the mean number of medications was 9.2; 38% were on more than 10 medications, and 40% were judged to be taking potentially inappropriate medication.11 Overall, 77% were on cholesterol-lowering drugs. The relevance of statins in elderly patients with cancer, unless they are being taken for secondary prevention, should be questioned.

The newly updated Beers criteria for potentially inappropriate medication use in older adults provide a guide to drugs that should be avoided in the elderly based on their association with adverse outcomes including confusion, falls, and

cokinetic interactions with new hormonal agents used in advanced prostate cancer.

Wide Range of Topics The meeting covered a wide range of topics including multiple solid tumors, hematologic malignancies, issues in supportive and palliative care, geriatric oncology training, nutrition, and nursing.

Sessions on multidisciplinary care emphasized the complex nature of caring for the older patient. SIOG has placed great importance on the development of guidelines through multiple task forces. This is an important component of the educational mission. SIOG Young Investigators and SIOG Nursing and Allied Health Professionals make valuable contributions to the meeting and the Society as a whole.

The Society presented a number of annual awards, including the Paul ­Calabresi Award (Hans Wildiers, MD, of University Hospitals Leuven, Belgium); the National Representative of the Year (Kwok-Leung Cheung, MD, University of Nottingham); the BJ Kennedy Award for Best Poster (Shabbir Alibhai, MSc, MD, FRCPC, Univer-

All of those taking care of older adult cancer patients are geriatric oncologists. We need to educate ourselves to best manage these complex and vulnerable patients. Our elders deserve nothing less.

—Stuart M. Lichtman, MD

mortality.12 The STOPP criteria are an alternative.13 Reducing polypharmacy reduces complications including adverse drug events and may lead to improvements in costs and possibly quality of life.14 “De-prescribing” should be attempted but needs to be thoughtful, evidence-based, and negotiated with other clinicians, caregivers, and patients themselves.

A session on drug-drug interactions in the elderly cancer patient was chaired

by Stuart M. Lichtman, MD, Memorial Sloan Kettering Cancer Center, New York, and Romano Danesi, MD, University of Pisa, Italy. Drugs taken for cancer can interact with each other, with agents taken as part of supportive care, with drugs taken for comorbid conditions—which are particularly common in the elderly—and with herbal supplements and complementary medicines.

We tend to focus on the narrow therapeutic window of cytotoxics, but the metabolism of tyrosine kinase inhibitors by the cytochrome P450 3A4 enzyme (CYP3A4) makes some of these agents particularly prone to interference with or from other agents sharing this pathway. There is also the potential for adverse pharma-

sity of Toronto); the Nursing & Allied Health Investigator Award (Doris L. van Abbema, RN, MSc, Maastricht University Medical Centre, Netherlands); and the Young Investigator Award was given to ­Cindy Kenis, BSN, PhD candidate, of the University Hospitals Leuven, Belgium).

The next meeting of SIOG will take place November 17–19, 2016, in Milan.

More detailed information about the annual meeting and other society activities are available online at www.siog.org. We encourage everyone to join SIOG, contribute to our journal (Journal of Geriatric Oncology), and participate in our events.

Those caring for older adult cancer patients are all geriatric oncologists. We need to educate ourselves to best manage these complex and vulnerable patients.

Our elders deserve nothing less. n Acknowledgment: The author thanks Robert Stepney for his help in the preparation of the manuscript.

References 1. SPRINT Research Group: A randomized trial of intensive versus standard blood-

pressure control. N Engl J Med 373:21032116, 2015.

2. Benetos A, Rossignol P, Cherubini A, et al: Polypharmacy in the aging patient. JAMA 314:170-180, 2015.

3. Biganzoli L, Lichtman S, Michel JP, et al: Oral single-agent chemotherapy in older patients with solid tumours: A position paper from the International Society of Geriatric Oncology (SIOG). Eur J Cancer 51:24912500, 2015.

4. Morrison VA, Hamlin P, Soubeyran P, et al: Approach to therapy of diffuse large B-cell lymphoma in the elderly: SIOG expert position commentary. Ann Oncol 26:1058-1068, 2015.

5. Papamichael D, Audisio RA, Glimelius B, et al: Treatment of colorectal cancer in older patients: SIOG consensus recommendations 2013. Ann Oncol 26:463-476, 2015.

6. Roa W, Kepka L, Kumar N, et al: International atomic energy agency randomized phase III study of radiation therapy in elderly and/or frail patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 33:4145-4150, 2015.

7. Nanda RH, Liu Y, Gillespie TW, et al: Stereotactic body radiation therapy versus no treatment for early stage non-small cell lung cancer in medically inoperable elderly patients. Cancer 121:4222-4230, 2015.

8. Kunkler IH, Williams LJ, Jack WJ, et al: Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II). Lancet Oncol 16:266-273, 2015.

9. Deckx L, van Abbema DL, van den Akker M, et al: A cohort study on the evolution of psychosocial problems in older patients with breast or colorectal cancer. BMC Geriatr 15:79, 2015.

10. Pergolotti M, Deal AM, Lavery J, et al: The prevalence of potentially modifiable functional deficits and the subsequent use of occupational and physical therapy by older adults with cancer. J Geriatr Oncol 6:194-201, 2015.

11. Nightingale G, Hajjar E, Swartz K, et al: Evaluation of a pharmacist-led medication assessment used to identify prevalence of and associations with polypharmacy and potentially inappropriate medication use among ambulatory senior adults with cancer. J Clin Oncol 33:1453-1459, 2015.

12. Fick DM, Semla TP, Beizer J, et al: American Geriatrics Society 2015 Updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 63:2227-2246, 2015.

13. O’Mahony D, O’Sullivan D, Byrne S, et al: STOPP/START criteria for potentially inappropriate prescribing in older people: Version 2. Age Ageing 44:213-218, 2015.

14. LeBlanc TW, McNeil MJ, Kamal AH, et al: Polypharmacy in patients with advanced cancer and the role of medication discontinuation. Lancet Oncol 16:e333-e341, 2015.

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Education in Oncology Professional Development

How to Help Mentees Succeed

A Conversation With David H. Johnson, MD, MACP, FASCO

By Jo Cavallo

A

lthough formal mentoring programs in medical education were not launched in the United States until the late 1990s,1 today they are regarded as playing an essential role in the career development of medical trainees and have been associated with improvements in research, teaching, and patient care.2 Mentoring is defined as a personal developmental relationship in which a more experienced or more knowledgeable person (the mentor) provides guidance for a less experienced or less knowledgeable person (the mentee).3

tion (FDA) in the treatment of lung cancer. Dr. Johnson served as ASCO President from 2004–2005 and was instrumental in advancing ASCO’s Quality Oncology Practice Initiative (QOPI®), as well as the development of ASCO’s Cancer Survivorship Program. He has also served on the FDA Oncologic Drugs Advisory Committee, as well as on the Board of Directors of the National Comprehensive Cancer Network, the International Association for the Study of Lung Cancer, and the LIVESTRONG Foundation.

A satisfying, successful mentorship relationship never really ends. Those who helped me during my early training are people I still turn to for guidance today. It is a different kind of relationship, more like a strong friendship between two colleagues than a parent/child relationship, but it still provides me with the tools I need for continued professional growth.

—David H. Johnson, MD, MACP, FASCO

Mentors can have a profound impact on the career direction of young trainees, said David H. Johnson, MD, MACP, FASCO. Dr. Johnson credits his own early mentor, Paul Webster, MD, who was Chairman of Medicine at the Medical College of Georgia when Dr. Johnson was Chief Resident there in the late 1970s, with steering him toward a career in academic medicine and a specialty in oncology, especially in the research and treatment of lung cancer.

During Dr. Johnson’s tenure at Vanderbilt University Medical School, where he served as Director of the Division of Hematology and Medical Oncology and Deputy Director of the Vanderbilt-Ingram Cancer Center, he helped develop bevacizumab (Avastin) and erlotinib, both now approved by the U.S. Food and Drug Administra-

In addition to these career achievements, Dr. Johnson said that he is most proud of the successes of the young trainees and junior faculty he has mentored over his 35-year career in oncology. The ASCO Post talked with Dr. Johnson, the Donald W. Seldin Distinguished Chair in Internal Medicine and Chairman of the Department of Internal Medicine at the University of Texas Southwestern Medical Center in Dallas, about the value of mentorship and the qualities necessary to be an effective mentor.

Choosing the Right Mentor Please talk about the benefits and value of mentorship.

One of the most important decisions a person preparing for a career in medicine can make is choosing the

right mentor. Mentoring usually starts in medical school and can be instrumental in helping students choose a specialty and subspecialty to pursue and decide on a career in academics, community practice, government, or private industry.

The key component to career development is having the right mentor.

Mentorship does not need to end once physicians are established in their career. It is a useful relationship to have throughout one’s career. I still have mentors and feel very fortunate to have people I can turn to for advice, insight, and guidance all the way through my career.

Necessary Qualities What are the qualities of a good mentor?

A good mentor is someone who is well regarded in his or her field, possesses high standards, is objective, honest, direct, patient, approachable, and a good listener, observer, and problem solver. Most important, a good mentor tends to be selfless and interested in the successes of others; he or she does not use trainees or mentees for personal benefit. I know that sounds obvious, but it is an important point to make.

Personal Sacrifices The Accreditation Council for Graduate Medical Education has identified six core competencies to evaluate residents in training. They include patient care, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice. How can mentors help mentees succeed in these areas?

The main way is through role modeling. If the mentor has the attributes I described earlier, he or she will have competency in these six areas of training.

Mentors have to have medical knowledge, have to be good communicators, and have to understand how institutional systems work; this does not mean just how hospitals and clinics function but also the systems needed to make scientific laboratories work effectively and efficiently.

Leora Horn, MD, MSc

E

GUEST EDITOR

ducation in Oncology focuses on faculty development, medical education curricula, fellowship training, and communication skills. The column is guest edited by ­Leora Horn, MD, MSc, Associate Professor of Medicine, Assistant Director of the Educator Development Program, and Clinical Director of the Thoracic Oncology Program at Vanderbilt University School of Medicine, Nashville.

Mentoring is more like a parent/ child relationship than a teacher/student relationship. There are some elements of teacher and student in mentoring, but a good mentor, like a good parent, is going to make personal sacrifices for the benefit of the trainee/ mentee. Although many good teachers do make personal sacrifices for their students, it is not necessarily an inherent part of their role.

Role of the Mentee What are the key responsibilities of a mentee?

Mentees cannot outsource their career development. They must be full participants in their advancement. They have to take charge of their program of study, have to read, do their course work, and hone their technical skills.

Mentees should continuously apprise their mentor of their progress and any problems they are experiencing and work proactively with their mentor to solve potential difficulties.

Mentees also have the responsibility

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | DECEMBER 25, 2015

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Education in Oncology

to recognize when the relationship with their mentor is no longer working and make a change if necessary. And, because mentors have different strengths and qualities, it is important for mentees to establish relationships with multiple advisors to become exposed to a variety of professional experiences and perspectives.

Role of the Mentor What are some of the key responsibilities of a mentor?

Mentors have many roles in the career development of their mentees. They are teachers, role models, networkers, and counselors. They schedule regular, structured meetings for advising their mentees on developing a career plan that includes professional milestones to be met. Mentors help mentees develop better writing, speaking, and strategic thinking skills. They also teach trainees how to assess journal articles critically, write technical papers and grants, and revise manuscripts.

Career Goals and Expectations How often should mentors and mentees meet, and what should be discussed at these meetings?

There is not a hard and fast rule on the optimal number of times to meet.

It depends on the needs of the mentee and the schedules of the mentor and mentee. Some mentees need structured, directed guidance and require regularly scheduled meetings, whereas other mentees may be more advanced, preferring less structured supervision.

Regardless, at the initial meeting, the mentee’s professional goals, knowledge, and skill gaps should be assessed.

Understanding these items can help guide the frequency of meetings. Common mentee needs include help with establishing career goals, choosing fellowships, developing communication and time management skills, and networking.

Creating specific written career development goals to be accomplished over a set period (1 month, 6 months,

5 years) is a good idea. The mentor and mentee should also establish the best way of communicating, such as in person, by phone, via e-mail, or all three. During each meeting, the mentee should describe progress he or she has made since the last meeting and ask what is expected in terms of accomplishments before the next meeting.

Transitioning to Independence How can mentors help mentees transition to independence?

We use the term progression-free survival, or PFS, to describe how well a cancer treatment works. I use PFS as an abbreviation for “prolonged fellow syndrome” to describe the danger of trainees becoming long-term extensions of their mentors—always a “risk” if the mentee remains at the institution where he or she trained.

A good mentor will develop a separation plan early in the relationship, as the mentee progresses in his or her career development and after the men-

tee has achieved his or her goals.

That said, a satisfying, successful mentorship relationship never really ends. Those who helped me during my early training are people I still turn to for guidance today. It is a different kind of relationship, more like a strong friendship between two colleagues than a parent/child relationship, but it still provides me with the tools I need for continued professional growth. n

Disclosure: Dr. Johnson reported no potential conflicts of interest.

References 1. Buddeberg-Fischer B, Herta KD: Formal mentoring programmes for medical students and doctors—A review of the Medline literature. Med Teach 28:248-257, 2006.

2. Illes J, Glover GH, Wexler L, et al: A model for faculty mentoring in academic radiology. Acad Radiol 7:717-726, 2000.

3. Detsky AS, Baerlocher MO: Academic mentoring—How to give it and how to get it. JAMA 297:2134-2136, 2007.

Announcements

UnitedHealthcare Signs Agreement With Foundation Medicine for Genomic Profiling Assay for Non–Small Cell Lung Cancer

F

oundation Medicine, Inc. recently announced that it has signed a national agreement for the company’s comprehensive genomic profiling as-

The assay is a comprehensive genomic profile that enables physicians to make treatment decisions for patients with cancer by identifying the mo-

Lack of reimbursement for comprehensive genomic profiling tests continues to be one of the major barriers impeding patient access to potentially life-extending therapies for which the patient is a molecular match.

—Bonnie J. Addario

say for solid tumors, called FoundationOne, with UnitedHealthcare. The agreement, which became effective December 15, 2015, covers the assay for patients with stage IV non-small cell lung cancer (NSCLC).

lecular growth drivers of their cancers and by helping oncologists match the identified drivers with relevant targeted therapeutic options. Requiring only a small amount of tumor tissue, the assay interrogates the entire coding sequence

of 315 cancer-related genes plus select introns from 28 genes that are known to be altered in solid tumors.

“UnitedHealthcare’s coverage decision is a critical first step towards ensuring that comprehensive genomic profiling becomes standard-of-care treatment for patients with metastatic disease,” said Bonnie J. Addario, lung cancer survivor, and Founder of the Bonnie J. Addario Lung Cancer Foundation and the Addario Lung Cancer Medical Institute. “Lack of reimbursement for comprehensive genomic profiling tests continues to be one of the major barriers impeding patient access to potentially life-extending therapies for which the patient is a molecular match.”

“This national coverage agreement with UnitedHealthcare is an important step towards broader reimbursement for Foundation Medicine, and importantly, it’s a significant advance for patients with metastatic NSCLC,” said

Michael Pellini, MD

Michael Pellini, MD, Chief Executive Officer for Foundation Medicine.

“Studies demonstrate that improved clinical outcomes are achieved by matching patients to targeted therapies based on the unique genomic alterations contributing to the disease. We look forward to building upon our relationship with UnitedHealthcare and other national insurers as we continue to demonstrate clinical and economic evidence supporting coverage and payment for FoundationOne in additional cancer types.” n

The ASCO Post | DECEMBER 25, 2015

PAGE 126

Book Review

The Lawless and Uncertain World of Medicine

By Ronald Piana

T

he Emperor of All Maladies, written by the Indian-born American oncologist Siddhartha Mukherjee, MD, PhD, won the 2011 Pulitzer Prize for General Nonfiction. His 500-pluspage book traces the history of cancer from its first recorded identification 4,600 years ago by the Egyptian physician Imhotep. Dr. Mukherjee recently published another book, The Laws of Medicine, which—given that it’s 96 pages—is a flyweight compared with its heavyweight predecessor. A central reason for the book’s slenderness is that it was derived from a TED talk, which is usually limited to 18 to 20 minutes.

TED has joined forces with publishing titan Simon & Schuster to create a new imprint called TED Books. It’s a clever concept, since a lot of very bright people showcase their bright ideas in TED talks, which, if interesting enough, can now be packaged as a book.

Castle uses the experience to summarize the dilemma of modern medicine: “It’s easy to make perfect decisions with perfect information. Medicine asks you to make perfect decisions with imperfect information.” This is the crux of Dr. Mukherjee’s thesis.

Point of Enlightenment After graduating from medical school, and during his internship, residency, and fellowship, Dr. Mukherjee found himself running into as many questions as answers. It’s worth noting that this is not an uncommon point of enlightenment for many bright young doctors who are not as famous as the author. He writes, “My medical education had taught me plenty of facts, but little about the spaces that live between facts…. I wondered if the compulsive naming of parts, diseases, and chemical reactions … was a mecha-

Although windy at times, there are little gems within this slim book worth searching for. The Laws of Medicine is a recommended read.

Perfect Decisions With Imperfect Information Dr. Mukherjee has a flair for heavy messaging with colorful anecdotes.

In his prologue, for example, he tells a story from his days as a medical resident at Massachusetts General Hospital. The central character of the story is Dr. ­Castle, a hard-nosed surgeon from Texas who was so technically adept at surgery that he allowed his students to do most of the operating, knowing that he could anticipate their mistakes and correct them swiftly thereafter.

This book is about information, imperfection, uncertainty, and, according to its high-minded author, the future of medicine. To that end, the author describes a woman in her 50s with a modest-sized tumor in her intestine, who is in the operating room as a resident begins the surgical procedure to excise the tumor, under supervision by the famous Dr. Castle.

The case takes a quick turn for the worse when the resident reaches down to cut the tumor out, and the blood vessels surrounding it begin to leak.

He goes into slow-motion panic, but under Dr. Castle’s supervision, the procedure ends a success. Nevertheless, after the successful operation, Dr.

nism invented by doctors to defend themselves against a largely unknowable sphere of knowledge.”

Perhaps a Pulitzer Prize winner can get away with sweeping accusations that doctors invent mechanisms to defend themselves against things that they simply do not know. Still, it’s a soft statement that needs to be backed up by anecdotal data. But this is not a book that is data driven. That’s not necessarily a problem, as long as you don’t stray too far into musings that wax poetic but are at odds with the reality of clinical care.

Dr. Mukherjee likes to use evocative prose and analogy in his writing. In the buildup to his “three laws of medicine,” he lays the philosophical underpinnings in recalling his early days as a resident at Massachusetts General Hospital, running along the banks of the Charles River and ruminating “on cases that I had seen that week. By the end of the first 6 months, I had witnessed more than a dozen deaths, including that of a young man, no older than I, who died of organ failure while awaiting a heart transplant.” Unfortunately there are just so many viable hearts available. You can’t fault the system for that.

In the same section, Dr. Mukherjee has a moment of insight while recall-

ing a patient: “Illness reminds you that spontaneity, too, is a human right.” Putting aside the shakiness of that assumption, Dr. Mukherjee segues directly into this: “Part of the horror of hospitals is that everything is on time: medicines arrive on schedule; the sheets are changed on schedule; the doctors round at set times; even urine is collected in a graduated pouch on a timer.” Imagine if urine wasn’t collected on time?

“Horror” is an aggressive noun denoting a very strong feeling of fear, dread, and shock. It doesn’t fit, especially when the author blames hospital efficiency for that horror. Perhaps Dr. Mukherjee is pointing out that in a health-care system based increasingly on guidelines and digitized protocols, we begin to pay less attention to the art of medicine. It’s a valid point, and as a cancer specialist, he should know that the oncology community wrestles with technology and guidelines that too often rob doctors of precious one-on-one time with their patients, which is so needed in quality care.

The Three Laws The Laws of Medicine is structured around three laws, and for reductionist readers, Dr. Mukherjee’s honing the solutions to the problems of our $3 trillion health-care system into three laws over a measly 96 pages might be satisfying.

These are his three laws: Law One: A strong intuition is much more powerful than a weak test.

Law Two: “Normals” teach us rules; “outliers” teach us laws.

Law Three: For every perfect medical experiment, there is a perfect human bias.

Dr. Mukherjee devotes a chapter to each law and begins each with a well-written historic example of a forward-looking doctor or scientist who understood that outliers and intuition coupled with critical thinking skills could lead to positive change in the practice of medicine. He also offers his own vivid experiences in the clinic to make his points.

For example, he describes a compelling diagnostic conundrum he faced with a patient experiencing weight loss, fatigue, malaise, and other symptoms that could point to cancer. After putting his patient through a battery of standard tests, he remained flummoxed. He then had an epiphany triggered by simple

Bookmark Title: The Laws of Medicine: Field Notes From an Uncertain Science Author: Siddhartha Mukherjee Publisher: TED Books/ Simon & Schuster Publication date: October 13, 2015 Price: $16.99; hardcover, 96 pages observation of his patient’s social environment. Without the patient’s explicit knowledge, Dr. Mukherjee tested him for HIV and discovered that the patient had AIDS, the point being: Dr. ­Mukherjee conducted his own investigation outside the constraints of standard testing.

Vital Factor As Dr. Mukherjee eloquently points out in his three laws, we need to embrace the art of medicine. He uses anecdotes and some data to make this point, much of which is cancer-based.

For instance, he offers some clarity about the ever-contentious prostatespecific antigen–screening debate as well as the emerging field of immunotherapy. He stresses, above all, that human decision-making remains absolutely vital to medicine. “The medical revolution will not be algorithmized,” he declares.

He’ll get no argument from The ASCO Post readers. Although windy at times, there are little gems within this slim book worth searching for. The Laws of Medicine is a recommended read. n

DID YOU KNOW? FOR NEARLY 15 YEARS (1999-2014), NO FDAAPPROVED, SECOND-LINE REGIMEN EXTENDED OVERALL SURVIVAL VERSUS DOCETAXEL ACROSS A BROAD POPULATION OF PATIENTS WITH METASTATIC NSCLC1-4

NSCLC=non-small cell lung cancer.

Visit www.CYRAMZAHCP.com for more information CYRAMZA® (ramucirumab), in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

ADVANCING THE SECOND-LINE TREATMENT OF METASTATIC NSCLC5 CYRAMZA is the first antiangiogenic agent FDA approved in combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.5

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event.

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events.

In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel.

Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs)

• Serious, sometimes fatal, ATEs including myocardial infarction, cardiac

arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension

• An increased incidence of severe hypertension occurred in patients

receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue

CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs. Gastrointestinal Perforations

• CYRAMZA is an antiangiogenic therapy that can increase the risk of

gastrointestinal perforation, a potentially fatal event. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

• Impaired wound healing can occur with antibodies inhibiting the VEGF

pathway. CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis

• Clinical deterioration, manifested by new onset or worsening

encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

• RPLS has been reported at a rate of <0.1% in clinical studies with

CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

• Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio

for the development of worsening of proteinuria during CYRAMZA therapy.

Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

CYRAMZA plus docetaxel demonstrated a statistically significant improvement in overall survival vs docetaxel5 OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) CYRAMZA + docetaxel (n=628)

1.0

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

10.5

15% INCREASE IN MEDIAN OS

MONTHS

(9.5, 11.2) Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

3

6

12

15

18

21

24

27

30

33

36

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

9

527

415

329

231

156

103

70

45

23

11

2

0

501

386

306

197

129

86

56

36

23

9

0

0

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively 5

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)5 • Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001) — The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively • ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)* CI=confidence interval; OS=overall survival; PFS=progression-free survival; ORR=objective response rate. *Intent-to-treat population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.6 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253) The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.5 Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction

• Monitor thyroid function during treatment with CYRAMZA.

Embryofetal Toxicity

• Based on its mechanism of action, CYRAMZA can cause fetal harm

when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions

• The most commonly reported adverse reactions (all grades; grade 3/4)

occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/ mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).

• The most common serious adverse events with CYRAMZA plus docetaxel

in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

• In patients ≥65 years of age, there were 18 (8%) deaths on treatment

or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.

• Treatment discontinuation due to adverse reactions occurred more

frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

• For patients with nonsquamous histology, the overall incidence of

pulmonary hemorrhage was 7% and the incidence of grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and

the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel.

• Clinically relevant adverse reactions reported in ≥1% and <5% of

CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions

• No pharmacokinetic interactions were observed between ramucirumab

and docetaxel.

Use in Specific Populations

• Pregnancy: Based on its mechanism of action, CYRAMZA can cause

fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks.

No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.

• Lactation: Because of the potential risk for serious adverse reactions in

nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.

• Females of Reproductive Potential: Advise females of reproductive potential

that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page.

RB-L HCP ISI 24APR2015 References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.

Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/fda-docetaxel/print. Accessed August 26, 2014.

4. National Cancer Institute. Cancer drug information. FDA approval for ramucirumab. http://www.cancer.gov/ cancertopics/treatment/drugs/fda-ramucirumab#nsclc. Accessed May 4, 2015. 5. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 6. Garon EB, Ciuleanu T-E, Arrieta O, et al.

Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

RB96549 05/2015 PRINTED IN USA © Lilly USA, LLC 2015. All rights reserved.

CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown.

In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients.

Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women.

Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease.

Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intratumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology.

Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation.

Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxeltreated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%).

The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3.

Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3 CYRAMZA plus docetaxel Placebo plus docetaxel (N=627) (N=618) Adverse Reactions (MedDRA) System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 10 10 Neutropenia 55 49 46 40 Thrombocytopenia 13 3 5 <1 Gastrointestinal Disorders Stomatitis/Mucosal inflammation 37 7 19 2 Eye Disorders Lacrimation increased 13 <1 5 0 General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 50 11 Peripheral edema 16 0 9 <1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 7 <1 Vascular Disorders Hypertension 11 6 5 2 Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36).

Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.

Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to docetaxel, refer to the current respective prescribing information.

PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event.

• Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment.

• Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA. Additional information can be found at www.CYRAMZAhcp.com.

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2015, Eli Lilly and Company. All rights reserved.

RB-L HCP BS 04MAY2015 CYRAMZA® (ramucirumab) injection

RB-L HCP BS 04MAY2015

ASCOPost.com | DECEMBER 25, 2015

PAGE 131

ASH Annual Meeting ASH Announces 2016 Scholar Award Recipients

T

he American Society of Hematology (ASH) has announced the recipients of its 2016 Scholar Awards. One of ASH’s most prestigious award programs, the ASH Scholar Award program financially supports fellows and junior faculty dedicated to careers in hematology research as they transition from training programs to careers as independent investigators.

Each Scholar Award provides up to $100,000 for fellows and $150,000 for junior faculty over a 2- to 3-year period. The program funds hematologists in North America who conduct basic, translational, and clinical research that furthers the understanding and treatment of blood disorders. ASH Scholar Awards are made possible through support from the ASH Foundation, as well as from the corporate community, individual donors, and funds committed by the Society. ASH recognizes this year’s corporate supporters: Bayer HealthCare, Celgene Corporation, Genentech, Inc., Gilead Sciences, Inc, Jake Wetchler Foundation for Innovative Pediatric Cancer Research, and Takeda Oncology.

“For 30 years, the ASH Scholar Award program has supported young hematologists, many of whom are now leaders in the field,” said 2015 ASH President David A. Williams, MD, President of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Leland Fikes Professor of Pediatrics at Harvard Medical School. “I am very pleased that for the past 2 years, the ASH Executive Committee has committed additional funding for this very important initiative, allowing us to fund many more scholars. Even with this additional funding, these awards are highly competitive.

When talented scholars are provided the resources, time, and support they need to establish independent careers through programs like the ASH Scholar Awards, their careers thrive, and they are well positioned to make a notable impact on research and patient care. I congratulate all of the recipients and hope that this award is as important to their careers as it was to mine many years ago.”

The 2016 Scholar Award recipients are: Basic Research Fellows • Connie Arthur, PhD, Emory University • Timothy Campbell, MD, PhD, Uni-

versity of California, San Francisco • Hamza Celik, PhD, Washington University School of Medicine, St. Louis • Timothy Chlon, PhD, Cincinnati Children’s Hospital • Jesús Delgado-Calle, PhD, Indiana University School of Medicine • Maria Kleppe, PhD, Memorial Sloan Kettering Cancer Center • Jana Krietsch, PhD, University of California, Santa Cruz • Maksim Mamonkin, PhD, Baylor College of Medicine • Julia Maxson, PhD, Fred Hutchinson Cancer Research Center • Ryohichi Sugimura, MD, PhD, Boston Children’s Hospital • Alberto Yanez-Boyer, PhD, Cedars Sinai Medical Center • Steven Yea, MD, PhD, University of California, Los Angeles School of Medicine Clinical Research Fellows • Connie Batlevi, MD, PhD, Memorial Sloan Kettering Cancer Center • Andrew Branagan, MD, Yale School of Medicine • Brian Parkin, MD, University of Michigan Basic Junior Faculty • Shannon Carty, MD, University of Pennsylvania • Rikhia Chakraborty, PhD, Baylor College of Medicine • Satiro De Oliveira, MD, University of California, Los Angeles • Joji Fujisaki, MD, PhD, Columbia University • Malay Haldar, MD, PhD, University of Pennsylvania • Sang Min, MD, PhD, University of Pennsylvania • Stephen Oh, MD, PhD, Washington University School of Medicine, St. Louis • Qin Qin, PhD, The Johns Hopkins University • Christopher Sturgeon, PhD, Washington University School of Medicine, St. Louis • Owen Tamplin, PhD, Boston Children’s Hospital/Harvard Medical School • Valeria Visconte, PhD, Cleveland Clinic • Pamela Wenzel, PhD, The University of Texas Medical School at Houston Clinical Junior Faculty • M. Paula Aristizabal, MD, University of California, San Diego • Jonathon Cohen, MD, Emory University • Amy Sobota, MD, MPH, Boston University School of Medicine continued on page 133

The ASCO Post | DECEMBER 25, 2015

PAGE 132

Issues in Oncology End-of-Life Care

Perceptions of End-of-Life Care Differ Sharply Between African Americans and White Americans

By Ronald Piana

S

tudies demonstrate that patients with advanced cancer who are not actively engaged in planning their endof-life care often receive overly aggressive, physically taxing, costly and unnecessary treatment toward life’s end.

Recent findings indicate that African

likely than white Americans to entrust their end-of-life care to palliative care specialists and hospice experts.

“However, my research shows that today’s ongoing disparities in our health-care system among African Americans are actually more relevant

Put simply, many African Americans feel that they receive lower quality health-care services than white Americans.

—Kimberly S. Johnson, MD

Americans appear to be more apt to request aggressive end-of-life care than white patients—and far less likely to embrace palliative care and hospice programs. These clinical biases among African Americans with advanced disease result in poorer outcomes compared with their white counterparts.

A Multilayered Issue of Trust According to federal data, only one-third of eligible African American Medicare beneficiaries enroll in hospice, compared with one-half of white beneficiaries—a racial gap that is expected to grow. Likewise, the gap between the races is even wider in advanced care planning, with about 40% of white seniors over the age of 70 having advanced care–planning documents vs approximately 16% of African American seniors. Also, as more minority seniors join the ranks of Medicare—up to 42% of those over the age of 65 by the year 2050—the racial gap in quality care is likely to widen.

This disparity in quality end-of-life care among African Americans may reflect lack of access to providers, insufficient health insurance, patients living in poverty, or a general mistrust of the health-care system. According to K ­ imberly S. Johnson, MD, a geriatrician and palliative care specialist at Duke University, endemic suspicion of the U.S. health-care system stemming from historical exploitation—such as the infamous Tuskegee syphilis experiment carried out from 1932–1972 on unsuspecting black men in Alabama— is one reason African Americans are less

to this issue than the historical backdrop. Put simply, many African Americans feel that they receive lower quality health-care services than white Americans,” commented Dr. Johnson.

She continued: “So if you believe that the system is unfairly prejudiced against you and someone proposes hospice as a choice, which essentially focuses entirely on comfort instead of the more costly disease-modifying therapies, you’re probably going to be suspicious and far less likely to embrace hospice.”

Policy and Education Dr. Johnson noted that some disparity-of-care issues could be dealt with on the policy level. “There’s a demonstration project called the Medicare Choices program, which is testing a model of care in which patients will be able to receive hospice-type care along with diseasemodifying care, so they are not asked to choose one care direction over another.

This approach might improve the relationship and trust African Americans have with the health-care system, which in turn would lead to greater utilization of hospice,” said Dr. Johnson.

When asked whether the relatively new initiative to integrate spirituality into the continuum of end-of-life care could help bridge some of the mistrust of the system among African Americans, Dr. Johnson replied: “There are really no data that can link bringing spirituality into care helps the mistrust issue. However, studies such as those by Tracy Balboni, MD, MPH, and others do indeed show that support of terminally ill patients’ spiritual needs by the

medical team is associated with fewer calls for aggressive care, greater hospice utilization, and overall better quality of life near death.”

Noting that education is key to bridging the trust gap among African Americans, Dr. Johnson commented: “Given the strong ties African Americans have traditionally held with their churches, there is the opportunity for pastors and other religious leaders to serve as outreach and educational conduits to their congregations about the benefits of programs like hospice.”

Disparity of Doctors Several studies have found that patients who are treated by physicians with whom they share racial or gender characteristics report greater satisfaction with their care and higher rates of medication compliance. Moreover, African American medical students appear to be likelier than any other group to have a firm commitment to practicing in underserved areas, with 55% saying they plan to do so. Furthermore, African Americans account for 13% of the U.S. population, but only 6% of 2011 matriculants were African American, as are just 4% of practicing doctors.

Academic Medicine’s Role in Closing the Racial Gap

B

ringing in physicians from the community to serve as faculty to help increase the presence of African American males; Strategic recruitment of future doctors from underserved communities; Working with Minority Serving Institutions; and Improved career-path advising in high school and college From the Association of American Medical Colleges annual report (https://members. aamc.org/). the problem has deep roots, and we still have a long way to go.”

In 2010, President Obama signed the Affordable Care Act (ACA) into law, which not only brought health coverage to most uninsured Americans, but also had certain provisions

The black community in south Los Angeles has always been desperate for health-care coverage. But what good does coverage do if there are no providers in the community?

—Loretta Jones

Asked how the lack of African American doctors affects end-of-life care, Dr. Johnson said: “Certainly in the clinical settings of palliative care and hospice, people naturally feel more comfortable having a doctor that looks like them and shares cultural similarities. A recent report by the Association of American Medical Colleges (AAMC) assessed the issue of underrepresentation of African American doctors in the system and offered several ways forward. There have been local initiatives to recruit African American students into medical schools, with some success, but

designed to close the disparitiesof-care gap. Loretta Jones is the Founder and CEO of Healthy African American Families (HAAF), a project based in Los Angeles that is funded by the Centers for Disease Control and Prevention.

The ASCO Post asked Ms. Jones for her on-the-ground evaluation of her community’s trust in the health-care system and how the ACA has helped to bridge the disparities-of-care gap.

“I’m very glad that the ACA was passed into law. The black community in south Los Angeles has always been desperate for health-care cover-

ASCOPost.com | DECEMBER 25, 2015

PAGE 133

Issues in Oncology

age. But what good does coverage do if there are no providers in the community? If I develop breast cancer, there are no oncologists in this area to treat me,” she stated.

Ms. Jones continued: “We have what we call storefront doctor mills, which are staffed by people from overseas and do not have the best interest of the black community in mind. Plus, there is a cultural void that people in our community don’t feel comfortable with.”

adopted an end-of-life model of care that is tailored for the white middle class. And it’s important to note that

Traditionally, we’ve adopted an end-of-life model of care that is tailored for the white middle class. And it’s important to note that the word perception [in perception barriers] is misleading, because this clinical disparity is supported by the literature.

Perception Barriers Camille P. Wicher, PhD, is Vice President of Corporate Ethics and Research Subject Protection at Roswell Park Cancer Institute. Her doctoral dissertation was titled, “End-of-Life Care: Different Perceptions Between African Americans and white Americans.”

When asked to comment on the perception barriers that dissuade many African Americans from taking advantage of best practices end-of-life care, Dr. Wicher, replied: “To truly make progress in end-of-life care in the African American community, we first need to realize the cultural differences that affect the way people view health care. Traditionally, we’ve

—Camille P. Wicher, PhD

the word perception is misleading, because this clinical disparity is supported by the literature.”

Dr. Wicher explained that her research consisted of the current literature and her own fact-finding forays within the African American community in Buffalo, which she described as a fairly generalizable population across the country. She spoke to a cross-section of people, from the average lay public to church and civic leaders. Surprisingly, she found that once the goals of hospice were out-

Education Barriers Dr. Wicher said that trust in the system is still a huge issue above and beyond historical abuses. “Many of the African Americans I spoke to believe that the barriers of the past still exist today. Other issues compound the mistrust,” she explained.

Dr. Wicher continued: “For instance, many patients and their caregivers didn’t recognize that the end was near.

And that was largely due to ambiguous physicians who were reluctant to broach the subject of dying. More-

over, the families that I spoke to felt that no one could provide the kind of care for their loved ones but the family itself. They firmly believe that it is their responsibility to care for dying family members at home.”

Dr. Wicher concluded: “None of the people I spoke to knew about the hospice in-home care benefit. So besides a cultural perception issue, this is largely an education issue.”

Awareness of a problem within a health-care system is the key for substantive change. The fields of palliative care, hospice, and psychosocial oncology services began with awareness and recognition of clinical need.

The oncology community, the most introspective of medical disciplines, has worked diligently to address disparities of care within our patient populations. Oncology has the knowledge and the tools to address the special needs of our patients with advanced disease. The next challenge is to ensure that these vital end-oflife services are embraced by all of our patients. n Disclosure: Drs. Johnson, Balboni, and Wicher as well as Ms. Jones reported no potential conflicts of interest.

Drew Ridge, MD, PhD, FACS, Elected to Medical Staff President at Fox Chase Cancer Center–Temple Health

Scholar Award Recipients continued from page 131

Joanne Levy, MD, Memorial Award for Outstanding Achievement Omar Abdel-Wahab, MD, of Memorial Sloan Kettering Cancer Center, received the 2015 Joanne Levy, MD, Memorial Award for Outstanding Achievement. This award is made possible by the family of past ASH Scholar Award recipient and distinguished Society member Joanne Levy, MD, who passed away in 2004, and is presented to the current ASH Scholar with the highest-scoring abstract for the ASH Annual Meeting and Exposition, as determined by the appointed abstract reviewers.

Dr. Abdel-Wahad is being honored for his plenary abstract (Abstract 4), “Therapeutic Targeting of Spliceosomal Mutant Myeloid Leukemias Through Modulation of Splicing Catalysis.” His current research focuses on the functional understanding of genetic alterations in patients with chronic myeloid and lymphoid leukemias. Supported by the ASH

lined in detail, they aligned with most of the desires African Americans have for end-of-life care.

J Omar Abdel-Wahab, MD

Scholar Award, Dr. Abdel-Wahab is working to understand the biological and therapeutic significance of epigenetic and transcriptional alterations in patients with myelodysplastic syndromes. In addition, Dr. Abdel-Wahab and his colleagues are investigating therapeutic approaches for selective targeting of splicesomal mutant cancers.

Dr. Abdel-Wahab received his medical degree from Duke University School of Medicine and is currently an Assistant Attending Physician on the Leukemia Service at Memorial Sloan Kettering Cancer Center and a member of the Human Oncology and Pathogenesis Program. n

Visit The ASCO Post website at

ASCOPost.com

ohn Andrew “Drew” Ridge, MD, PhD, FACS, Chief of Head and Neck Surgery and Louis Della Penna Family Chair in Head and Neck Oncology at Fox Chase Cancer Center–Temple Health, has been elected President of the Medical Staff at the Center.

John Andrew “Drew” Ridge, MD, PhD, FACS

In his new role, Dr. Ridge will work with President and CEO Richard Fisher, MD, and hospital administration to improve physician credentialing and privileging processes, and select physician representatives to committees that oversee patient safety and quality control.

“Dr. Ridge has a longstanding interest in quality of care and he has an excellent reputation among his peers, which makes him uniquely qualified to be Medical Staff President,” said James Helstrom, MD, MBA, Chief Medical Officer of Fox Chase Cancer Center. “I’m confident he’ll be very successful in taking on these responsibilities.”

Dr. Ridge is one of the leading voices in surgical oncology today. His extensive expertise in treating head and neck cancers has been recognized nationally and abroad. He has been Co-Chair of the National Cancer Institute Head and Neck Steering Committee, as well as President of the American Head and Neck Society and the American Radium Society. He has held leadership positions in the Eastern Cooperative Oncology Group and NRG Oncology cooperative groups.

“I’m honored by this sign of respect from my colleagues,” Dr. Ridge said. “I look forward to working with the medical staff at Fox Chase to implement the quality and safety structures that lead to better clinical outcomes.” n

When multiple myeloma relapses

INDICATION Kyprolis® (carfilzomib) for Injection is a proteasome inhibitor that is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.

IMPORTANT SAFETY INFORMATION Cardiac Toxicities: New onset or worsening of pre-existing cardiac

failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration.

• Withhold

Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis based on a benefit/ risk assessment.

• Adequate

hydration is required prior to each dose in Cycle 1. Monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.

• Patients

≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities may be at greater risk for cardiac complications.

until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment.

Dyspnea: Dyspnea was reported in patients treated with Kyprolis.

Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Hypertension: Hypertension, including hypertensive crisis and

hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Venous Thrombosis: Venous thromboembolic events (including

deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. Thromboprophylaxis is recommended and should be based on an assessment of the patient’s underlying risks, treatment regimen, and clinical status.

Acute Renal Failure: Cases of acute renal failure and renal

Infusion Reactions: Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.

Tumor Lysis Syndrome: Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving Kyprolis.

Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold Kyprolis until TLS is resolved.

Thrombocytopenia: Kyprolis causes thrombocytopenia with

insufficiency adverse events (renal impairment, acute renal failure, renal failure) have occurred in patients receiving Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy.

This risk was greater in patients with a baseline reduced estimated creatinine clearance. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS),

acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving Kyprolis. Some events have been fatal.

In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in patients treated with Kyprolis. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for PAH

recovery to baseline platelet count usually by the start of the next cycle.

Thrombocytopenia was reported in patients receiving Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure,

including fatal cases, have been reported during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate.

Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS): Cases of TTP/HUS including fatal outcome

have occurred in patients receiving Kyprolis. Monitor for signs and symptoms of TTP/HUS. Discontinue Kyprolis if diagnosis is suspected.

If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, KYPROLIS, and KYPROLIS logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2015 Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary, Thousand Oaks, CA USA-KYPR-118488 November 2015 Printed in USA

Ne w

RESPOND

In dic at

ion

with the power of significantly improved progression-free survival (PFS)

Posterior Reversible Encephalopathy Syndrome (PRES):

Cases of PRES have occurred in patients receiving Kyprolis. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

Embryo-fetal Toxicity: Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. â&#x20AC;˘ Females of reproductive potential should be advised to avoid becoming

pregnant while being treated with Kyprolis and the potential hazard to the fetus if Kyprolis is used during pregnancy.

ADVERSE REACTIONS The most common adverse events occurring in at least 20% of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch or call 1-800-FDA-1088.

References: 1. KYPROLIS [prescribing information]. Thousand Oaks, CA: Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary; 2015. 2. Stewart AK, Rajkumar SV, Dimopoulos MA, et al; for the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

N Engl J Med. 2015;372(2):142-152.

Please see Brief Summary of full Prescribing Information on adjacent pages.

The KYPROLIS regimen significantly improved PFS in patients with relapsed multiple myeloma1 ÂŽ

In the ASPIRE study of KYPROLIS + lenalidomide + low-dose dexamethasone (KRd) vs lenalidomide + low-dose dexamethasone (Rd), the KYPROLIS regimen delivered improved efficacy with a safety profile comparable to Rd.1,2*

26.3 months median progression-free

survival with the KYPROLIS regimen vs 17.6 months with Rd, a 49% improvement over Rd (P value [two-sided] 0.0001)1

Find out more at www.kyprolis.com/hcp *ASPIRE was a global, multicenter, open-label, randomized phase 3 pivotal trial that evaluated KYPROLIS in combination with lenalidomide and low-dose dexamethasone (KRd) vs lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed multiple myeloma who had received 1 to 3 prior lines of therapy. 792 patients were randomized in a 1:1 ratio (396 patients to KRd, 396 to Rd). Patients received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity.1,2 KYPROLIS was discontinued after Cycle 18. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, overall response rate (partial response or better), duration of response, and safety.2

The ASCO Post | DECEMBER 25, 2015

PAGE 136

Announcements

West Cancer Center Opens East Campus Location

W

est Cancer Center celebrated the grand opening of its East Campus location with a ribbon-cutting ceremony on November 17th.

Located at 7945 Wolf River Boulevard in Memphis, Tennessee, the 123,000 square foot facility combines multi-

specialty services including medical, surgical, diagnostic, and radiation oncology, in addition to West’s clinical research program. The result is a collaborative environment that will both foster West Cancer Center’s comprehensive approach to treatment and

transform the delivery of oncology care in the Mid-South.

“This marks another milestone in the transformation of how we care for and treat our patients,” said Erich Mounce, CEO of West Cancer Center.

“By physically combining the forces of

our multidisciplinary specialty teams into one facility, we are creating an environment that truly fosters collaboration and produces a unique understanding of what each specialty requires, allowing everyone to perform at their highest level.”

5.10 Thrombocytopenia 5.10 Thrombocytopenia KYPROLIS® (carfilzomib) KYPROLIS® (carfilzomib) for injection, for intravenous injection, foruse intravenous use Brief Summary Brief of Prescribing Summary ofInformation.

Prescribing Information.

Kyprolis causesKyprolis thrombocytopenia causes thrombocytopenia with platelet nadirs with platelet observed nadirs between observed Day 8between and Day 8 and Please see the Please KYPROLIS see the package KYPROLIS insert package for full insert prescribing for fullinformation. prescribing information.Day 15 of eachDay 28-day 15 ofcycle eachwith 28-day recovery cycle to with baseline recovery platelet to baseline count usually platelet by count the usually start by the start of the next cycle. of the Thrombocytopenia next cycle. Thrombocytopenia was reported inwas approximately reported in approximately 40% of patients 40% of patients 1. INDICATIONS 1. INDICATIONS AND USAGE AND USAGE in clinical trialsinwith clinical Kyprolis. trials Monitor with Kyprolis. plateletMonitor countsplatelet frequently counts during frequently treatment during withtreatment with Kyprolis in combination Kyprolis inwith combination lenalidomide withand lenalidomide dexamethasone and dexamethasone is indicated foristhe indicated for the Kyprolis. Reduce Kyprolis. or withhold Reduce dose or withhold as appropriate. dose as appropriate. treatment of patients treatment withofrelapsed patients multiple with relapsed myeloma multiple who myeloma have received who have one toreceived one to 5.11 Hepatic 5.11 Toxicity Hepatic and Hepatic Toxicity Failure and Hepatic Failure three prior linesthree of therapy. prior lines of therapy.

Cases of hepatic Cases failure, of hepatic including failure, fatal including cases, have fatalbeen cases, reported have been (<1%)reported during treatment (<1%) during treatment 5. WARNINGS5.AND WARNINGS PRECAUTIONS AND PRECAUTIONS with Kyprolis. Kyprolis with Kyprolis. can cause Kyprolis increased can cause serum increased transaminases. serum transaminases.

Monitor liver enzymes Monitor liver enzymes regularly. Reduce regularly. or withhold Reduce dose or withhold as appropriate. dose as appropriate.

5.1 Cardiac Toxicities 5.1 Cardiac Toxicities 5.12 Thrombotic 5.12Thrombocytopenic Thrombotic Thrombocytopenic Purpura/Hemolytic Purpura/Hemolytic Uremic Syndrome Uremic (TTP/HUS) Syndrome (TTP/HUS) New onset or worsening New onsetoforpre-existing worsening ofcardiac pre-existing failurecardiac (e.g., congestive failure (e.g., heart congestive failure, heart failure, pulmonary edema, pulmonary decreased edema, ejection decreased fraction), ejection restrictive fraction), cardiomyopathy, restrictive cardiomyopathy, myocardial myocardial Cases of TTP/HUS Cases including of TTP/HUS fatal including outcome fatal have outcome been reported have been in patients reported whoinreceived patients who received ischemia, and ischemia, myocardialand infarction myocardial including infarction fatalities including have fatalities occurredhave following occurred followingKyprolis. Monitor Kyprolis. for signs Monitor and symptoms for signs and of TTP/HUS. symptomsIf of theTTP/HUS. diagnosisIf isthesuspected, diagnosis stop is suspected, stop administrationadministration of Kyprolis. In clinical of Kyprolis. studies In clinical with Kyprolis, studies these with Kyprolis, events typically these events occurred typicallyKyprolis occurred and evaluate.

Kyprolis Ifand theevaluate. diagnosisIf of theTTP/HUS diagnosis is of excluded, TTP/HUSKyprolis is excluded, may be Kyprolis restarted. may be restarted. early in the course early ofin Kyprolis the course therapy of Kyprolis (<5 cycles). therapyDeath (<5 cycles). due to cardiac Death due arrest to cardiac has arrest The has safety of reinitiating The safetyKyprolis of reinitiating therapy Kyprolis in patients therapy previously in patients experiencing previouslyTTP/HUS experiencing is TTP/HUS is occurred withinoccurred a day ofwithin Kyprolis a day administration. of Kyprolis administration. not known. not known.

Withhold Kyprolis Withhold for Grade Kyprolis 3 or for 4 cardiac Grade 3adverse or 4 cardiac eventsadverse until recovery, events until and consider recovery, and consider 5.13 Posterior5.13 Reversible Posterior Encephalopathy Reversible Encephalopathy Syndrome (PRES) Syndrome (PRES) whether to restart whether Kyprolis to restart at 1 dose Kyprolis levelatreduction 1 dose level based reduction on a benefit/risk based on assessment. a benefit/risk assessment.

Cases of PRESCases have been of PRES reported have been in patients reported receiving in patients Kyprolis. receiving Posterior Kyprolis. Posterior While adequateWhile hydration adequate is required hydration prior is to required each dose priorintoCycle each 1, dose all patients in Cycle should 1, all patients reversible should encephalopathy reversible encephalopathy syndrome (PRES), syndrome formerly (PRES), termed formerly Reversible termed Posterior Reversible Posterior also be monitored also for be evidence monitoredoffor volume evidence overload, of volume especially overload, patients especially at riskpatients for cardiac at risk for cardiac Leukoencephalopathy Leukoencephalopathy Syndrome (RPLS), Syndrome is a neurological (RPLS), is adisorder neurological whichdisorder can present which can present failure. Adjust total failure. fluid Adjust intake total as fluid clinically intake appropriate as clinically in appropriate patients withinbaseline patients cardiac with baselinewith cardiac seizure, headache, with seizure, lethargy, headache, confusion, lethargy, blindness, confusion, altered blindness, consciousness, altered consciousness, and other and other failure or who failure are at risk or who for cardiac are at risk failure. for cardiac failure. visual and neurological visual anddisturbances, neurological along disturbances, with hypertension, along with and hypertension, the diagnosis and isthe diagnosis is confirmed confirmed by neuro-radiological imaging (MRI).imaging Discontinue (MRI).Kyprolis Discontinue if PRES Kyprolis is suspected if PRES is suspected In patients ≥75Inyears patients of age, ≥75the years riskofofage, cardiac the risk failure of cardiac is increased. failurePatients is increased. with New Patients with New by neuro-radiological and safety evaluate. of reinitiating The safetyKyprolis of reinitiating therapy Kyprolis in patients therapy previously in patients experiencing previously experiencing York Heart Association York Heart Class Association III and IVClass heartIIIfailure, and IVrecent heart failure, myocardial recent infarction, myocardial andinfarction,and andevaluate. The PRES is not known. conduction abnormalities conduction uncontrolled abnormalitiesbyuncontrolled medicationsbywere medications not eligible were fornot theeligible clinical for the PRES clinicalis not known. trials. These patients trials. These may be patients at greater mayrisk be at forgreater cardiacrisk complications. for cardiac complications.

5.14 Embryo-fetal 5.14 Embryo-fetal Toxicity Toxicity 5.2 Acute Renal 5.2Failure Acute Renal Failure Kyprolis can cause Kyprolis fetalcan harm cause when fetal administered harm whentoadministered a pregnant woman to a pregnant based woman based on itsofmechanism action and findings of actioninand animals. findings There in animals. are no adequate There areand no adequate and Cases of acuteCases renal of failure acutehave renaloccurred failure have in patients occurred receiving in patients Kyprolis. receiving RenalKyprolis. Renalon its mechanism studies in pregnant studies women in pregnant using Kyprolis. women using Carfilzomib Kyprolis. caused Carfilzomib caused insufficiency adverse insufficiency eventsadverse (renal impairment, events (renalacute impairment, renal failure, acuterenal renalfailure) failure,occurred renal failure)well-controlled occurred well-controlled embryo-fetal toxicity embryo-fetal in pregnant toxicity rabbits in pregnant at doses rabbits that were at doses lowerthat than were in patients lower than in patients in approximately in approximately 8% patients in8% a randomized patients in acontrolled randomized trial.controlled Acute renal trial.failure Acutewas renal failure was receiving the recommended receiving the recommended dose. dose. reported morereported frequently more in patients frequently withinadvanced patients with relapsed advanced and refractory relapsed and multiple refractory multiple myeloma who myeloma received Kyprolis who received monotherapy.

Kyprolis monotherapy.

This risk was greater This riskinwas patients greater withinapatientsFemales with a of reproductive Females ofpotential reproductive should potential be advised should to avoid be advised becoming to avoid pregnant becoming whilepregnant while baseline reduced baseline estimated reduced creatinine estimated clearance creatinine (calculated clearance using (calculated Cockcroftusing and Cockcroft Gault and Gault being treated with beingKyprolis. treated Ifwith thisKyprolis. drug is used If thisduring drug ispregnancy, used during or ifpregnancy, the patientor if the patient equation). Monitor equation). renal function Monitor renal with regular functionmeasurement with regular measurement of the serum creatinine of the serum and/creatinine and/pregnant becomes becomes whilepregnant taking this while drug, taking the patient this drug, should the patient be apprised shouldofbe theapprised potentialof the potential or estimated creatinine or estimated clearance. creatinine Reduce clearance. or withhold Reduce Kyprolis or withhold dose as Kyprolis appropriate. dose as appropriate. hazard to the fetus. hazard to the fetus.

5.3 Tumor Lysis 5.3Syndrome Tumor Lysis (TLS) Syndrome (TLS) 6. ADVERSE REACTIONS 6. ADVERSE REACTIONS Cases of TLS, Cases including of TLS, fatal including outcomes,fatal have outcomes, been reported have been in patients reported whoinreceived patients who received The following adverse The following reactions adverse havereactions been discussed have been above discussed and canabove be found and the can be found the Kyprolis. Patients Kyprolis. with multiple Patientsmyeloma with multiple and amyeloma high tumor andburden a high tumor shouldburden be considered should be considered Warning and Precautions Warning andsection Precautions of the prescribing section of the information. prescribingThey information. include Cardiac They include Cardiac to be at greatertorisk be at forgreater TLS. Ensure risk forpatients TLS. Ensure are well patients hydrated are before well hydrated administration before administration Toxicities, Acute Toxicities, Renal Failure, Acute TLS, RenalPulmonary Failure, TLS, Toxicity, Pulmonary Pulmonary Toxicity, Hypertension, Pulmonary Hypertension, Dyspnea, Dyspnea, of Kyprolis in Cycle of Kyprolis 1, andininCycle subsequent 1, and incycles subsequent as needed. cycles Consider as needed. uric acid Consider lowering uric acid Hypertension, lowering Venous Hypertension, Thrombosis, VenousInfusion Thrombosis, Reactions, Infusion Thrombocytopenia, Reactions, Thrombocytopenia, Hepatic Hepatic drugs in patients drugs at risk in patients for TLS.atMonitor risk for for TLS.evidence Monitoroffor TLS evidence during treatment of TLS during and treatment Toxicity and and Hepatic ToxicityFailure, and Hepatic TTP/HUS Failure, and PRES. TTP/HUS and PRES. manage promptly manage including promptly interruption including of interruption Kyprolis untilofTLS Kyprolis is resolved. until TLS is resolved.

6.1 Clinical Trials 6.1 Clinical Safety Trials Experience Safety Experience 5.4 Pulmonary 5.4Toxicity Pulmonary Toxicity Because clinical Because trials are clinical conducted trials are under conducted widely varying under widely conditions, varying adverse conditions, reaction adverse reaction K Acute Respiratory Acute Distress Respiratory Syndrome Distress (ARDS), Syndrome acute respiratory (ARDS), acute failure, respiratory and acute failure, diffuse and acuterates diffuse observedrates in theobserved clinical trials in theofclinical a drugtrials cannot of abedrug directly cannot compared be directly withcompared rates in the with rates in thel infiltrative pulmonary infiltrative disease pulmonary such as disease pneumonitis such asand pneumonitis interstitial and lunginterstitial disease have lung disease have clinical trials ofclinical anothertrials drug, of and another maydrug, not reflect and may the not rates reflect observed the rates in medical observed practice. in medical practice. a occurred in lessoccurred than 1%inofless patients than 1% receiving of patients Kyprolis. receiving SomeKyprolis. events have Somebeen events fatal.have In been fatal.

In The safety of Kyprolis The safety in combination of Kyprolis inwith combination lenalidomide withand lenalidomide dexamethasone and dexamethasone (KRd) was (KRd) was b the event of drug-induced the event of pulmonary drug-induced toxicity, pulmonary discontinue toxicity, Kyprolis. discontinue Kyprolis. evaluated in anevaluated open-label in an randomized open-labelstudy randomized in patients study withinrelapsed patients multiple with relapsed myeloma. multiple myeloma.

5.5 Pulmonary 5.5Hypertension Pulmonary Hypertension (PAH) (PAH) The median number The median of cycles number initiated of cycles was 22 initiated cycleswas for the 22 KRd cycles arm forand the 14 KRdcycles arm and for 14 cycles for c Rd arm. the Rd arm.

PAH was reported PAH inwas approximately reported in approximately 1% of patients1% treated of patients with Kyprolis treatedand withwas Kyprolis Gradeand 3 wastheGrade 3 d or greater in less or greater than 1%inofless patients. than 1%Evaluate of patients. with cardiac Evaluateimaging with cardiac and/orimaging other and/or other Deaths due to Deaths adversedue events to adverse within 30 events dayswithin of the30 lastdays doseofoftheany lasttherapy dose ofin any the therapy KRd in the KRd tests as indicated. tests Withhold as indicated.

Kyprolis Withhold for PAH Kyprolis until resolved for PAH or until returned resolved to or baseline returned andto baseline arm and vs. Rd armarm wasvs.27/392 Rd arm(7%) waspatients 27/392 vs.

(7%) 27/389 patients (7%) vs.patients 27/389 in (7%) thepatients Rd arm.inThe the Rd arm. The e consider whether consider to restart whether Kyprolis to restart basedKyprolis on a benefit/risk based on assessment. a benefit/risk assessment. most commonmost causecommon of deaths cause occurring of deaths in patients occurring (%)incardiac patients 10(%) (3%) cardiac vs. 7 (2%), 10 (3%) vs. 7 (2%), infection 9 (2%) infection vs.

10 (3%), 9 (2%) renal vs.

10 0 (0%) (3%), vs. renal 1 (<1%), 0 (0%) and vs. other 1 (<1%), adverse and other events adverse 9 (2%) events 9 (2%) 5.6 Dyspnea 5.6 Dyspnea vs. 10 adverse (3%). Serious eventsadverse were reported events were in 60% reported vs. 54% in 60% of patients vs. 54% in the of patients in the T Dyspnea was reported Dyspnea inwas 28% reported of patients in 28% treated of patients with Kyprolis treatedand withwas Kyprolis Gradeand 3 orwas Grade vs.

3 or10 (3%). Serious KRd arm vs. RdKRd arm. armThe vs.most Rd arm. common The most serious common adverse serious eventsadverse reportedevents in thereported KRd armin the KRd arm T greater in 4% greater of patients. in 4% Evaluate of patients. dyspnea Evaluate to exclude dyspnea cardiopulmonary to exclude cardiopulmonary conditions conditions verses arm were thepneumonia Rd arm were (14% pneumonia vs. 11%),(14% respiratory vs. 11%), tract respiratory infection tract (4% vs. infection (4% vs. G including cardiac including failurecardiac and pulmonary failure and syndromes. pulmonaryStop syndromes.

Kyprolis for Stop Grade Kyprolis 3 or for 4 Grade 3 or 4 the Rd verses 1.5%), pyrexia1.5%), (4% vs.pyrexia 2%), and (4%pulmonary vs. 2%), and embolism pulmonary (3%embolism vs. 2%). Discontinuation (3% vs. 2%). Discontinuation due due s dyspnea until resolved dyspnea or until returned resolved to or baseline. returned Consider to baseline. whether Consider to restart whether Kyprolis to restart basedKyprolis based to any adversetoevent any adverse occurredevent in 26% occurred in the KRd in 26% arminvs. the25% KRdinarm thevs.

Rd25% arm.inAdverse the Rd arm. Adverse h on a benefit/risk on assessment. a benefit/risk assessment. events leadingevents to discontinuation leading to discontinuation of Kyprolis occurred of Kyprolis in 12% occurred of patients in 12% andofthe patients most and the most 5.7 Hypertension 5.7 Hypertension L common events common includedevents pneumonia included (1%), pneumonia myocardial (1%), infarction myocardial (0.8%), infarction and upper (0.8%), and upper Hypertension, Hypertension, including hypertensive includingcrisis hypertensive and hypertensive crisis andemergency, hypertensivehas emergency, been has been respiratory tract respiratory infection tract (0.8%). infection (0.8%). observed with observed Kyprolis. Some with Kyprolis. of theseSome eventsofhave thesebeen events fatal. have Monitor been blood fatal. Monitor pressureblood pressure Common Adverse Common Events Adverse (≥ 10% Events in the(≥KRd 10% Arm) in the Occurring KRd Arm) in Cycles Occurring 1–12 in Cycles 1–12 regularly in all regularly patients. in If hypertension all patients. Ifcannot hypertension be adequately cannot be controlled, adequately withhold controlled, Kyprolis withhold Kyprolis (Combination(Combination Therapy) Therapy) and evaluate. Consider and evaluate. whether Consider to restart whether Kyprolis to restart basedKyprolis on a benefit/risk based on assessment. a benefit/risk assessment.

KRd Arm KRd Arm Rd Arm Rd Arm 5.8 Venous Thrombosis 5.8 Venous Thrombosis System Organ Class System Organ Class (N = 392) (N = 392) (N = 389) (N = 389) Venous thromboembolic Venous thromboembolic events (including events deep(including venous thrombosis deep venous andthrombosis pulmonaryand pulmonary embolism) haveembolism) been observed have been with Kyprolis. observedInwith theKyprolis. combination In thestudy, combination the incidence study,ofthe incidence of Preferred Term Preferred TermAny Grade ≥ Any Grade Grade 3 Any ≥ Grade Grade 3 ≥ Any Grade Grade 3 ≥ Grade 3 venous thromboembolic venous thromboembolic events in the first events 12 cycles in the was first 12 13% cycles in thewas Kyprolis 13% combination in the Kyprolis combination Blood and Lymphatic Blood and System Lymphatic Disorders System Disorders arm versus 6%arm in the versus control 6%arm. in the With control Kyprolis arm.monotherapy, With Kyprolis the monotherapy, incidence ofthevenous incidence of venous thromboembolic thromboembolic events was 2%.events Thromboprophylaxis was 2%. Thromboprophylaxis is recommended is recommended and should be and based should beAnemia based Anemia 138 (35%) 53 138 (14%) (35%) 127 53(33%) (14%) 47 127 (12%) (33%) 47 (12%) on an assessment on anof assessment the patient’sofunderlying the patient’s risks, underlying treatmentrisks, regimen, treatment and clinical regimen, status. and clinical status.

Neutropenia Neutropenia 124 (32%) 104 124(27%) (32%) 115 104(30%) (27%) 89 115 (23%) (30%) 89 (23%) 5.9 Infusion Reactions 5.9 Infusion Reactions Thrombocytopenia 100 (26%) 58 100 (15%) (26%) 7558(19%) (15%) 3975(10%) (19%) 39 (10%) Infusion reactions, Infusion including reactions, life-threatening including life-threatening reactions, havereactions, occurredhave in patients occurred in patients Thrombocytopenia receiving Kyprolis. receiving Symptoms Kyprolis. include Symptoms fever, chills, includearthralgia, fever, chills, myalgia, arthralgia, facialmyalgia, flushing,facial flushing, GastrointestinalGastrointestinal Disorders Disorders facial edema, vomiting, facial edema, weakness, vomiting, shortness weakness, of breath, shortness hypotension, of breath,syncope, hypotension, chestsyncope, chest Diarrhea 115 (29%) 115 7 (2%) (29%) 1057(27%) (2%) 12 105(3%) (27%) 12 (3%) K tightness, or angina. tightness, These or angina. reactions These can occur reactions immediately can occurfollowing immediately or upfollowing to 24 hours or up to 24 Diarrhea hours after administration after administration of Kyprolis. Administer of Kyprolis. dexamethasone Administer dexamethasone prior to Kyprolisprior to reduce to Kyprolis the to reduce the Constipation Constipation 68 (17%) 680(17%) 53 (14%) 0 153(0%) (14%) 1 (0%) l incidence and incidence severity ofand infusion severity reactions. of infusion Inform reactions. patientsInform of thepatients risk andofofthe symptoms risk and of symptoms Nausea 60 (15%) 160(0%) (15%) 39 1(10%) (0%) 339(1%) (10%) 3 (1%) and to contactand a physician to contact immediately a physicianif immediately symptoms ofifan symptoms infusion reaction of an infusion occur.reaction occur. Nausea

t

ASCOPost.com | DECEMBER 25, 2015

PAGE 137

Announcements A Multidisciplinary Partnership The grand opening is a result of a partnership between Methodist Healthcare, the University of Tennessee Health Science Center (UTHSC), and West Clinic, who joined together in January 2012 to form West Cancer Center.

This partnership unites the foremost leaders in education, research, and pa-

tient care to advance the field of oncology. Combining the nation’s premier oncologists and researchers with the leading experts in radiation and surgical oncology fosters a collaborative environment to improve patient care.

The new West Cancer Center location draws upon all three organizations to house both clinical and research

General Disorders General and Administration Disorders and Administration Site ConditionsSite Conditions Fatigue

Fatigue

Pyrexia

Pyrexia

109 (28%)

21 109(5%) (28%) 10421(27%) (5%)

20 104(5%) (27%)

93 (24%)

593(1%) (24%)

64 5(17%) (1%)

164(0%) (17%)

Edema PeripheralEdema Peripheral

63 (16%)

263(1%) (16%)

57 2(15%) (1%)

257(1%) (15%)

Asthenia

53 (14%)

11 53(3%) (14%)

4611 (12%) (3%)

746(2%) (12%)

785(2%) (22%)

52 7(13%) (2%)

352(1%) (13%)

Asthenia

Infections and Infections Infestations and Infestations Upper Respiratory Upper TractRespiratory Infection Tract Infection 85 (22%) Nasopharyngitis Nasopharyngitis

63 (16%)

630(16%)

43 (11%) 0

430(11%)

Bronchitis

Bronchitis

54 (14%)

554(1%) (14%)

39 5(10%) (1%)

239(1%) (10%)

Pneumoniaa

Pneumoniaa

54 (14%)

35 54(9%) (14%)

4335 (11%) (9%)

27 43(7%) (11%)

services, care support resources, innovative drug therapy, a comprehensive breast center, and survivorship services in order to better meet the needs of an ever-expanding patient population.

Focus on Research West Cancer Center’s research program combines clinical research in the

6.2 Post-marketing 6.2 Post-marketing Experience Experience The following adverse The following reactions adverse werereactions reported were in thereported post-marketing in the post-marketing experience with experience with 20 (5%) Because Kyprolis.

Kyprolis. theseBecause reactionsthese are reported reactionsvoluntarily are reported fromvoluntarily a population fromofauncertain population of uncertain size, it is not always size, itpossible is not always to reliably possible estimate to reliably their estimate frequencytheir or establish frequencya causal or establish a causal 1 (0%) relationship to relationship drug exposure: to drug dehydration, exposure:TTP/HUS, dehydration, TLS TTP/HUS, including fatal TLS including outcomes,fatal outcomes, 2 (1%) and PRES. and PRES. (2%) INTERACTIONS 7.7DRUG 7. DRUG INTERACTIONS Kyprolis is primarily Kyprolis metabolized is primarilyviametabolized peptidase and via peptidase epoxide hydrolase and epoxide activities, hydrolase and activities, as and as a 3result, a result, the pharmacokinetic profile of Kyprolis profile is unlikely of Kyprolis to beis affected unlikely to bybe concomitant affected by concomitant (1%) the pharmacokinetic administrationadministration of cytochromeofP450 cytochrome inhibitorsP450 and inhibitors inducers. and Kyprolis inducers. is not Kyprolis expectedis tonot expected to 0 influence exposure influence of other exposure drugs.of other drugs.

(1%) IN SPECIFIC 8.2USE 8. USEPOPULATIONS IN SPECIFIC POPULATIONS 8.1 8.1 Pregnancy 27 Pregnancy (7%) Kyprolis may cause Kyprolis fetal may harm. cause There fetalare harm. no adequate There areand no adequate well-controlled and well-controlled studies in studies in Metabolism and Metabolism Nutrition Disorders and Nutrition Disorders pregnant women pregnant using Kyprolis. women using Kyprolis.

Hypokalemia Hypokalemia 78 (20%) 22 78(6%) (20%) 3522(9%) (6%) 1235(3%) (9%) 12 (3%) of reproductive Females Females ofpotential reproductive should potential be advised should to avoid be advised becoming to avoid pregnant becoming whilepregnant while treated with beingKyprolis. treated with Consider Kyprolis. the benefits Considerand therisks benefits of Kyprolis and risks andofpossible Kyprolisrisks and possible risks Hypocalcemia Hypocalcemia 55 (14%) 10 55(3%) (14%) 3910 (10%) (3%) 539(1%) (10%) being 5 (1%) to the fetus when to the prescribing fetus when Kyprolis prescribing to a pregnant Kyprolis woman. to a pregnant If Kyprolis woman. is used If Kyprolis duringis used during Hyperglycemia Hyperglycemia 43 (11%) 18 43(5%) (11%) 3318(9%) (5%) 1533(4%) (9%) 15 (4%) pregnancy, or ifpregnancy, the patientorbecomes if the patient pregnant becomes whilepregnant taking Kyprolis, while taking adviseKyprolis, the patient advise of the patient of the potential hazard the potential to the fetus. hazard to the fetus.

MusculoskeletalMusculoskeletal and Connectiveand Tissue Connective Disorders Tissue Disorders 8.2 Lactation8.2 Lactation Muscle Spasms Muscle Spasms 88 (22%) 388(1%) (22%) 73 3(19%) (1%) 373(1%) (19%) 3 (1%) There is no information There is no regarding information the presence regarding oftheKyprolis presence in human of Kyprolis milk,inthe human effects milk, on the effects on Nervous System Nervous Disorders System Disorders the breastfed infant, the breastfed or the effects infant, on or the milkeffects production. on milkThe production. developmental The developmental and health and health benefits of breastfeeding should be considered should be along considered with the along mother’s withclinical the mother’s need for clinical need for b 43b (11%) 743(2%) (11%) 37 7(10%) (2%) 437(1%) (10%) benefits 4 (1%) of breastfeeding Peripheral Neuropathies Peripheral NEC Neuropathies NEC Kyprolis and any Kyprolis potential andadverse any potential effectsadverse on the effects breastfed on infant the breastfed from Kyprolis infant or from from Kyprolis or from Psychiatric Disorders Psychiatric Disorders the underlyingthe maternal underlying condition. maternal condition.

Contraception 8.3 Contraception Insomnia Insomnia 63 (16%) 663(2%) (16%) 50 6(13%) (2%) 850(2%) (13%) 8.3 8 (2%) Kyprolis can cause Kyprolis fetalcan harm cause when fetal administered harm whentoadministered pregnant women. to pregnant Advisewomen. femalesAdvise females Respiratory, Thoracic, Respiratory, and Mediastinal Thoracic, and Disorders Mediastinal Disorders of reproductiveofpotential reproductive to usepotential effectivetocontraception use effective contraception measures to prevent measures pregnancy to prevent pregnancy Cough Cough 85 (22%) 185(0%) (22%) 46 1(12%) (0%) 460(12%) during 0 treatment during withtreatment Kyprolis and withforKyprolis at leastand 2 weeks for at least following 2 weeks completion following of therapy. completion of therapy.

Pediatric 8.4 UsePediatric Use 70 (18%) 970(2%) (18%) 58 9(15%) (2%) 658(2%) (15%) 8.4 6 (2%) Dyspneac Dyspneac The safety and The effectiveness safety and ofeffectiveness Kyprolis in pediatric of Kyprolis patients in pediatric have not patients beenhave established. not been established.

Skin and Subcutaneous Skin and Tissue Subcutaneous Tissue 8.5 Geriatric Use 8.5 Geriatric Use Disorders Disorders Of5392 patientsOftreated 392 patients with Kyprolis treatedinwith combination Kyprolis inwith combination lenalidomide withand lenalidomide and Rash Rash 45 (12%) 545(1%) (12%) 53 5(14%) (1%) 553(1%) (14%) (1%) dexamethasone, dexamethasone, 185 patients (47%) 185 patients were ≥65 (47%) years were of age ≥65and years 43 of patients age and (11%) 43 patients were (11%) were Vascular Disorders Vascular Disorders ≥75 years of age. ≥75 No years overall of age. differences No overall in effectiveness differences inwere effectiveness observedwere between observed thesebetween these , and younger patients. and younger The incidence patients. The of serious incidence adverse of serious eventsadverse was 50% events in patients was 50% in patients 49 (13%) 16 49(4%) (13%) 2216(6%) (4%) 922 (2%) (6%) 9 (2%) Embolic and Thrombotic Embolic Events, and Thrombotic Events, ≤65 years of age, ≤6570% yearsinofpatients age, 70% 65 in to patients 74 years65 of to age, 74and years 74% of age, in patients and 74% ≥75inyears patients ≥75 years Venousd Venousd of age. of age. e e 41 (11%) 12 41(3%) (11%) 1512(4%) (3%) 415 (1%) (4%) 4 (1%) Hypertension Hypertension 8.6 Renal Impairment 8.6 Renal Impairment KRd = Kyprolis,KRd lenalidomide, = Kyprolis, and lenalidomide, low-dose and dexamethasone; low-dose dexamethasone; Rd = lenalidomide Rd =and lenalidomide Noand starting dose Noadjustment starting dose is required adjustment in patients is required withinbaseline patients mild, with baseline moderate, mild, moderate, low-dose dexamethasone low-dose dexamethasone or severe renalorimpairment severe renal or impairment patients on or chronic patients dialysis on chronic based dialysis on a phase based 2 on a phase 2 a pharmacokinetic and safety trialand of Kyprolis. safety trialThe of pharmacokinetics Kyprolis. The pharmacokinetics of Kyprolis wasofnot Kyprolis was not Pneumonia aincludes Pneumonia preferred includes termspreferred of pneumonia, terms ofbronchopneumonia pneumonia, bronchopneumonia pharmacokinetic influenced by the influenced degree by of baseline the degree renal of baseline impairment, renalincluding impairment, whenincluding patients when were patients were b b Peripheral neuropathies PeripheralNEC neuropathies includes preferred NEC includes termspreferred under HLT terms peripheral under HLT peripheral receiving dialysis. receiving Administer dialysis.

KYPROLIS Administer afterKYPROLIS the dialysis after procedure. the dialysis procedure. neuropathies NEC neuropathies NEC 8.7 Hepatic Impairment 8.7 Hepatic Impairment c c Dyspnea includes Dyspnea preferred includes termspreferred of dyspnea, termsdyspnea of dyspnea, exertional dyspnea exertional The safety, efficacy The safety, and pharmacokinetics efficacy and pharmacokinetics of Kyprolis have of not Kyprolis beenhave evaluated not been in patients evaluated in patients d Embolic andd thrombotic Embolic and events, thrombotic venousevents, includevenous preferred include termspreferred in MedDRA terms SMQ in MedDRA SMQ with baseline hepatic with baseline impairment. hepaticPatients impairment. with the Patients following withlaboratory the following values laboratory were values were narrow scope narrow search of scope embolic search andofthrombotic embolic and events, thrombotic venous.events, venous. excluded fromexcluded the Kyprolis fromclinical the Kyprolis trials: ALT/AST clinical trials: ≥3 ×ALT/AST upper limit ≥3 of× normal upper limit (ULN)of and normal (ULN) and e e Hypertension includes Hypertension preferred includes termspreferred of hypertension, terms of hypertensive hypertension,crisis, hypertensive crisis, bilirubin ≥2 × bilirubin ULN. ≥2 × ULN. hypertensive emergency hypertensive emergency 8.8 Cardiac Impairment 8.8 Cardiac Impairment There were 274 There (70%) were patients 274 (70%) in thepatients KRd arminwho the received KRd arm treatment who received beyond treatment Cycle 12. beyond Cycle 12.

Safety of patients Safety withofNew patients York with HeartNew Association York Heart Class Association III and IVClass heartIIIfailure and IVorheart recent failure or recent There were noThere new clinically were no relevant new clinically AEs that relevant emerged AEs in that theemerged later treatment in the later cycles. treatment cycles. myocardial infarction myocardial (within infarction 3 to 6 months) (within 3has to 6not months) been evaluated. has not been evaluated.

Grade 3 and higher Gradeadverse 3 and higher reactions adverse that reactions occurred during that occurred Cycles 1-12 duringwith Cycles a 1-12 with a 10. OVERDOSAGE 10. OVERDOSAGE substantial difference substantial (≥2%) difference between(≥2%) the two between arms were the two neutropenia, arms werethrombocytopenia, neutropenia, thrombocytopenia, hypokalemia, and hypokalemia, hypophosphatemia. and hypophosphatemia.

Acute onset ofAcute chills,onset hypotension, of chills,renal hypotension, insufficiency, renalthrombocytopenia insufficiency, thrombocytopenia and lymphopenia and lymphopenia has been reported has been following reported a dose following of 200 amg dose of Kyprolis of 200 mg administered of Kyprolisinadministered error. in error.

Laboratory Abnormalities Laboratory Abnormalities There antidote is no specific for Kyprolis antidote overdosage. for KyprolisInoverdosage. the event ofInoverdose, the eventthe of patient overdose, the patient Grade 3–4 Laboratory Grade 3–4Abnormalities Laboratory Abnormalities ( ≥10%) in Cycles ( ≥10%) 1-12in Cycles 1-12 There is no specific should be monitored, should be specifically monitored, forspecifically the adverseforreactions the adverse in thereactions adverse inreaction the adverse section. reaction section.

(Combination(Combination Therapy) Therapy) 2. DOSAGE AND 2. DOSAGE ADMINISTRATION AND ADMINISTRATION KRd KRd Rd Rd Adequate hydration Adequate is required hydration prior is to required dosingprior in Cycle to dosing 1, especially in Cyclein1,patients especially at high in patients at high Laboratory Abnormality Laboratory Abnormality (N = 392) (N = 392) (N = 389) (N = 389) risk of TLS or renal risk oftoxicity TLS orand renal following toxicity the andadministration following the administration of Kyprolis withofboth Kyprolis oral with and both oral and Decreased Lymphocytes Decreased Lymphocytes 182 (46%) 182 (46%) 119 (31%) 119 (31%) intravenous (IV)intravenous fluids, if needed.

(IV) fluids, Premedicate if needed. with Premedicate dexamethasone with dexamethasone prior to administering prior to administering Kyprolis for monotherapy.

Kyprolis for monotherapy.

Calculate the Kyprolis Calculatedose the using Kyprolis thedose patient’s usingactual the patient’s body actual body Decreased Absolute Decreased Neutrophil Absolute CountNeutrophil Count152 (39%) 152 (39%) 140 (36%) 140 (36%) surface area atsurface baseline. areaAdminister at baseline.

Kyprolis Administer over aKyprolis 10-minute overIVainfusion.

10-minuteDoIVnot infusion. Do not Decreased Phosphorus Decreased Phosphorus 122 (31%) 122 (31%) 106 (27%) 106 (27%) administer as aadminister bolus. Flush as athe bolus.

IV line Flush withthe normal IV linesaline with or normal 5% dextrose saline orinjection 5% dextrose injection immediately before immediately and after before Kyprolis and administration. after Kyprolis administration.

Do not mix Kyprolis Do notwith mixorKyprolis with or Decreased Platelets Decreased Platelets 101 (26%) 101 (26%) 59 (15%) 59 (15%) administer as an administer infusion as with another infusion medicines. with other Thromboprophylaxis medicines. Thromboprophylaxis is recommendisforrecommend for Decreased Total Decreased White BloodTotal CellWhite CountBlood Cell Count 97 (25%) 97 (25%) 71 (18%) 71 (18%) patients being patients treated with beingthe treated combination with theofcombination Kyprolis, lenalidomide of Kyprolis,and lenalidomide dexamethasone. and dexamethasone.

Consider antiviral Consider prophylaxis antiviral in prophylaxis patients being in patients treated with beingKyprolis. treated with Kyprolis.

Decreased Hemoglobin Decreased Hemoglobin 58 (15%) 58 (15%) 68 (18%) 68 (18%) The risk information The riskprovided information hereprovided is not comprehensive. here is not comprehensive.

The FDA-approved The FDA-approved Decreased Potassium Decreased Potassium 41 (11%) 41 (11%) 23 (6%) 23 (6%) product labeling product can be labeling foundcan at www.kyprolis.com be found at www.kyprolis.com or contact Amgen or contact Medical Amgen Medical Information at Information 1-800-772-6436. at 1-800-772-6436.

KRd = KYPROLIS, KRd lenalidomide, = KYPROLIS, and lenalidomide, low-dose and dexamethasone; low-dose dexamethasone; Rd = lenalidomide Rd =and lenalidomide and low-dose dexamethasone low-dose dexamethasone This Brief Summary This Brief is based Summary on theis Kyprolis based onPrescribing the KyprolisInformation Prescribingv9,Information 07/15. v9, 07/15.

U.S. Patent Numbers: U.S. Patent http://pat.amgen.com/kyprolis Numbers: http://pat.amgen.com/kyprolis

USA-KYPR-108328(1) USA-KYPR-108328(1)

Erich Mounce, CEO of West Cancer Center in Memphis, Tennessee, announces the grand opening of its new 123,000 square foot comprehensive cancer center, uniting world-class, multidisciplinary cancer care under one roof.

(PRNewsFoto/West Cancer Center).

patient-focused setting with translational methodology in the University of Tennessee Health Science Center laboratories—creating a bench-to-bedside model to deliver the most innovative and effective care for our patients.

“We have an extraordinarily dedicated team of professors and researchers who are searching for and discovering medical breakthroughs,” said Steve Schwab, Chancellor of UTHSC. “By partnering with West Cancer Center and Methodist, we have the ability to advance health care and impact patients’ lives through personalized clinical trials and lifesaving research.”

This dedication to research and innovation is reflected in West’s commitment to bringing the latest advancements in immuno-oncology and other targeted therapies to patients in the Mid-South, allowing them to be among the first to benefit from the most advanced improvements in cancer care.

Providing Care The American Cancer Society expects the number of new cancer cases diagnosed in the Mid-South to exceed 72,000 in 2015. The number of new cancer cases is expected to rise by 70% over the next 2 decades. By bringing every aspect of cancer care under one roof and creating one cancer treatment home for all stages of the cancer treatment journey, care is much more accessible for patients, especially for those with tight financial budgets who find it a challenge to travel to multiple sites of care. It also helps to create a streamlined navigational process for patients.

“Our mission at Methodist Healthcare is to provide high-quality health care for everyone who needs it, regardless of their ability to pay,” said Gary Shorb, CEO of Methodist Healthcare.

“The multidisciplinary approach at West Cancer Center will provide accessible and unparalleled cancer care for the entire Mid-South and beyond.” n

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2016 Oncology Meetings January 2016 4th AACR-IASLC International Joint Conference: Lung Cancer Translational Science January 4-7 • San Diego, California For more information: www.aacr.org

Personalized World Medicine Conference January 24-27 • Mountain View, California For more information: http://2016sv.pmwcintl.com/ index.php

Genitourinary Cancers Symposium January 7-9 • San Francisco, California For more information: http://gucasym.org

8th Immunotherapeutics & Immunomonitoring Conference January 25-26 • San Diego, CA For more information: https://www.gtcbio.com/ conferences/immunotherapeuticsimmunomonitoring-overview

Breast and Gynaecological International Cancer Society (BGICS) Conference January 14-15 • Cairo, Egypt For more information: www.bgicc.eg.net/Home.aspx

8th Annual T-Cell Lymphoma Forum January 28-30 • San Francisco, CA For more information: www.tcellforum.com/

Cancer Survivorship Symposium: Primary Care and Oncology Collaboration January 15-16 • San Francisco, California For more information: www.survivorsym.org/ Advances in Medical and Surgical Management of Thyroid Cancer January 15-16 • Tempe, Arizona For more information: www.aace.com/meetings/symposia/ january/thyroid-cancer 14th Oncology Update: Advances and Controversies January 15-18 • Steamboat Springs, Colorado For more information: www.mdanderson.org/educationand-research/education-and-training/ schools-and-programs/cmeconference-management/conferences/ cme/conference-management-14thoncology-update-advances-andcontroversies.html Gastrointestinal Cancers Symposium January 21-23 • San Francisco, CA For more information: http://gicasym.org

2016

Scripps’ 36th Annual Conference: Clinical Hematology & Oncology February 4 • Houston, Texas For more information: http://www.mdanderson.org/ education-and-research/educationand-training/schools-and-programs/ cme-conference-management/ conferences/cme/conferencemanagement-fourth-state-of-thescience-cancer-survivorship-researchsymposium.html

25th Conference of the Asian Pacific Association for the Study of the Liver February 20-24 • Tokyo, Japan For more information: http://www.apasl2016.org

18th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 4-6 • San Diego, CA For more information: www.imedex.com/anti-angiogenesisand-immune-therapies/

Cancer Center Business Summit February 24-25 • Phoenix, Arizona For more information: http://cancerbusinesssummit.com

Advances in Systemic Therapy for Breast Cancer 2016 February 12-13 • Ponte Vedra Beach, Florida For more information: https://ce.mayo.edu/node/5816 3rd Annual University of Southern California Multidisciplinary Breast Cancer Symposium January 30 • Los Angeles, CA For more information: http://keck.usc. edu/About/Administrative_Offices/ Office_of_Continuing_Education/ Courses/~/media/Office%20of%20 CME/FINAL_brochure_2016%20 breast%20cancer.pdf

10th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics February 16-20 • Maui, Hawaii For more information: www.aacr.org

February 27th International Congress of AntiCancer Treatment (ICACT) February 2-4 • Paris, France For more information: http://www.icact.fr 4th State of the Science Cancer Survivorship Research Symposium February 4 • Houston, Texas For more information: www.mdanderson.org

The Biomarker Conference February 18-20 • San Diego, California For more information: www.mnmconferences.com/thebiomarker-conference-florida.html Multidisciplinary Head and Neck Cancer Symposium February 18-20 • Scottsdale, Arizona For more information: www.headandnecksymposium.org

3rd Annual International Conference on Advances in Cancer Medical Research (ACMR 2016) February 22-23 • Singapore For more information: http://cancerresearch-conf.org/

ASCO Quality Care Symposium February 26-27 • Phoenix, Arizona For more information: http://quality.asco.org Winship Cancer Institute 2016 Melanoma Conference February 27 • Atlanta, Georgia For more information: www .winshipmelanomaconference.com AACR Precision Medicine Series: Cancer Cell Cycle–Tumor Progression and Therapeutic Response February 28-March 2 • Maui, Hawaii For more information: www.aacr.org/Meetings/Pages/ MeetingDetail.aspx?EventItemID=76#.

Vbb2qKTbJjo 6th World Congress on Cell & Stem Cell Research February 29-March 2 • Philadelphia, Pennsylvania For more information: http://stemcell.omicsgroup.com/

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2016

2016 Oncology Meetings March Society of Surgical Oncology Annual Cancer Symposia March 2-5 • Boston, Massachusetts For more information: www.surgonc.org 22nd Annual Blood-Brain Barrier and Neuro-oncology Meeting March 3-5 • Stevenson, Washington For more information: www.ohsu.edu/bbb 4th Annual UC San Diego Essentials and Advances in Apheresis Therapies March 3-5 • San Diego, California For more information: https://cme.ucsd.edu/apheresis/ 8th Annual Asian Oncology Summit March 3-6 • Kyoto, Japan For more information: www.asianoncologysummit.com Hematology and Medical Oncology Board Review: Contemporary Practice From Memorial Sloan Kettering Cancer Center March 4-7 • New York, New York For more information: www.mskcc.org/event/hematologyand-medical-oncology-boardreview-contemporary-practice Second Annual New Treatments in Oncology March 5-6 • Scottsdale, Arizona For more information: www.cvent.com/events/annualnew-treatments-in-oncologyconference-presented-by-cancertreatment-centers-of-america-/ event-summary-2fb116562f6447cca49 2c89064760b02.aspx American Association of Physicists in Medicine Spring Clinical Meeting March 5-8 • Salt Lake City, Utah For more information: http://www.aapm.org/ meetings/2016SCM/ ILCA School of Liver Cancer 2016 March 7-8 • Barcelona, Spain For more information: www.ilcaonline.org/sitecore/content/bebruga/ilca-online/School%20of%20 Liver%20Cancer/2016.aspx

Moffitt Cancer Center Neuro-Oncology Conference March 10-11 • Clearwater Beach, FL For more information: http://myana.org/events/moffittcancer-center-neuro-oncologyconference

The 16th Multidisciplinary Management of Cancers: A Case-Based Approach March 18-20 • Napa, California For more information: https://med.stanford.edu/cme/ courses/2016/multicancer2016.html

3rd St. Gallen International Gastrointestinal Cancer Conference March 10-12 • St. Gallen, Switzerland For more information: www.oncoconferences.ch/dynasite .cfm?dsmid=500294

Society of Gynecologic Oncology Annual Meeting on Women’s Cancer March 19-22 • San Diego, California For more information: www.sgo.org

33rd Annual Miami Breast Cancer Conference March 10-13 • Miami, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/33rd-AnnualMiami-Breast-Cancer-Conference 2016 ASTRO Annual Refresher Course March 11-13 • La Jolla, California For more information: www.astro.org/Meetings-andEvents/2016-Annual-RefresherCourse/Index.aspx Annual European Association of Urology Congress March 11-15 • Munich, Germany For more information: http://eaumunich2016.uroweb.org 40th Annual American Society of Preventive Oncology (ASPO) Conference March 12-15 • Columbus, Ohio For more information: https://aspo.org/annual-meeting 2016 Methods in Clinical Research Workshop for Minority Physicians March 17-20 • Fort Lauderdale, Florida For more information: www.roswellpark.edu/education/ diversity-clinical-researchworkshop

International Conference on Pancreatic and Colorectal Cancer March 29-30 • Atlanta, Georgia For more information: http://pancreatic-colorectal .cancersummit.org

European Lung Cancer Conference April 13-16 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2016-Lung-Cancer American Society for Colposcopy and Cervical Pathology (ASCCP) Annual Meeting April 13-16 • New Orleans, Louisiana For more information: www.asccp.org/2016annualmeeting Clinical Immunology Society Annual Meeting April 14-17 • Boston, Massachusetts For more information: www.clinimmsoc.org/education/ meetings/2016-annual-meeting

NCCN 21st Annual Conference: Advancing the Standard of Cancer CareTM March 31-April 2 • Hollywood, Florida For more information: www.nccn.org

April New Frontiers in Diagnosis, Screening, and Management of Inherited Cancer Syndromes April 8-9 • Chicago, Illinois For more information: https://cme.uchicago.edu/NFD2016 Gastrointestinal Cancer Multidisciplinary Symposium 2016: Current Update on State of the Art Screening, Diagnosis and Treatment April 9 • Columbus, Ohio For more information: https://ccme.osu.edu/ 26th Annual Interdisciplinary Breast Cancer Center Conference April 9-13 • Las Vegas, Nevada For more information: http://www2.breastcare.org/ welcome-to-the-24th-annualnational-interdisciplinary-breastcenter-conference/

American Association of Cancer Research Annual Meeting April 16-20 • New Orleans, Louisiana For more information: www.aacr.org 16th Pan Arab Cancer Conference April 28-30 • Cairo, Egypt For more information: www.pacc16.org 2016 Head and Neck Cancer Symposium Fifth Annual April 30 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx

May Markers in Cancer Diagnostic Development Tutorial May 2-3 • Bethesda, Maryland For more information: http://markersincancer.org Palliative Care Education and Practice (PCEP) May 4-10 • Cambridge, Massachusetts For more information: www.hms.harvard.edu/pallcare/ PCEP/PCEP.htm continued on page 146

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2016

2016 Oncology Meetings Oncology Meetings continued from page 139

June

19th SIS World Congress on Breast Healthcare May 5-8 • Warsaw, Poland For more information: www.siscongress.org 14th CIMT Annual Meeting: Mechanisms of Efficacy in Cancer Immunotherapy May 10-12 • Mainz, Germany For more information: www.meeting.cimt.eu

2016 ASCO Annual Meeting June 3-7 • Chicago, Illinois For more information: http://am.asco.org

IMPAKT 2016 Breast Cancer Conference May 12-14 • Brussels, Belgium For more information: www.esmo.org/Conferences/ IMPAKT-2016-Breast-Cancer

IARC: Global Cancer: Occurrence, Causes, and Avenues to Prevention June 7-10 • Lyon, France For more information: http://iarc-conference2016.com

Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology Annual Meeting on Supportive Care in Cancer June 23-25 • Adelaide, Australia For more information: www.mascc.org Best of ASCO® Chicago June 24-25 • Chicago, Illinois For more information: http://boa.asco.org

Mayo Clinic Oncology Review 2016 July 23 • Minneapolis, Minnesota For your information: https://ce.mayo.edu/hematologyand-oncology/content/mayo-cliniconcology-review-2016

July

August

24th Biennial Congress of the European Association for Cancer Research (EACR24) July 9-12 • Manchester, United Kingdom For more information: www.ecco-org.eu/EACR

The 33rd World Congress of Internal Medicine (WCIM) August 22-25 • Bali, Indonesia For more information: www.wcimbali2016.org

WCIO 2016 June 9-12 • Boston, Massachusetts For more information: www.wcioevents.org

Lymphoma: State-of-the-Art in Biology, Therapy, and Patient Care May 13-14 • New York, New York For more information: www.mskcc.org/event/lymphomastate-art-biology-therapy-andpatient-care AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer May 16-19 • Miami, Florida For more information: www.aacr.org/Meetings/ Pages/MeetingDetail. aspx?EventItemID=78#.Vbel9qTbJjo

The Society of Nuclear Medicine & Molecular Imaging Annual Meeting June 11-15 • San Diego, California For more information: www.snmmi.org/AM/

Best of ASCO® Los Angeles July 22-23 • Los Angeles, California For more information: http://boa.asco.org

September 2nd World Congress on Controversies in Breast Cancer (CoBrCa) September 8-11 • Barcelona, Spain For more information: http://congressmed.com/cobrca/ Best of ASCO® Washington, DC July 15-16 • Washington, DC For more information: http://boa.asco.org

IARC: Emerging Issues in Oncogenic Virus Research June 15-19 • Puglia, Italy For more information: www.iarc.fr/oncogenicviruses2016/

AHNS 9th International Conference on Head and Neck Cancer July 16-20 • Seattle, Washington For more information: www.ahns2016.org/

2016 ASH Meeting on Lymphoma Biology June 18-21 • Colorado Springs, CO For more information: www.hematology.org/ Lymphoma-Biology/

Pan Pacific Lymphoma Conference July 18-22 • Koloa, Hawaii For more information: www.unmc.edu/cce/catalog/clinicmed/ panpacificlymphoma/index.html

October ESMO 2016 Congress October 7-11 • Copenhagen, Denmark For more information: http://www.esmo.org/Conferences/ ESMO-2016-Congress

November SIOG Annual Conference November 17-19 • Milan, Italy For more information: http://siog.org

November 3-6, 2016 Washington, DC

Gaylord National Hotel | National Harbor, MD

ASCOPost.com | DECEMBER 25, 2015

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Art of Oncology Beautiful Imperfections

By Richard M. Boulay, MD The ASCO Post is pleased to reproduce installments of the “Art of Oncology” as published previously in the Journal of Clinical Oncology ( JCO). These articles focus on the experience of suffering from cancer or of caring for people diagnosed with cancer, and they include narratives, topical essays, historical vignettes, poems, and photographic essays.

To read more, visit http://jco. ascopubs.org/ and search “Art of Oncology.”

J

udy repositioned the oxygen mask and then pressed her thin arms against the white linens of the hospital bed to lift herself up. “Would you consider…I’m not quite sure how to ask this…” she began with an uncharacteristic stammer. “Would you consider singing at my…funeral?”

I fiddled with the stethoscope in my pocket, and, trying to hide my awkwardness, I managed to reply, “I’d be honored. Is there something you had in mind?”

“No, not really,” she said, replacing her oxygen mask while half dropping back onto her hospital bed. “Nothing sad, though,” she continued, seemingly breathing easier. “I want people to celebrate my life. I want people to wear white.

Sing something beautiful, like Bach.”

Transformative Power Judy’s journey with cancer began over 7 years ago after a prolonged workup for irritable bowel syndrome.

I explained to her that ovarian cancer symptoms mimic benign diseases and can be easily misdiagnosed as a bowel or bladder abnormality. The many months of discomfort, invasive testing, and misdiagnoses initially led her to mistrust the medical community; however, Judy quickly went from anger to acceptance, her resentment of the limitations of modern medicine replaced with a deep love for the world around her—her grace startling in its transformative power.

She soared through her aggresRichard M. Boulay, MD, is Chief, Division of Gynecologic Oncology, Obstetrics and Gynecology, and Gynecologic Oncology/ Gynecology, Lehigh Valley Health Network, Allentown, PA.

sive debulking surgery and returned to the rigors of yoga post haste. Her monthly hospitalizations for intraperitoneal chemotherapy were attended by a grateful staff that looked forward to spending a few days in the company of a beloved patient. As the drip began, she would gesture to the window at the beautiful blossoms of the cherry trees. In remission, she spent time caring for other patients who carried the burden of their disease or treatment far less deftly than she did. Through parable and philosophy, she taught anew these patients and their medical staff the simple but profound joys of the beauty of each day.

deeply and love? It wasn’t that I didn’t try hard enough; she had an optimal surgery, and her chemotherapy treatments were cutting edge. The successes Judy had had along her cancer journey were shrouded in the shame of my imperfect work. If I couldn’t cure her, how could I face her family and lead a celebration of her life? Was I not the reason we were here in the first place? I had failed. I did not deserve this consideration.

In the end, I chose to sing, “If With All Your Hearts You Truly Seek Me,” from Mendelssohn’s Elijah. The simple, elegant message and soaring, joyful melody of the music echoed Judy’s philosophy of life. As anticipated, the memorial service was scheduled smack in the middle of an operating room day. Between patients, I left the operating room, donned a dark suit and white shirt, and dashed from the

As I was chosen to begin with Judy her cancer journey, I was also honored to help close it.

A Lasting Tribute When her disease recurred and intensified, her love of family, friends, and life grew only stronger. At age 72, as she prepared to leave this life, she bestowed upon me a lasting tribute: the opportunity to be the single voice singing her farewell—and all I wanted to do was run away.

It’s not that I couldn’t sing; I am a classically trained singer who performs regularly. It’s not that I wouldn’t sing; I recognize the deep honor of this request. It’s just that, perhaps, I shouldn’t. There are no less than a million reasons why I would gladly have traded this distinction for a seat in the congregation. My schedule is full: No doubt I would have to cancel patient office hours or reschedule surgery just to get to the service, an annoyance to affected patients and staff alike. And where could I warm up before the service? In the car on the way there? In the stairwell at the hospital? And what about allergy season? Will I squeak my way through the entire song? Then there is the whole emotional thing; it’s hard to sing through a giant lump in your throat. There was a whole lot stacking up against the perfect tribute that Judy deserved.

I was not really bothered, however, by schedules, warm ups, allergies, or even throat lumps. These hurdles were smoke screens masking my true avoidance: Why should I be recognized to celebrate a life that I was unable to save?

I know that most patients with this disease are not cured, and I understand that Judy outlived many, but I had the skills and training to cure so many others. Why could I not save the life of someone I had grown to respect

The Beauty of the Whole

—Richard M. Boulay, MD

Adapting to an Imperfect World As I struggled to reconcile my guilt over my imperfection and failure, I wondered, why would she choose me?

The past 7 years of Judy’s life were a testimony to adaptation to an imperfect world. She looked beyond the prolonged time to diagnosis and forgave those who diligently sought the cause of the symptoms she presented with yet missed her advanced cancer.

She faced each new physical insult, the surgical scars, the chemotherapyinduced baldness, and the colostomy, with poise, managing to live well and beyond her accumulating frailties.

What she “adored” (her word) remained at her side: her loving family, especially her grandchildren, her dog, yoga, her world, her God—all were manifest in splendor and beauty and wonder; each imperfection rendered invisible by the glory of the whole.

It was now my turn to learn from her teaching and to shed my vain and destructive self-image of the perfect physician; that Doc wasn’t who I was or who I could ever be. It was time to forgive my human limitations and to see my own frailties and know that, rather than being consumed by them, I could choose to find beauty and harmony within them. I released the selfimposed burden of attaining perfection and accepted my vulnerabilities, seeking the poise and grace Judy had shown so many times before.

hospital locker room to my car, where I warmed up my voice. On the way to church that morning, snow lay on the daffodil and forsythia blooms—an oddly imperfect beauty and a wonderful metaphor for all the wisdom that Judy had gently bestowed.

The bereaved gathered, as they do, in small conversational groups in the hallways leading to the chapel. I sequestered myself in an anteroom to prepare for the task at hand, but what I heard outside sounded different from other funerals. Rather than in hushed tones, people spoke openly, eagerly sharing the joys Judy brought to them. There was lightness and laughter in these conversations.

A quick peak around the doorjamb revealed spring colors in flowers and fabrics as well as a swiftness of foot as congregants greeted each other.

Seeing Judy’s son, I quit the shadows to express my deep condolences to him and his family. He, in turn, shared his profound thanks for my role in keeping the family intact for all these years; for the seven more years Judy had with her beloved grandchildren, family, and friends; for 7 more years of Mom. And as I was chosen to begin with Judy her cancer journey, I was also honored to help close it. That which began in anger and fear ended in joy and song, and each imperfection along the way faded through forgiveness and love into the beauty of the whole. n

The ASCO Post | DECEMBER 25, 2015

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Announcements

The Department of Veterans Affairs, ASTRO, and Washington University Combine Forces to Drive Better Care for Veterans With Cancer

T

he Department of Veterans Affairs (VA) has announced a new Radiation Oncology Practice Assessment (ROPA) program to leverage recent advances in information technology to improve radiation therapy cancer care for our nation’s veterans.

VA is working with the American Society for Radiation Oncology ­(ASTRO) and Washington University to provide radiation oncologists with continuous feedback on the progress of cancer therapy.

“We are pleased to be working with this country’s leading-class organizations on this innovative program, the first of its kind nationwide. Our veterans deserve nothing less,” said Maureen McCarthy, MD, VA Acting Assistant Deputy Under Secretary for Health for Patient Care Services.

ROPA Details Under ROPA, data will be abstracted from the VA’s highly sophisticated electronic medical record system and the treatment management systems used to control radiation therapy delivery. Feedback reports will be provided to VA radiation oncologists with a detailed analysis of each patient treatment compared against national standards. Combined with the traditional cancer outcome measures of recurrence and patient survival, this assessment will provide the oncologist with a complete picture of the accuracy of each patient’s therapy and the patient’s response to therapy.

Washington University is excited to take the lead role in managing the program. “We have significant experience working with the National Cancer Institute to provide the platform we will use for these assessments. We are excited to bring that experience to bear on this landmark project on behalf of our nation’s veterans,” said Jeff ­Michalski, MD, Washington University’s ViceChair of Radiation Oncology. “We are also pleased to engage a local radiation oncology informatics company, Radialogica LLC, who will provide a platform and services for data security, extraction, and management.”

In the first year of the project, A ­ STRO’s disease site–specific experts will review measures for prostate and lung cancers, identifying metrics from electronic medical records to assess each one.

Once ROPA is fully implemented, VA radiation oncologists will receive

continuously updated electronic peer reviews of each patient’s cancer evaluation, treatment, and treatment outcome. Currently, VA hospitals, similar to community hospitals, use traditional, sporadic

peer reviews in a process referred to as Ongoing Professional Peer Evaluation (OPPE). ROPA peer reviews go well beyond the traditional OPPE and practice accreditation to create comprehensive,

patient-centered reports in a web-based environment. VA radiation oncologists will see how changes in their clinical practice impact the success of each veteran’s cancer treatment. n

ASCOPost.com | DECEMBER 25, 2015

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Announcements

New Medical Director of Supportive Care Services at Cedars-Sinai

S

cott Irwin, MD, PhD, FAPM, FAPA, an expert in the fields of oncology supportive care, palliative care psychiatry, and psychosomatic medicine, has been named Medical Director of Supportive Care Services at Cedars-Sinai’s Samuel Oschin Comprehensive Cancer

Institute. Dr. Irwin will oversee oncology Supportive Care Services at the Institute and across Cedars-Sinai Health System.

Dr. Irwin also will lead research into the feasibility and safety of using ketamine to treat depression in patients with head and neck cancers and will investigate the

impact of supportive care services on patients’ psychosocial and cancer outcomes.

Prior to joining Cedars-Sinai, Dr. Irwin served as Director of Patient and Family Support Services at the University of California, San Diego, Moores Cancer Center. n

Scott Irwin, MD, PhD, FAPM, FAPA

ASCOPost.com | DECEMBER 25, 2015

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Patient’s Corner

Hoping for a Cure

My oncologist believes multiple myeloma will be cured in 10 years.

I’m doing my part to turn that goal into a reality.

By Roger Rawlings, as told to Jo Cavallo

U

nless you have a type of cancer that can be surgically removed or blasted into oblivion with chemotherapy or radiation therapy rendering a cure, having a chronic cancer like multiple myeloma robs you of a normal life. Learning to accept that fact is an adjustment.

old son’s soccer games. Living with the feeling that the clock is ticking down also propelled me to enroll in a research study to make whatever contribution I can to ensure that my oncologist’s dream of curing myeloma in 10 years becomes a reality—if not for me,

When you have cancer, you can get stuck in a place of feeling sorry for yourself, or you can move forward and become an active participant in your fate. I chose the latter.

—Roger Rawlings

I was diagnosed with multiple myeloma 2 years ago, when I was just 54.

Although I’m happy that a stem cell transplant and a continuous maintenance regimen of lenalidomide (Revlimid) and dexamethasone have kept my cancer stable, I know that at some point, it will progress. I wish that I and other myeloma survivors could be permanently rid of this cancer, and maybe that will be possible in the future.

My oncologist believes myeloma will be cured over the next decade, and I’m hoping he is right. In the meantime, I try not to waste a moment of my day and make sure to pay attention to the important things in my life, like spending time with my wife, Christie, and attending every one of my 15-year-

then for the thousands of people who will be diagnosed with the cancer over that time.

Participating in Research Soon after my diagnosis, my oncologist told me about the CoMMpass (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile) study and asked me to join. CoMMpass was launched in 2011 by the Multiple Myeloma Research Foundation (themmrf.org) so researchers could gain access to myeloma patients’ genetic material at various stages of their cancer, including from before treatment begins to remission and relapse, to learn how patients respond to therapy over the history of their dis-

ease. I immediately said yes, because it seemed like the most logical thing to do. When you have cancer, you can get stuck in a place of feeling sorry for yourself, or you can move forward and become an active participant in your fate.

I chose the latter.

Coping With Incurable Cancer Getting a cancer diagnosis, of course, is overwhelming—and frightening. When the cancer is incurable, those feelings get ticked up a notch, because you have to remain persistently vigilant about monitoring any changes in your disease that signal disease progression and can never relax your guard. I have IgG kappa myeloma, and although maintenance therapy is succeeding in keeping me in near remission, I know my status can change at any time.

I was fortunate to find a leading expert in myeloma who is knowledgeable about the cutting-edge research being done in the disease, and I’m confident that he will do everything he can to ensure that I live many years, perhaps even decades, with this cancer.

A New Full-Time Job For me, the most surprising—and challenging—aspect of coping with cancer is how much time it takes out of your daily life, especially when the cancer is chronic and requires frequent monitoring. Having cancer has become my new full-time job. I’m lucky because

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

I’m self-employed and can take off when I need to for doctor visits or laboratory tests and then make up the time I’ve lost on nights and weekends; so I never get too far behind. Other survivors, I know, aren’t so fortunate.

The cost of having cancer is another unexpected burden, although having good health insurance coverage and a reduction in the price of some medications (thanks to drug manufacturer patient assistance programs) has helped keep me financially intact. Still, managing the treatment schedule and cost of having chronic cancer takes a lot of extra planning and discipline I wasn’t expecting.

The True Burden of Cancer I’m grateful for the excellent medical care I receive from the members of my oncology team, but I wish that part of this care included information about the time and cost involved in having cancer. If I had had that conversation early in my diagnosis, it would have better prepared me for the many challenges cancer has presented over the past 2 years.

Explaining to patients how cancer will impact their lives financially as well as in time spent for treatment and longterm monitoring is just as important as explaining the details of the disease, treatment, and prognosis. n Roger Rawlings, 56, lives in Lakeville, Connecticut.

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

The ASCO Post | DECEMBER 25, 2015

PAGE 152

Reflections

Closure

By Kenneth R. Adler, MD, FACP

T

he following essay by ­Kenneth R. Adler, MD, FACP, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon.com and thebigcasino.org.

W

hen I met Cecelia 18 months ago, she was a dynamic 82-year-old optimist with a gracious smile and a fierce devotion to her family. Cecelia had lost her husband to a sudden heart attack 10 years before, but with the support of her 8 children and 21 grandchildren, she still enjoyed a good degree of independence.

Now here she was in my office, diagnosed with locally advanced rectal cancer.

Cecelia wanted to be very proactive about her condition, so she underwent chemotherapy and radiation therapy for 3 months before electing to have her cancer surgically removed. Unfortunately, soon after surgery she developed liver metastasis and embarked on another round of chemotherapy, which was followed by another related opera-

tion for small bowel obstruction.

That second operation was enough for Cecelia. “My cancer is uncooperative,” she told me. She expressed gratitude for what she described as a “blessed life.” She said that she’d always believed in God and that she was at peace with going home with hospice care.

Cecelia had shared many stories about her life during her time in the hospital. Before she was discharged, I thanked her for our relationship and said my goodbye. She died at home some 2 weeks later surrounded by her family.

She was not in pain, and her family was at peace. I felt she’d had a good death.

During Cecelia’s illness I’d come to know many of her children, who’d taken turns at her bedside. When I feel a personal connection to a patient and his or her family, as I did with Cecelia, I find that attending the person’s funeral, wake, or shiva can help me to resolve my grief and cope with the sense of loss that always attends a patient’s death.

The hall where Cecelia’s family held her wake was full of family photographs and collages. Her children gladly pointed out the many highlights of her life.

It’s often remarkable how much I learn about my patients at these events, even if I’ve known them for years. No matter how long I’ve served as someone’s physician, there is always more to know.

Grieving for Patients Who Die We practitioners of hematology-oncology have the privilege of caring for people at what is often the most difficult time of their lives. “How do you do it?” is a constant query and a complicated one to answer. For me, the answer is bound up in my own practice of grieving for every one of my patients who dies— some of whom I may have known for 30 years—in a particular, personal way.

As physicians, we get to share whole-

heartedly in our patients’ joys—birthdays, graduations, weddings, and the arrival of children and grandchildren.

When a cancer recurs or becomes refractory to treatment, we also share in their sadness. When I attend a funeral or a wake, or visit a house of shiva, family members often raise unresolved medical questions. They may ask if we should have tried “one more drug to treat the cancer” or if we could have been “more

weeks always leave a lasting impression with a patient’s family. Staying in touch through that difficult time is critical in ending a good relationship.

Saying goodbye to families I may have known for more than 30 years is never easy or simple.

As I made the rounds of the photo collages at Cecelia’s wake, I enjoyed hearing about family events and milestones. Talking about Cecelia brought

Whether I have cared for someone for 3 months or 35 years, the final weeks always leave a lasting impression with a patient’s family.

Staying in touch through that difficult time is critical in ending a good relationship.

—Kenneth R. Adler, MD, FACP

aggressive” about a late-stage infection.

These are often difficult questions, but taking the time to answer them and clarify “what happened” helps many family members achieve closure.

I sense genuine appreciation from my patients’ families when I’m present at their final event or otherwise when I pay my respects. This isn’t always possible. This past week alone, four of my patients died at home on hospice care.

Closure becomes much more difficult when losses come in such proximity. As oncologists, we have to learn to grieve in our own private way. If time does not allow me to attend a wake or shiva, then I try to make a phone call or send a note to express my condolences.

Finding Comfort Whether I have cared for someone for 3 months or 35 years, the final

The ASCO Post Like us on Facebook facebook.com/TheASCOPost

her back to life for a moment. It was comforting to me and, I hope, to her family as well.

I do worry about the toll of suffering so much loss or of compassion fatigue. But by reflecting on my own process of grieving and doing what I can to find closure—with the support of my excellent colleagues and family—I manage to continue practicing hematology-oncology. The question becomes not “How do I do it?” but “How could I not?” n Dr. Adler is an attending hematologistoncologist at Morristown Medical Center in New Jersey and a member of Regional Cancer Care Associates. He also is Chairman of the New Jersey Commission on Cancer Research and a member of the American Society of Hematology Committee on Practice.

ASCOPost.com | DECEMBER 25, 2015

PAGE 153

Announcements

NIH Awards City of Hope $4.8 Million to Study Environment and Breast Cancer

T

he National Institutes of Health has awarded City of Hope a 5-year, $4.8 million grant to study the possible role of chemicals in the environment in the development of breast cancer during the menopausal transition in women.

The coprincipal investigators on the

study are two City of Hope researchers known for their work in the potential connection between breast cancer and environmental factors: Shiuan Chen, PhD, Professor and Chair of the Department of Cancer Biology, and Susan L. Neuhausen, PhD, The Morris &

Horowitz Families Professor in Cancer Etiology & Outcomes Research.

The grant is funded through the Breast Cancer and the Environment Research Program (BCERP), which is a joint effort cofunded by the National Institute of Environmental Health SciShiuan Chen, PhD

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Susan L. Neuhausen, PhD

ences and the National Cancer Institute.

City of Hope was among six U.S. institutions to receive a BCERP grant.

The title of the joint project is “Menopausal Transition—A Window of Susceptibility for the Promotion of Breast Cancer by Environmental Exposures.”

The study is based on a growing body of evidence suggesting there may be specific windows of susceptibility during which a woman’s body is more vulnerable to carcinogenic changes in breast tissue. Breast cancer statistics suggest that one such time of vulnerability could be the menopausal transition.

“We believe during this time, when natural hormone levels are declining, environmental endocrine-disrupting chemicals promote hormone-responsive breast cancers,” Dr. Chen said.

The City of Hope research team will assess the impact that a class of persistent organic pollutants has on estrogen and progesterone receptors in women going through menopause. The goal is to determine whether two types of compounds—bis-phenol A and polybrominated diphenyl ethers—raise breast cancer risk during this time of transition to menopause. To accomplish this, Drs. Chen and Neuhausen will evaluate these processes through in vitro cell line experiments, in vivo mouse models, and observational and biological studies in women in the menopausal transition.

The team will analyze blood samples from women who participated in the California Teachers Study, a cohort of educators followed since 1995 that allows researchers to investigate environmental, genetic, and other factors that may cause cancer. n

The ASCO Post | DECEMBER 25, 2015

PAGE 154

In the News Genitourinary Cancer

Decline in PSA Testing and Incidence of Early Prostate Cancer Coincide With 2012 Recommendation Against PSA Screening

By Charlotte Bath

T

wo recent studies1,2 found that the rates of prostate-specific antigen (PSA) screening have declined since the U.S. Preventive Services Task Force (USPSTF) recommended against PSA screening in 2012. One of those studies additionally found that the incidence of early-stage prostate cancer also coincided with the 2012 PSA screening recommendation, and “alternative explanations for the substantial decrease in incidence between 2011 and 2012 are unlikely.”1 Although the studies are limited by short-term follow-up, the findings have raised concerns that the longterm results of reduced screening may be higher rates of metastatic prostate cancer and mortality.

Furthermore, major media, including The New York Times, The Washington Post, and The Wall Street Journal, have reported on the studies, often including comments from prostate cancer experts and warnings about the projected increased mortality. One of those often quoted in these reports was David F. Penson, MD, MPH, who wrote an editorial3 accompanying the two studies reported in The Journal of the American Medical Association.

Dr. Penson is Professor and Chair, Department of Urologic Surgery, and Director, Center for Surgical Quality and Outcomes Research, at Vanderbilt University Medical Center, Nashville.

In a segment on National Public Radio, Dr. Penson called the decline in PSA testing “very disturbing.”4 Discussing the USPSTF 2012 recommendation with Reuters Health, Dr. Penson said an increase in advanced prostate cancers is “unfortunately what’s going to happen because of this recommendation.”5 Dr. Penson expanded on these and other themes in an interview with The ASCO Post.

Mortality Increase Unlikely Before 2022 “The first thing we are going to see is an increase in the number of men presenting with metastatic disease. Maybe that will be enough for people to rethink their positions, but it may not,” Dr. Penson said. “It may require, unfortunately, that people see an increase in mortality in order for them to say, maybe we shouldn’t have abandoned PSA screening completely. Maybe we

should have thought of more targeted ways to screen, ways to minimize the harms and maximize the benefits of what is, frankly, an imperfect test.”

The study by Jemal et al1 estimated that 33,519 fewer cases of prostate cancer were detected in 2012 than in 2011 in men 50 years and older. Using an extrapolation formula developed for the European Randomized Study of Screening for Prostate Cancer ­(ERSPC) that after 13 years of follow-up, 27 additional prostate cancer cases needed to be detected among those screened to prevent 1 prostate cancer

in PSA screening associated with the 2012 USPSTF recommendations,” the authors noted.

The study by Jemal et al1 looked at screening rates for a total of 18,385 men 50 years and older who responded to the National Health Interview Survey. They found that the percentage of men who reported having been screened during the previous year was 36.9% in 2005, 40.6% in 2008, 37.8% in 2010, and 30.8% in 2013.

“In relative terms,” according to the investigators, screening rates “de-

The solution is rather than saying no [PSA] screening, or tons of [PSA] screening, let’s figure out better ways to screen, and doing it every other year is a good first step.

—David F. Penson, MD, MPH

death, “would suggest that approximately 1,241 (33,519/27) more men will die of prostate cancer,” Dr. Penson wrote in the editorial. “This estimate may even be somewhat conservative,” he added.

“Prostate-cancer mortality, when it occurs, happens long after diagnosis,” he noted.

“Therefore, the increase in prostate cancer mortality rates associated with the 2012 decrease in PSA screening is unlikely to be detected for 7 to 10 years or later.”

Two Studies, Similar Findings Both studies relied on self-reported responses to the National Health Interview Survey to determine PSA screening rates before and after the 2012 recommendations, although using different exclusion criteria and analyses resulted in slightly different study populations and results. The results are based on short-term followup, with screening rates last reported in 2013 and incidence rates reported in 2012. It should be noted, however, that the 2012 USPSTF recommendations were publicly announced in draft form in October 2011.

The study by Sammon et al2 included a total of 20,757 men, with 34% reporting screening in 2000 and 2005; 35%, in 2010; and 31%, in 2013. “After adjusting for patient factors, there were significant reductions

creased by 18%” between 2010 and 2013. Looking at prostate cancer incidence between 2005 and 2012, Jemal et al found “the largest year-over-year decline in incidence per 100,000 occurred between 2011 and 2012,” from 498.3 to 416.2—“an absolute decline of 82.1 cases per 100,000 men and a relative decline of 16%.”

Deploying PSA Testing More Effectively “The PSA test is certainly imperfect, but perhaps,” Dr. Penson wrote in the editorial, “the PSA test can be deployed more effectively (or strategically), maximizing benefit while minimizing harm. For example, the American Urological Association’s Early Detection of Prostate Cancer guidelines suggest that a routine screening interval of 2 years or longer may be preferred over annual screening.” Those guidelines recommend offering PSA testing to men 55–69 years old.

“We have always been taught that we should be doing annual screening,” Dr. Penson told The ASCO Post, so the option of every-other-year PSA screening has not been really explored.

“I think we need to start exploring it,” he added, “because to me, that is probably one possible solution. The solution is rather than saying no screening,

or tons of screening, let’s figure out better ways to screen, and doing it every other year is a good first step.”

Other possible strategies are basing the frequency of PSA screening on a single initial measurement at a relatively young age (although that age has not been defined) and using nomograms to identify men at increased risk of prostate cancer. Although nomograms are widely available, they are not widely used. The reasons include lack of awareness and the perception that sitting down at the computer to use them “is going to slow down the doctor-patient interaction,” Dr. Penson said. “But the reality is nomograms are of value. The Prostate Cancer Prevention Trial risk calculator will show patients the risk of whether or not they have a clinically meaningful cancer,” he added, and will help them to decide whether or not to have a biopsy or to follow a more targeted screening strategy.

The Potential of Biomarkers The Stockholm 3 (STHLM3) study, recently reported in The Lancet Oncology, found that using a combination of plasma protein biomarkers (including PSA), genetic polymorphisms, and clinical variables (age, family history, previous prostate biopsy, prostate exam) “performed significantly better than PSA alone for detection of cancers with a Gleason score of at least 7.”6 The STHLM3 model “could reduce unnecessary biopsies” and “could be a step toward personalized risk–based prostate cancer diagnosis programs,” the investigators stated.

“We need to develop more data to see if that particular set of biomarkers is helpful,” Dr. Penson explained.

“There are other tests out there as well, where we have preliminary data: the 4K Score and the Prostate Cancer Index (PHI). We have to start looking in greater detail at these biomarkers and see if they actually improve our ability to detect clinically meaningful prostate cancer and make an intervention.”

‘Reconsider Their Position’ Dr. Penson said that he would like to see the members of the ­USPSTF “reconsider their position” on prostate cancer screening. “I am not saying that annual PSA screening is somecontinued on page 156

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The ASCO Post | DECEMBER 25, 2015

PAGE 156

In the News Prostate Cancer Screening continued from page 154

thing that deserves a grade A or grade B recommendation, because the evidence doesn’t support that,” he noted.

(Both grades A and B indicate that the USPSTF recommends the service and practitioners should offer or provide it, but grade A confers a higher certainty of benefit.) However, he continued, the evidence “doesn’t necessarily sup-

port a grade D,” which is the current grade given by the ­USPSTF, “or even a grade C recommendation. (Grade D means that the USPSTF recommends against the service because of a moderate to high certainty that the service has no real benefit. For grade C recommendations, “there is at least moderate certainty that the net benefit is small,” and the USPSTF recommends selectively offering or providing the servic-

es to individuals based on professional judgment and patient preference.)

Studies “show that in some men, there is benefit to screening,” Dr. Penson said.

“The rate of overtreatment has dropped considerably in the past 5 to 10 years. So hopefully,” he added, USPSTF members “will take that into account. There is real justification for them to rethink their recommendation and to consider being a little bit less extremist about it.”

In fact, the USPSTF prostate cancer screening recommendation “is in the process of being updated,” according to information on the Task Force’s website. Draft research is available at www. uspreventiveservicestaskforce.org.

A Swinging Pendulum The current recommendation against prostate cancer screening may represent a swinging of the pendu-

Expect Questions About Prostate Cancer Screening and Active Surveillance

A

study finding that the incidence of prostate cancer has declined in recent years may at first seem like good news to physicians and patients, but, as widely reported by the media, the decline is not seen as an indication that prostate cancer has become less prevalent, but that screening for it has become less common. That study and another published in the same issue of The Journal of the American Medi-

said that by 2010, it was already “understood that prostate cancer screening in men in their late 70s and 80s was not as valuable as for men in their 50s and 60s.”

The recommendation against screening for younger men was a more abrupt change, but one that seems to be readily accepted by the men and their physicians. “Primary care physicians have a lot on their plate. They are not just worrying about prostate

There is little doubt that if screening rates had remained stable, many men who would have been diagnosed with prostate cancer would have had clinically indolent disease and been exposed to the considerable adverse effects of surgery or radiation with little or no survival benefit.

—David F. Penson, MD, MPH

cal Association reported that prostatespecific antigen (PSA) screening rates have declined since the U.S. Preventive Services Task Force (USPSTF) recommended omitting PSA screening from routine primary care for men.1,2 In an accompanying editorial3 and an interview with The ASCO Post, David F. Penson, MD, MPH, acknowledged the benefits associated with reduced PSA screening but expressed concerns about future increases of metastatic prostate cancer and mortality. Dr. Penson is Professor and Chair, Department of Urologic Surgery, and Director, Center for Surgical Quality and Outcomes Research, at Vanderbilt University Medical Center, Nashville.

Screening Decline Greater for Younger Men Both studies found that although PSA testing declined for all age groups between 2010 and 2013, the decline was not as great for men over age 75, who already had been advised in 2008 not to have PSA screening. Dr. Penson

cancer screening. They are worrying about other cancer screening. They are worrying about cardiovascular health,” Dr. Penson commented. So when the USPSTF recommended not screening, that fit in nicely with the need of busy primary practices to save time. “But is it the right thing to do? I don’t think so,” Dr. Penson said.

Dr. Penson stated there are “some primary care physicians who don’t accept the USPSTF recommendation” and “patients who have made it very clear to their primary care physicians that they want the PSA test.” In most cases, if patients ask for a PSA test, they will get it, he added.

Troublesome for High-Risk Men The prostate cancer–screening rates and incidence have dropped for both low-risk and high-risk men, and that could be particularly troublesome down the line for high-risk men. “One of the key points that people forget,” Dr. Penson reminded, is that prostate

screening recommendations “apply to men with clinically normal risk for prostate cancer, in other words, the general population. But screening rates have dropped for everybody, even for high-risk men, and that could be a very bad thing, but we don’t know yet because we just don’t have the information,” he added.

“We don’t have good randomized clinical trials for men at higher risk,” Dr. Penson admitted. Applying findings about normal-risk individuals to a high-risk individual, such as an African American man with a family history of prostate cancer, “is the wrong thing to do, because the data are not based on someone like him,” he explained.

Uptick in Active Surveillance “There are also benefits associated with reduced PSA screening,” Dr. Penson wrote in the editorial. “There is little doubt that if screening rates had remained stable, many men who would have been diagnosed with prostate cancer would have had clinically indolent disease and been exposed to the considerable adverse effects of surgery or radiation, such as sexual, urinary, or bowel problems, with little or no survival benefit. Acknowledging this, there is increasing evidence that active surveillance is becoming a preferred management strategy for men with low-risk disease.”

Patients are now more likely to understand that active surveillance is not the same as “watchful waiting” or doing nothing; rather it involves serial PSA measurements, with follow-up prostate biopsies, and intervention only if there is evidence of disease progression. This increased understanding “is one of the reasons why we are seeing an uptick in the use of active surveillance, because if you ask a guy would you rather have a prostate biopsy every 2 years or a

radical prostatectomy tomorrow, most men would take option A,” Dr. Penson reasoned.

The Math Is Changing “The math is changing in prostate cancer, and the concept of the harms of PSA screening is changing, because we are seeing a little more thoughtfulness on the part of both patients and providers, not just about when to get the PSA test, but also what to do once you get it, what to do once you have a biopsy,” Dr. Penson declared.

He conjectured that policy makers and USPSTF members may be “doing the math and in their minds they feel that the risks of treatment, of overtreatment, and the harms of being treated outweigh the benefit of avoiding a certain number of prostate cancer deaths.

In my mind, I think everyone is entitled to make their own decisions about their health care. Some people are willing to accept the risk of overtreatment and harms of treatment for the potential benefit of avoiding a prostate cancer– related death.” Dr. Penson concluded: “Conversely, there are going to be men who say, my quality of life is very important to me, and I am not willing to risk it for a potential benefit in quantity of life.

So I think it is an individual decision.” n

Disclosure: Dr. Penson reported no potential conflicts of interest.

References 1. Jemal A, Fedewa SA, Ma J, et al: Prostate cancer incidence and PSA testing patterns in relation to USPSTF screening recommendations. JAMA 314:20542061, 2015.

2. Sammon JD, Abdollah F, Choueiri TK, et al: Prostate-specific-antigen screening after 2012 US Preventive Services Task Force recommendations.

JAMA 314:2077-2079, 2015.

3. Penson DF: The pendulum of prostate cancer screening. JAMA 314:20312033, 2015.

ASCOPost.com | DECEMBER 25, 2015

PAGE 157

In the News

lum after 2 decades of an “overly aggressive” approach to screening and treatment, Dr. Penson noted. He encourages reaching a consensus about prostate cancer– screening strategies “and ultimately helping men by stopping the swinging pendulum somewhere in the middle.”

Just where that middle might or should be is difficult to determine, admitted Dr. Penson. “We need more research to figure out what is the best way to screen. But I am certain of two things,” he said: “to do no screening at all is wrong, and to do populationwide screening on an annual basis is also wrong.

The right way may be somewhere between these polar opposites, Dr. Penson revealed. “Maybe it is every other year screening. Maybe it is personalized screening strategies based on a baseline PSA and other risk factors or a nomogram. There are a number of different ways we can spin this.

But it is somewhere in there.”

The ASCO Post asked Dr. Penson that if consensus is not reached, does he think it will take rising mortality rates to swing the pendulum back the other way? “Unfortunately, I do,” he answered. “Given the way the two sides have dug in, and the fact that we are dealing with so much emotion and rhetoric, I think we are going to have to see some real hard changes in the way prostate cancer presents and the outcomes associated with it for people to realize that we need to sit back down at the table and think this out.” n Disclosure: Dr. Penson has received research support from Astellas, Medivation, AHRQ, and PCORI.

References 1. Jemal A, Fedewa SA, Ma J, et al: Prostate cancer incidence and PSA testing patterns in relation to USPSTF screening recommendations. JAMA 314:20542061, 2015.

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication

2. Sammon JD, Abdollah F, Choueiri TK, et al: Prostate-specific-antigen screening after 2012 US Preventive Services Task Force recommendations.

JAMA 314:2077-2079, 2015.

3. Penson DF: The pendulum of prostate cancer screening. JAMA 314:20312033, 2015.

4. Stein R: Prostate cancer screening drops

sharply, and so do cancer cancers. National Public Radio, November 18, 2015. Available at http://www.npr.org/sections/healthshots/2015/11/17/456201282/prostatescreening-drops-sharply-and-so-do-cancercases. Accessed December 10, 2015.

5. Seaman AM: Prostate cancer screening, early cases, in decline. Reuters Health, November 17, 2015. Available at http://

mobile.reuters.com/article/healthNews/ idUSKCN0T620M20151117. Accessed December 10, 2015.

6. Grönberg H, Adolfsson J, Aly M, et al: Prostate cancer screening in men aged 50-69 years (STHLM3): A prospective population-based diagnostic study.

Lancet Oncol. November 9, 2015 (early release online).

NEW IN 2016 Journal of Oncology Practice now includes highly practical clinical reviews Editor-in-Chief: John V. Cox, DO, MBA, FACP, FASCO; University of Texas Southwestern Medical Center, Dallas, Texas Deputy Editor: James O. Armitage, MD; University of Nebraska Medical Center, Omaha, Nebraska

JOP has expanded editorially to include highly practical clinical content. Increasing in frequency from bimonthly to monthly, JOP’s clinical expansion is anchored by practical clinical reviews written specifically for busy, practicing clinicians who treat patients on a daily basis, including: >> Highly practical, clinical review articles every month from thought leaders in oncology and relevant subspecialties accompanied by expert commentaries and linkages to relevant care delivery issues when appropriate. These reviews may take the format of a classic review or may include: • “How I Treat” articles in which experts share their personal approach and bias in treating certain cancers and cancer-related complications.

• Clinical Vignettes that describe challenging clinical problems in the form of a case vignette accompanied by expert-written management options. >> ASCO Clinical Guideline Summaries that provide clinicians with a more user-friendly version of ASCO’s full clinical guidelines.

No other journal in the field delivers an authoritative and balanced mix of both healthcare delivery research and highly practical, clinical content.

To Access Issues or Subscribe Visit JOP.ascopubs.org

The ASCO Post | DECEMBER 25, 2015

PAGE 158

In the Literature

Emerging Clinical Data on Cancer Management MULTIPLE MYELOMA Better Quality of Life With Melphalan and Prednisone Used With Lenalidomide Than With Thalidomide A phase III Eastern Cooperative Oncology Group (ECOG) trial (E1A060) comparing melphalan, prednisone, and thalidomide (Thalomid) with melphalan, prednisone, and lenalidomide (Revlimid) in elderly patients with untreated multiple myeloma found that at the end of the induction period, patients receiving melphalan, prednisone, and lenalidomide had “a statistically superior” quality of life.

“Much of this difference appears attributable to lower neuropathy rates with lenalidomide than with thalidomide,” A. Keith Stewart, MBChB, of Mayo Clinic Arizona in Scottsdale, and colleagues reported in Blood. There were no statistical or clinically relevant differences in response rates, progression-free survival, or overall survival.

A total of 306 patients enrolled: 154 in the melphalan, prednisone, and thalidomide arm and 152 in the melpha-

lan, prednisone, and lenalidomide arm.

“Seven cooperative groups contributed, with 66% of patients coming from 33 participating ECOG centers,” the researchers noted.

“Eligible patients required a confirmed diagnosis of multiple myeloma as well as evidence of end-organ damage at the time of diagnosis. Patients were ≥ 65 years and had declined alternative treatment or were < 65 years and were not candidates for autologous stem cell transplantation or had declined transplant,” the investigators explained. The median age of the study participants was 75.7 years. ECOG performance status ≤ 2 was required.

For induction therapy, patients received either 9 mg/m2 of melphalan and 100 mg of prednisone orally on days 1 to 4 with 100 mg of thalidomide daily or 5 mg/m2 of melphalan and 100 mg of prednisone orally on days 1 to 4 with 10 mg of lenalidomide orally on days 1 to 21. The authors explained that they used “the designation melphalan, prednisone, and lenalidomide to delineate the lower doses of melphalan that can be coadministered as well as

continuous use of lenalidomide, with a hypothesis that melphalan, prednisone, and lenalidomide would be noninferior and possibly superior in terms of toxicity and survival outcomes.”

Patients continued on therapy for 12 28-day cycles followed by 100 mg of thalidomide or 10 mg of lenalidomide daily until progression or unacceptable toxicity. “Mean duration of overall treatment (induction and maintenance) was 15.6 months on melphalan, prednisone, and thalidomide and 14.9 months on melphalan, prednisone, and lenalidomide for the entire study cohort,” the authors noted.

Survival Findings The median follow-up was 40.7 months. For the primary intention-totreat analysis, the median progressionfree survival observed was 21.0 months for patients receiving melphalan, prednisone, and thalidomide vs 18.7 months for those receiving melphalan, prednisone, and lenalidomide (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.64–1.09; P = .186). Overall survival was 52.6 months with melphalan, prednisone, and thalidomide vs 47.7 months with melphalan, prednisone, and lenalidomide (HR, 0.88; 95% CI, 0.63–1.24; P = .476). “Per-protocol response rates were 63.6% (melphalan, prednisone, and thalidomide) and 59.9% (melphalan, prednisone, and lenalidomide; P = .557),” the investigators reported.

Toxicity

© Liza Donnelly/The New Yorker Collection/www.cartoonbank.com

“Both regimens proved toxic,” the authors wrote. “At least 58% of melphalan, prednisone, and lenalidomide patients and 73% of melphalan, prednisone, and thalidomide patients experienced grade 3 toxicity, and half the patients discontinued treatment before finishing 12 months of planned induction therapy, with toxicity being the primary reason (42%) for stopping treatment.”

Patients receiving melphalan, prednisone, and thalidomide had significantly higher ≥ grade 3 nonhematologic toxicity, 59.5% vs 40.0% receiving melphalan, prednisone, and lenalidomide (P = .001). “There was also a notable age effect in the melphalan, prednisone, and thalidomide arm,” the investigators noted, with 47.2% of those > 75 years experiencing a grade ≥ 3 adverse event vs 35.6% of patients < 75 years. “This difference in tolerability by age was not significant in melphalan, prednisone, and lenalidomide

patients,” the authors wrote.

Grade ≥ 3 events occurring in > 5% of patients included anemia, leukopenia, lymphopenia, neutropenia, fatigue, constipation, and dyspnea (in the melphalan, prednisone, and thalidomide arm only). Deep vein thrombosis or pulmonary embolism was observed in 8.8% of the melphalan, prednisone, and thalidomide patients and 6.7% of the melphalan, prednisone, and lenalidomide patients. Second malignancies occurred in 18 melphalan, prednisone, and thalidomide patients and 14 melphalan, prednisone, and lenalidomide patients.

Stewart AK, et al: Blood 126:12941301, 2015.

CERVICAL CANCER Women Coinfected With Human Papillomavirus Had Reduced Risk for Invasive Cervical Cancer Women coinfected with low-risk and high-risk human papillomavirus (HPV) had a reduced risk for invasive squamous cervical carcinoma and a longer time to progression than did women infected with high-risk human papillomavirus alone, according to a Swedish study published in the Journal of the National Cancer Institute. “We propose that coinfection with low-risk human papillomavirus interferes with the rate of progression to invasive cervical cancer,” wrote Karin ­Sundström, MD, PhD, of the Karolinska Institutet, Stockholm, and colleagues.

Using data from the Swedish National Cervical Screening Register and the Swedish National Cancer Register, the researchers identified women who had normal baseline smears and later developed cancer in situ (n = 524) or squamous cervical cancer (n = 378), as well as individually matched control subjects who remained free of disease during study follow-up. A total of 4,659 smears were collected and all were tested for HPV. “The median time from the first smear to diagnosis of the case subject was 6.4 to 7.8 years, yielding a median age at diagnosis of 32 years for cancer in situ and 41 years for squamous cervical cancer,” the authors reported. Infection with high-risk HPV was prevalent in the smears before either a diagnosis of cancer in situ (49%–67%) or squamous cervical cancer (50%–57%).

ASCOPost.com | DECEMBER 25, 2015

PAGE 159

In the Literature

“The proportion of smears only positive for low-risk HPV was universally low, at 1% to 3%,” the investigators noted. “The proportion of smears positive for both high-risk HPV and low-risk HPV was slightly higher, at 1% to 5%.” Smears coinfected with high-risk and low-risk HPV had between one and six high-risk HPV types, but most had only one low-risk type. The most prevalent low-risk type was HPV42.

The researchers analyzed separately the risk associated with HPV infection in the first and the last smears before a patient’s diagnosis. Women who were coinfected with high-risk HPV and low-risk HPV “had a tendency for a decreased risk for squamous cervical cancer if found in the first smear (relative risk [RR] = 0.4, 95% confidence interval [CI] = 0.10– 2.0) and a statistically significantly decreased risk for squamous cervical cancer if found in the last smear (RR = 0.2, 95% CI = 0.04–0.99, P = .049),” the researchers reported. The risks for cancer in situ were the same for women with single and double HPV infection (RR first smear = 0.8, 95% CI = 0.3–1.7; RR last smear = 1.10, 95% CI = 0.4–3.6).

The authors commented: “Antagonistic interaction effects between high-risk and low-risk types of HPV have now been shown in several independent cohorts, using both differing

biological material and timing in relation to diagnosis of invasive cancer.”

The reasons for the interaction found in this study, however, are not clear, and the authors stated their finding “may merit further replication in other cervical DNA-based studies and investigation of potential underlying mechanisms.”

Sundström K, et al: J Natl Cancer Inst.

July 9, 2015 (early release online).

LUNG CANCER

the patient at increased risk of toxicity without an established palliative or survival advantage,” the investigators stated.

“This demonstrates that a substantial number of patients requiring palliative thoracic radiotherapy are overtreated, and further work is necessary to ensure these patients are treated according to evidencedbased guidelines,” the authors ­concluded.

Strongest Predictive Factors

‘Substantial Number’ of Patients Requiring Palliative Radiotherapy for Stage IV NSCLC Are Overtreated An analysis of data from 46,803 patients with stage IV non–small cell lung cancer (NSCLC) who received palliative chest radiation therapy found that 49% received radiotherapy for longer than 15 fractions, and 28% received more than 25 fractions. This treatment pattern “is inconsistent with the results of published phase III studies,” Matthew Koshy, MD, of the University of Chicago, and colleagues pointed out in the Journal of the National Cancer Institute. In addition, approximately 19% of the patients received concurrent chemoradiation, “a practice that is not only unsupported by the evidence, but one that places

The study participants were identified using the National Cancer Database from 2004 to 2012. The median age of the patients was 67 years, and the median primary tumor size was 5 cm.

“The strongest independent predictors of long-course radiation therapy were private insurance (odds ratio [OR] = 1.40 vs uninsured, 95% confidence interval [CI] = 1.28– 1.53) and treatment in community cancer programs (OR = 1.49, 95% CI = 1.38–1.58) compared with academic research programs,” the authors reported. The strongest predictive factors for chemoradiotherapy were private insurance (OR = 1.38, 95% CI = 1.23–1.54) compared with uninsured patients and treatment in community cancer programs (OR = 1.44, 95% CI = 1.33–1.56) compared with academic programs.

‘Reverse Disparity’ “This study found that in patients who underwent palliative thoracic radiotherapy, a ‘reverse disparity’ exists in that the group of patients who usually receive care consistent with evidence-based guidelines (ie, white and insured patients) were overtreated with longer courses of radiotherapy and concurrent chemoradiotherapy.

These intensive treatments are associated with higher risks of morbidity— esophagitis, in particular—without a meaningful clinical gain, and thus further investigation into this pattern is important.”

Patients treated more recently, from 2009–2012 vs from 2004–2008, were less likely to be treated with more than 15 fractions of radiation therapy and slightly less likely to be treated with concurrent chemoradiotherapy.

The reduction in long-course radiation “suggests that population-level progress can be made and that clinical practice guidelines can change practice patterns,” the authors observed.

“Furthermore, early involvement with palliative care specialists can meaningfully improve outcomes and adherence to evidence-based treatment choices in the noncurative setting.” n Koshy M, et al: J Natl Cancer Inst.

September 30, 2015 (early release online).

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM). REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials FOR NEWLY DIAGNOSED MULTIPLE MYELOMA

SHAPE PROGRESSION-FREE SURVIVAL WITH CONTINUOUS TREATMENT Continuous REVLIMID + dex until progression showed a PFS and OS benefit in patients with newly diagnosed multiple myeloma vs MPT

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM See full prescribing information for complete boxed warning.

EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death.

• Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception.

REVLIMID is available only through a restricted distribution program called the REVLIMID REMS® program (formerly known as the “RevAssist® program”).

HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia.

• For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter.

VENOUS AND ARTERIAL THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving REVLIMID with dexamethasone.

Anti-thrombotic prophylaxis is recommended.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNINGS, on the following pages.

Learn more at www.REVLIMID.com

Median Progression-Free Survival (PFS) Rd Continuous (n=535) 25.5 mo (95% CI 20.7, 29.4) Rd18 (n=541) 20.7 mo (95% CI 19.4, 22.0) MPT (n=547) 21.2 mo (95% CI 19.3, 23.2)

100

Survival Probability (%)

80 Rd Continuous vs MPT Rd Continuous vs Rd18 Rd18 vs MPT

60

Logrank P value (2-sided) HR (95% CI) 0.72 (0.61, 0.85) P<0.0001 0.70 (0.60, 0.82) 1.03 (0.89, 1.20)

Planned duration of treatment in the Rd18 40 and MPT arms was 18 months 20

0

0

1

2

3

4

5

Progression-Free Survival (Years) •535 PFS Rd Continuous Rd18 541 MPT MM-020 547 Study design: The

Events: (52.0%), (64.3%), MPT=334/547 400Rd Continuous=278/535 319 265 218 Rd18=348/541 168 105 55 19 (61.1%)2 391 380 (FIRST)

319 265 167 304 244 compared REVLIMID170+

108 116 low-dose

56 30 58 28 (Rd) dexamethasone

7 2 6 1 Continuous until

0 0 0 progression,

trial fixed-cycle MPT, and fixed-cycle Rd18. MM-020 was a Phase 3, randomized, multicenter, open-label, 3-arm study enrolling 1623 newly diagnosed Number of Subjects at mg Risk patients who did not receive a stem cell transplant (SCT).

REVLIMID was given 25 once daily orally on Days 1 to 21 of 28-day cycles, PFS Events: Rd Continuous=278/535 (52.0%), Rd18=348/541 (64.3%), MPT=334/547 (61.1%) ≤75 years and 20 mg for patients and dex was dosed once daily orally on Days 1, 8, 15, and 22 of each 28-day cycle (40 mg for patients >75 years). The primary endpoint in the trial was progression-free survival (PFS), as the time from randomization to the first documentation of disease progression as determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd Continuous and MPT arms.

58.9 months median overall survival (OS) with Rd Continuous until progression in an interim analysis, compared with 48.5 months with MPT (HR 0.75 [95% CI 0.62, 0.90]) and 56.7 months with Rd18 (HR 0.91 [95% CI 0.75, 1.09]) • At median follow-up of 45.5 months, only 78% of prespecified events had occurred (697/896 of the final OS events) • OS is defined as the time from randomization to death from any cause ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75% Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, StevensJohnson syndrome, toxic epidermal necrolysis) to lenalidomide

Treatment is a science. Patient care is your art.

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM) REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS® program (formerly known as the “RevAssist®” program).

Information about the REVLIMID REMS® program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in offspring of female monkeys who received drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide is present in the semen of patients receiving the drug.

Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID REVLIMID REMS® Program Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS® program (formerly known as the “RevAssist®” program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS®

program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436 Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter.

Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and PE (3.7%) occurred in patients with MM after at least one prior therapy, treated with REVLIMID/dex compared to placebo/dex (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In NDMM study, in which nearly all patients received antithrombotic prophylaxis, DVT (3.6%) and PE (3.8%) were reported in the Rd continuous arm. Myocardial infarction (MI, 1.7%) and stroke (CVA, 2.3%) are increased in patients with MM after at least 1 prior therapy who were treated with REVLIMID/dex therapy compared with placebo/dex (0.6%, and 0.9%) in clinical trials. In NDMM study, MI (including acute) was reported (2.3%) in the Rd Continuous arm. Frequency of serious adverse reactions of CVA was (0.8%) in the Rd Continuous arm. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events occurred in patients with refractory and relapsed MM who were treated with REVLIMID/dex compared to 8.3% thrombosis in the placebo/dex group. Median time to first thrombosis event was 2.8 months. In NDMM study, which nearly all patients received antithrombotic prophylaxis, overall frequency of thrombotic events was 17.4% in combined Rd Continuous and Rd18 arms. Median time to first thrombosis event was 4.37 months.

Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision. See Boxed WARNINGS Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41] consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID

WARNINGS AND PRECAUTIONS (continued) treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials Second Primary Malignancies: In clinical trials in patients with MM receiving REVLIMID, an increase of invasive second primary malignancies (SPM) notably AML and MDS have been observed. The increase of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (5.3%) or immediately following high dose intravenous melphalan and ASCT (up to 5.2%). The frequency of AML and MDS cases in the REVLIMID/dex arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received REVLIMID in the post-ASCT setting. Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and risk of second primary malignancies when considering treatment Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID in combination with dex. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash.

REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken Tumor Flare Reaction: Tumor flare reaction (TFR) has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash.

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are autologous stem cell transplant (ASCT) candidates, referral to a transplant center should occur early in treatment to optimize timing of the stem cell collection ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75%

Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous • After at least one prior therapy most adverse reactions and Grade 3 or 4 adverse reactions were more frequent in MM patients who received the combination of REVLIMID/dex compared to placebo/dex. Grade 3 or 4 adverse reactions included neutropenia 33.4% vs 3.4%, febrile neutropenia 2.3% vs 0%, DVT 8.2% vs 3.4% and PE 4% vs 0.9% respectively Adverse reactions reported in ≥15% of MM patients (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%) DRUG INTERACTIONS Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436 Nursing Mothers: It is not known whether REVLIMID is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother Pediatric Use: Safety and effectiveness in patients below the age of 18 have not been established Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the following pages.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®.

REVLIMID® and REVLIMID REMS® are registered trademarks of Celgene Corporation. © 2015 Celgene Corporation 07/15 US-REV140068a(1)

The ASCO Post | DECEMBER 25, 2015

PAGE 164

Announcements

Breast Care Services at Henry Ford Health System Gains New Director, Three New Surgeons

I

nternationally renowned breast cancer surgeon Lisa A. Newman, MD, MPH, has joined Henry Ford Health System to lead its metro Detroit breast cancer program and new international

breast cancer research center. She begins work in December as the Director of the Breast Cancer Program at Henry Ford.

Dr. Newman comes to Henry Ford from the University of Michigan (U-M)

Health System, bringing with her two colleagues from U-M, Jessica Bensenhaver, MD, and Monique Swain, MD, and one from Moffitt Cancer Center, Dunya ­Atisha, MD, to joinT:7” Henry Ford’s nation-

ally recognized breast cancer team.

Dr. Bensenhaver is a breast cancer surgeon specializing in benign and malignant breast diseases. Her research focuses on socioeconomic, geographic, and ethnicity-

REVLIMID [lenalidomide] capsules, for oral use

Table 1: Dose Adjustments for Hematologic Toxicities for MM

The following is a Brief Summary; refer to full Prescribing Information for complete product information.

Platelet counts

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study.

Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2).

Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia.

Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study.

Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)].

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM).

1.4 Limitations of Use: REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)].

2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed.

2.1 Multiple Myeloma Multiple Myeloma The recommended starting dose of REVLIMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone.

Refer to Section 14.1 for specific dexamethasone dosing. For patients > 75 years old, the starting dose of dexamethasone may be reduced.

Treatment should be continued until disease progression or unacceptable toxicity.

In patients who are not eligible for autologous stem cell transplantation (ASCT), treatment should continue until disease progression or unacceptable toxicity. For patients who are ASCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a REVLIMID-containing therapy [see Warnings and Precautions (5.11)].

Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID.

When Platelets

Recommended Course

Fall to <30,000/mcL

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at next lower dose.

Do not dose below 2.5 mg daily

Return to ≥30,000/mcL For each subsequent drop <30,000/mcL Return to ≥30,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose.

Do not dose below 2.5 mg daily

Absolute Neutrophil counts (ANC) Neutropenia in MM When Neutrophils

Recommended Course

Fall to <1000/mcL Return to ≥1,000/mcL and neutropenia is the only toxicity

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at 25 mg daily or initial starting dose

Return to ≥1,000/mcL and if other toxicity

Resume REVLIMID at next lower dose.

Do not dose below 2.5 mg daily

For each subsequent drop <1,000/mcL Return to ≥1,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose.

Do not dose below 2.5 mg daily

Other Toxicities in MM For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2.

Starting Dose Adjustment for Renal Impairment in MM: [See Dosage and Administration (2.4)].

2.4 Starting Dose for Renal Impairment in MM Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min.

The recommendations for initial starting doses for patients with MM are as follows: Table 3: Starting Dose Adjustments for Patients with Renal Impairment in MM Category

Renal Function (Cockcroft-Gault)

Dose in MM

Moderate Renal Impairment

CLcr 30-50 mL/min

10 mg Every 24 hours

Severe Renal Impairment

CLcr < 30 mL/min (not requiring dialysis)

15 mg Every 48 hours

End Stage Renal Disease

CLcr < 30 mL/min (requiring dialysis)

5 mg Once daily. On dialysis days, administer the dose following dialysis.

Moderate renal impairment for MM: Consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity.

After initiation of REVLIMID therapy, subsequent REVLIMID dose increase or decrease is based on individual patient treatment tolerance, as described elsewhere [See Dosage and Administration (2.1-2.3)].

4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female.

Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)].

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Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism.

Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.

Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions (5.4)].

Thrombocytopenia in MM

ASCOPost.com | DECEMBER 25, 2015

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Announcements

Lisa A. Newman, MD, MPH

T:7” Jessica Bensenhaver, MD

4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.8)].

5.2 REVLIMID REMS™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program).

Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements.

• Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)].

• Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements.

Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.

5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia.

Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking REVLIMID should have their complete blood counts assessed periodically as described below [see Dosage and Administration (2.1, 2.2, 2.3)].

Patients taking REVLIMID in combination with dexamethasone for MM should have their complete blood counts (CBC) assessed every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every

necology surgeon who specializes in women at high risk for breast cancer due to abnormal genetics, including BRCA1 and BRCA2 mutations, and benign breast cancer patients. She manages gynecologic side effects of breast cancer treatment, including menopausal symptoms and sexual dysfunction; she also continued on page 166

28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see Dosage and Administration (2.1)].

Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter.

Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days).

In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days) [see Boxed Warning and Dosage and Administration (2.2)].

Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients.

5.4 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) [see Boxed Warning and Adverse Reactions (6.1)].

Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction (including acute) was reported as a serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse Reactions (6.1)]. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking).

In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed multiple myeloma who were treated with REVLIMID and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months.

In the NDMM study in which nearly all patients received antithrombotic prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The median time to first thrombosis event was 4.37 months in the combined Rd Continuous and Rd18 Arms. Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events.

ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving REVLIMID [see Drug Interactions (7.2)].

5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013.

Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

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5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy.

REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)].

Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.

Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy.

Two negative pregnancy tests must be obtained prior to initiating therapy.

The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].

Males Lenalidomide is present in the semen of patients receiving the drug.

Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)].

Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID.

related variation in breast cancer, and features an outreach breast health program in Haiti. She received her medical degree from Marshall University Joan C. Edwards School of Medicine, and completed a fellowship in breast oncology at U-M. Dr. Bensenhaver will begin seeing patients at Henry Ford in January 2016.

Dr. Swain is an obstetrics and gy-

The ASCO Post | DECEMBER 25, 2015

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Announcements Henry Ford Health System continued from page 165

provides fertility-preservation counseling for premenopausal breast cancer patients. Dr. Swain received her medical degree from Wayne State University School of Medicine and completed her postgraduate training at Duke University Medical Center (DUMC) and U-M.

Monique Swain, MD

She sees patients at Henry Ford Medical Center–New Center One in Detroit and Henry Ford West Bloomfield Hospital.

Dr. Atisha is a microvascular plastic and reconstructive surgeon with a special interest in restorative breast surgery.

At Henry Ford, Dr. Atisha will offer flap reconstruction and surgical repair for T:7” lymphedema. She received her medical

5.6 Second Primary Malignancies In clinical trials in patients with multiple myeloma receiving REVLIMID an increase of invasive second primary malignancies notably AML and MDS have been observed. The increase of cases of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (frequency of 5.3%) or immediately following high dose intravenous melphalan and ASCT (frequency of up to 5.2%). The frequency of AML and MDS cases in the REVLIMID / dexamethasone arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received lenalidomide in the post-ASCT setting.

Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID. 5.7 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically.

Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

5.8 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions.

5.9 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

5.10 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1.

Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 5.11 Impaired Stem Cell Mobilization A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are ASCT candidates, referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a REVLIMID-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered.

6 ADVERSE REACTIONS The following adverse reactions are described in detail in other sections of the prescribing information: • Embryo-Fetal Toxicity [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Venous and arterial thromboembolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] • Second Primary Malignancies [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Allergic Reactions [see Warnings and Precautions (5.8)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.9)] • Tumor Flare Reactions [see Warnings and Precautions (5.10)] • Impaired Stem Cell Mobilization [see Warnings and Precautions (5.11)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Clinical Trials Experience Specific Populations Newly Diagnosed Multiple Myeloma: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7).

In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18.

In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID were infection events (3.4%).

In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous.

Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms* Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541) General disorders and administration site conditions Fatigue%

173 (32.5) 177 (32.8) 154 (28.5) 39 (7.3)

46 (8.5)

31 (5.7)

Asthenia

150 (28.2) 123 (22.8) 124 (22.9) 41 (7.7)

33 (6.1)

32 (5.9)

Pyrexiac

114 (21.4) 102 (18.9) 76 (14.0) 13 (2.4)

7 (1.3)

7 (1.3)

< 1%

< 1%

18 (3.3)

8 (1.5)

Non-cardiac chest pain f

29 (5.5)

31 (5.7)

18 (3.3)

<1%

Gastrointestinal disorders Diarrhea

242 (45.5) 208 (38.5) 89 (16.5) 21 (3.9)

Abdominal pain%f 109 (20.5) 78 (14.4) 60 (11.1) Dyspepsia f

57 (10.7)

28 (5.2)

7 (1.3)

9 (1.7)

< 1%

<1%

< 1%

0 (0.0)

36 (6.7)

(continued)

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REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.

Dunya Atisha, MD

ASCOPost.com | DECEMBER 25, 2015

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Announcements

degree from Michigan State University, and completed a fellowship in plastic and reconstructive surgery at DUMC. Dr. Attisha will begin seeing patients at Henry Ford in February 2016.

This team brings more than 40 years of combined experience in breast cancer care, allowing Henry Ford to expand its breast care services. They will

join current Henry Ford surgical breast oncologists David Nathanson, MD, and Erica Proctor, MD.

Dr. Newman’s Role and Research Dr. Newman will perform breast cancer surgery at Henry Ford Hospital in Detroit and Henry Ford West T:7” oversee a multidisBloomfield. She will

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms* All Adverse Reactionsa

ciplinary breast cancer conference and clinic each week at Henry Ford Medical Center-New Center One in Detroit and Henry Ford West Bloomfield Hospital.

She’ll also serve as Director of the Breast Cancer Global Health Research Program and Founding Medical Director of the International Center for the Study of Breast Cancer Subtypes at Henry Ford.

Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541)

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541)

Musculoskeletal and connective tissue disorders

Psychiatric disorders

170 ( 32) 145 (26.9) 116 (21.4)

37 (7)

34 (6.3)

28 (5.2)

Muscle spasms f

109 (20.5) 102 (18.9) 61 (11.3)

< 1%

< 1%

< 1%

Arthralgia f

101 (19.0) 71 (13.1) 66 (12.2)

9 (1.7)

8 (1.5)

8 (1.5)

Bone pain f

87 (16.4) 77 (14.3) 62 (11.5) 16 (3.0)

15 (2.8)

14 (2.6)

Pain in extremity f 79 (14.8) 66 (12.2) 61 (11.3)

8 (1.5)

8 (1.5)

7 (1.3)

Musculoskeletal pain f

67 (12.6) 59 (10.9)

36 (6.7)

< 1%

< 1%

< 1%

Musculoskeletal chest pain f

60 (11.3)

51 (9.4)

39 (7.2)

6 (1.1)

< 1%

< 1%

Muscular weakness f

43 (8.1)

35 (6.5)

29 (5.4)

< 1%

8 (1.5)

< 1%

40 (7.5)

19 (3.5)

10 (1.8)

< 1%

< 1%

< 1%

90 (16.9) 59 (10.9)

43 (7.9)

9 (1.7)

6 (1.1)

3 (0.6)

33 (6.1)

0 (0.0)

0 (0.0)

0 (0.0)

Neck pain

f

Infections and infestations Bronchitisc Nasopharyngitis f Urinary tract infection f

80 (15)

54 (10)

76 (14.3) 63 (11.7)

41 (7.6)

8 (1.5)

8 (1.5)

< 1%

Upper respiratory tract infectionc% f

69 (13.0)

Pneumoniac@

93 (17.5) 87 (16.1) 56 (10.4) 60 (11.3) 57 (10.5) 41 (7.6)

53 (9.8)

31 (5.7)

< 1%

8 (1.5)

< 1%

Respiratory tract infection%

35 (6.6)

25 (4.6)

21 ( 3.9)

7 ( 1.3)

4 ( 0.7)

1 ( 0.2)

Influenza f

33 (6.2)

23 (4.3)

15 (2.8)

< 1%

< 1%

0 (0.0)

Gastroenteritis f

32 (6.0)

17 (3.1)

13 (2.4)

0 (0.0)

< 1%

< 1%

29 (5.5)

14 (2.6)

16 (3.0)

10 (1.9)

3 (0.6)

3 (0.6)

Rhinitis f

29 ( 5.5)

24 ( 4.4) 14 ( 2.6)

0 (0.0)

0 (0.0)

0 (0.0)

Cellulitisc

< 5%

< 5%

< 5%

8 (1.5)

3 ( 0.6)

2 ( 0.4)

Sepsisc@

33 (6.2)

26-(4.8)

18 (3.3)

26 (4.9)

20 (3.7)

13 (2.4)

Nervous system disorders Headache f

75 (14.1)

52 (9.6)

56 (10.4)

< 1%

< 1%

< 1%

Dysgeusia f

39 (7.3)

45 (8.3)

22 (4.1)

< 1%

0 (0.0)

< 1%

Blood and lymphatic system disordersd Anemia

233 (43.8) 193 (35.7) 229 (42.3) 97 (18.2) 85 (15.7) 102 (18.9)

Neutropenia

186 (35.0) 178 (33) 328 (60.6) 148 (27.8) 143 (26.5) 243 (44.9)

Thrombocytopenia 104 (19.5) 100 (18.5) 135 (25.0) 44 (8.3)

43 (8.0)

60 (11.1)

Febrile neutropenia

7 (1.3)

17 (3.1)

15 (2.8)

6 (1.1)

16 (3.0)

14 (2.6)

Pancytopenia

5 (0.9)

6 (1.1)

7 (1.3)

1 (0.2)

3 (0.6)

5 (0.9)

Respiratory, thoracic and mediastinal disorders Cough f

121 (22.7) 94 (17.4) 68 (12.6)

Dyspneac,e

117 (22.0) 89 (16.5) 113 (20.9) 30 (5.6)

< 1%

< 1%

< 1%

22 (4.1)

18 (3.3)

Epistaxis f

32 (6.0)

31 (5.7)

17 (3.1)

< 1%

< 1%

0 (0.0)

Oropharyngeal pain f

30 (5.6)

22 (4.1)

14 (2.6)

0 (0.0)

0 (0.0)

0 (0.0)

Dyspnea exertional e

27 (5.1)

29 (5.4)

< 5%

6 (1.1)

2 (0.4)

0 (0.0)

Metabolism and nutrition disorders Decreased appetite

123 (23.1) 115 (21.3) 72 (13.3) 14 (2.6)

7 (1.3)

5 (0.9)

Hypokalemia%

91 ( 17.1) 62 (11.5)

20 (3.7)

11 (2.0)

38 ( 7)

35 (6.6)

Hyperglycemia

62 (11.7)

52 (9.6)

19 (3.5)

28 (5.3)

23 (4.3)

9 (1.7)

Hypocalcemia

57 (10.7) 56 (10.4)

31 (5.7)

23 (4.3)

19 (3.5)

8 (1.5)

Dehydration%

25 ( 4.7)

29 ( 5.4)

17 ( 3.1)

8 (1.5)

13 (2.4)

9 (1.7)

Gout e

< 5%

< 5%

< 5%

8 (1.5)

0 (0.0)

0 (0.0)

Diabetes mellitus% e

< 5%

< 5%

< 5%

8 (1.5)

4 (0.7)

2 (0.4)

Hypophosphatemia e

< 5%

< 5%

< 5%

7 (1.3)

3 (0.6)

1 (0.2)

Hyponatremia% e

< 5%

< 5%

< 5%

7 (1.3)

13 (2.4)

6 (1.1)

139 (26.1) 151 (28.0) 105 (19.4) 39 (7.3)

38 (7.0)

33 (6.1)

Skin and subcutaneous tissue disorders Rash Pruritus f

47 (8.8)

49 (9.1)

24 (4.4)

< 1%

< 1%

< 1% (continued)

Insomnia

147 (27.6) 127 (23.5) 53 (9.8)

4 (0.8)

6 (1.1)

0 (0.0)

Depression

58 (10.9)

46 (8.5)

30 (5.5)

10 (1.9)

4 (0.7)

1 (0.2)

Deep vein thrombosisc%

55 (10.3)

39 (7.2)

22 (4.1)

30 (5.6)

20 (3.7)

15 (2.8)

Hypotensionc%

51 (9.6)

35 (6.5)

36 (6.7)

11 (2.1)

8 (1.5)

6 (1.1)

Vascular disorders

Injury, Poisoning, and Procedural Complications Fall f

43 (8.1)

25 (4.6)

25 (4.6)

< 1%

6 (1.1)

6 (1.1)

Contusion f

33 (6.2)

24 (4.4)

15 (2.8)

< 1%

< 1%

0 (0.0)

73 (13.7)

31 (5.7)

5 (0.9)

31 (5.8)

14 (2.6)

3 (0.6)

< 5%

< 5%

< 5%

7 (1.3)

0 (0.0)

0 (0.0)

48 (8.9)

11 (2.1)

4 (0.7)

4 (0.7)

Eye disorders Cataract Cataract subcapsular e Investigations Weight decreased 72 (13.5) 78 (14.4) Cardiac disorders Atrial fibrillationc Myocardial infarction (including acute)c ,e

37 (7.0)

25 (4.6)

25 (4.6)

13 (2.4)

9 (1.7)

6 (1.1)

< 5%

< 5%

< 5%

10 (1.9)

3 (0.6)

5 (0.9)

54 (10.0)

37 (6.8)

28 (5.3)

33 (6.1)

29 (5.4)

Renal and Urinary disorders Renal failure (including acute)c@,f 49 (9.2)

Neoplasms benign, malignant and unspecified (Incl cysts and polyps) Squamous cell carcinomac e

< 5%

< 5%

< 5%

8 (1.5)

4 (0.7)

0 (0.0)

Basal cell carcinomac e,f

< 5%

< 5%

< 5%

< 1%

< 1%

0 (0.0)

Note: System organ classes (SOC) and preferred terms (PTs) reflect coding of adverse reactions using MedDRA. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable SOC/PT. a All treatment-emergent adverse reactions in at least 5.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 2.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders SOC were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) *PTs for combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalised, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis

After At Least One Prior Therapy for MM Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).

In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or Cosmos Communications

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Lower respiratory tract infection

continued on page 168

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms*

Grade 3/4 Adverse Reactionsb

Back painc

Leading the new international program will allow Dr. Newman to continue and grow her research on ethnicity-related variation in breast cancer, including triple-negative breast cancer, an aggressive form of the disease that disproportionately affects African American women and young patients.

The ASCO Post | DECEMBER 25, 2015

PAGE 168

Announcements Henry Ford Health System continued from page 167

Triple-negative breast cancer has been a focus of Dr. Newman’s ongoing work in Ghana, where the majority of cases are triple-negative. This research seeks to advance knowledge regarding the biologic and genetic origins of this disease. The international breast cancer program will

include research partners at several hospitals in Ghana and Ethiopia, as well as Dr. Bensenhaver’s program in Haiti. She currently serves as Chief National Medical Advisor for the Sisters Network, Inc., a national African American breast cancer survivors organization.

She has held leadership roles with several other prominent academic and

advocacy organizations such as ASCO, the American College of Surgeons, the Society of Surgical Oncology, the American Association of Cancer Research, the American Cancer Society, and the Susan G. Komen Breast Cancer Foundation.

Dr. Newman obtained her Masters of Public Health degree from Harvard University. She attendedT:7”medical school and

completed her general surgery residency training at the State University of New York Health Science Center at Brooklyn and completed her fellowship in surgical oncology at MD Anderson Cancer Center. Prior to joining Henry Ford, Dr. Newman was Professor of Surgery and Director of the Breast Care Center at the U-M Comprehensive Cancer Center. n

without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.

Table 5: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex* Placebo/Dex * (N=353) (N=350) n (%) n (%)

Tables 5, 6, and 7 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.

Metabolism and nutrition disorders Anorexia Hypokalemia Hypocalcemia Appetite Decreased Dehydration Hypomagnesemia Investigations Weight Decreased Eye disorders Blurred vision Vascular disorders Deep vein thrombosis% Hypertension Hypotension

55 (15.6) 48 (13.6) 31 (8.8) 24 (6.8) 23 (6.5) 24 (6.8)

34 (9.7) 21 (6.0) 10 (2.9) 14 (4.0) 15 (4.3) 10 (2.9)

69 (19.5)

52 (14.9)

61 (17.3)

40 (11.4)

33 (9.3) 28 (7.9) 25 (7.1)

15 (4.3) 20 (5.7) 15 (4.3)

Table 6: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups System Organ Class/ Preferred Term REVLIMID/Dex# Placebo/Dex# (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia% 118 (33.4) 12 (3.4) Thrombocytopenia@ 43 (12.2) 22 (6.3) Anemia@ 35 (9.9) 20 (5.7) Leukopenia 14 (4.0) 1 (0.3) Lymphopenia 10 (2.8) 4 (1.1) Febrile Neutropenia% 8 (2.3) 0 (0.0) General disorders and administration site conditions Fatigue 23 (6.5) 17 (4.9) Vascular disorders Deep vein thrombosis% 29 (8.2) 12 (3.4) Infections and infestations Pneumonia@ 30 (8.5) 19 (5.4) Urinary Tract Infection 5 (1.4) 1 (0.3) Metabolism and nutrition disorders Hypokalemia 17 (4.8) 5 (1.4) Hypocalcemia 13 (3.7) 6 (1.7) Hypophosphatemia 9 (2.5) 0 (0.0) Respiratory, thoracic and mediastinal disorders Pulmonary embolism@ 14 (4.0) 3 (0.9) Respiratory Distress@ 4 (1.1) 0 (0.0) Musculoskeletal and connective tissue disorders Muscle weakness 20 (5.7) 10 (2.9) Gastrointestinal disorders Diarrhea@ 11 (3.1) 4 (1.1) Constipation 7 (2.0) 1 (0.3) Nausea@ 6 (1.7) 2 (0.6) Cardiac disorders Atrial fibrillation@ 13 (3.7) 4 (1.1) Tachycardia 6 (1.7) 1 (0.3) Cardiac Failure Congestive@ 5 (1.4) 1 (0.3) Nervous System disorders Syncope 10 (2.8) 3 (0.9) Dizziness 7 (2.0) 3 (0.9) (continued)

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Table 5: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex* Placebo/Dex * (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia % 149 (42.2) 22 (6.3) Anemia@ 111 (31.4) 83 (23.7) Thrombocytopenia@ 76 (21.5) 37 (10.6) Leukopenia 28 (7.9) 4 (1.1) Lymphopenia 19 (5.4) 5 (1.4) General disorders and administration site conditions Fatigue 155 (43.9) 146 (41.7) Pyrexia 97 (27.5) 82 (23.4) Peripheral edema 93 (26.3) 74 (21.1) Chest Pain 29 ( 8.2) 20 (5.7) Lethargy 24 ( 6.8) 8 (2.3) Gastrointestinal disorders Constipation 143 (40.5) 74 (21.1) Diarrhea@ 136 (38.5) 96 (27.4) Nausea@ 92 (26.1) 75 (21.4) Vomiting@ 43 (12.2) 33 (9.4) Abdominal Pain@ 35 (9.9) 22 (6.3) Dry Mouth 25 (7.1) 13 (3.7) Musculoskeletal and connective tissue disorders Muscle cramp 118 (33.4) 74 (21.1) Back pain 91 (25.8) 65 (18.6) Bone Pain 48 (13.6) 39 (11.1) Pain in Limb 42 (11.9) 32 (9.1) Nervous system disorders Dizziness 82 (23.2) 59 (16.9) Tremor 75 (21.2) 26 (7.4) Dysgeusia 54 (15.3) 34 (9.7) Hypoaesthesia 36 (10.2) 25 (7.1) Neuropathyª 23 (6.5) 13 (3.7) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 83 (23.5) 60 (17.1) Nasopharyngitis 62 (17.6) 31 (8.9) Pharyngitis 48 (13.6) 33 (9.4) Bronchitis 40 (11.3) 30 (8.6) Infectionsb and infestations Upper respiratory tract infection 87 (24.6) 55 (15.7) Pneumonia@ 48 (13.6) 29 (8.3) Urinary Tract Infection 30 (8.5) 19 (5.4) Sinusitis 26 (7.4) 16 (4.6) Skin and subcutaneous system disorders Rashc 75 (21.2) 33 (9.4) Sweating Increased 35 (9.9) 25 (7.1) Dry Skin 33 (9.3) 14 (4.0) Pruritus 27 (7.6) 18 (5.1) (continued)

ASCOPost.com | DECEMBER 25, 2015

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Announcements

AACR Recognizes Anne-Lise Børresen-Dale, DSc, With 2015 Distinguished Lectureship in Breast Cancer Research

A

nne-Lise Børresen-Dale, DSc, Professor at the University of Oslo and Head of the Department of Genetics at the University Hospital Radiumhospitalet in Oslo, Norway, was honored with the 8th

Annual American Association for Cancer Research (AACR) Distinguished Lectureship in Breast Cancer Research at the 2015 San Antonio Breast Cancer Symposium.

T:7” The AACR Distinguished Lectureship

Table 6: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups System Organ Class/ Preferred Term REVLIMID/Dex# Placebo/Dex# (N=353) (N=350) n (%) n (%) Eye Disorders Cataract 6 (1.7) 1 (0.3) Cataract Unilateral 5 (1.4) 0 (0.0) Psychiatric Disorder Depression 10 (2.8) 6 (1.7)

Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)] Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively.

Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms.

Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious

Pioneer in Genetics Dr. Børresen-Dale is among the leading geneticists in research on molecular biology of breast cancer, and her continued on page 170

adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively).

Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/ dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively.

Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively.

Other Adverse Reactions: After At Least One Prior Therapy for MM In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported: Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia Cardiac disorders: bradycardia, myocardial infarction, angina pectoris Endocrine disorders: hirsutism Eye disorders: blindness, ocular hypertension Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia General disorders and administration site conditions: malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Nervous system disorders: cerebral ischemia Psychiatric disorders: mood swings, hallucination, loss of libido Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: cough, hoarseness Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation 6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/ cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.7 to 5.10)].

Cases of hypothyroidism and hyperthyroidism have also been reported.

Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.

7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions.

7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID [see Warnings and Precautions (5.4)].

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Table 7: Serious Adverse Reactions Reported in ≥1% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex& Placebo/Dex& (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Febrile Neutropenia% 6 (1.7) 0 (0.0) Vascular disorders Deep vein thrombosis% 26 (7.4) 11 (3.1) Infections and infestations Pneumonia@ 33 (9.3) 21 (6.0) Respiratory, thoracic, and mediastinal disorders Pulmonary embolism@ 13 (3.7) 3 (0.9) Cardiac disorders Atrial fibrillation@ 11 (3.1) 2 (0.6) Cardiac Failure Congestive@ 5 (1.4) 0 (0.0) Nervous system disorders Cerebrovascular accident@ 7 (2.0) 3 (0.9) Gastrointestinal disorders Diarrhea @ 6 (1.7) 2 (0.6) Musculoskeletal and connective tissue disorders Bone Pain 4 (1.1) 0 (0.0) For Tables 5, 6 and 7 above: @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.

in Breast Cancer Research was established to recognize outstanding science that has inspired or has the potential to inspire new perspectives on the etiology, diagnosis, treatment, or prevention of breast cancer.

The ASCO Post | DECEMBER 25, 2015

PAGE 170

Announcements AACR Award continued from page 169

group was among the pioneers in expression profiling of breast carcinomas in collaboration with groups at Stanford University, demonstrating that breast cancer can be divided into distinct subgroups with differences in molecular profiles and in overall and relapse-free

Anne-Lise Børresen-Dale, DSc

survival. Her achievements are seminal for understanding breast cancer evolution and have had an enormous impact on our view of the complexity of breast cancer.

Dr. Børresen-Dale’s current research projects focus on exploring the systems biology of breast cancer using high-diT:7” mensional data in integrated approach-

7.3 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1).]

NDMM: Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521 /1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all treatment arms, the frequency in most of the AE categories (eg, all AEs, grade 3/4 AEs, serious AEs) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. Grade 3 or 4 AEs in the General Disorders and Administration Site Conditions SOC were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment arms. Grade 3 or 4 TEAEs in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) SOCs were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. For other SOCs (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was a less consistent trend for increased frequency of grade 3/4 AEs in older vs younger subjects across all treatment arms Serious AEs were generally reported at a higher frequency in the older subjects than in the younger subjects across all treatment arms.

REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age.

Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%).

The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.

8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy.

Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.

Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation.

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Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue.

Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.

Lenalidomide caused thalidomide-type limb defects in monkey offspring.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.

Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis.

Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg.

Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats.

In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide.

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established.

8.5 Geriatric Use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 91 years of age.

After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients.

es. These studies aim to identify the genotypes and gene-expression profiles that contribute to elevated cancer risk, radiation sensitivity, tumor aggressiveness, and therapy resistance. The goal of this work is to follow the linear time course of tumor progression to dissect the molecular mechanisms triggered at each stage of disease. n

ASCOPost.com | DECEMBER 25, 2015

PAGE 171

Announcements

Mohamed Bentires-Alj, PharmD, PhD, Honored With 2015 AACR Outstanding Investigator Award for Breast Cancer Research

M

ohamed Bentires-Alj, PharmD, PhD, was recognized with the 8th Annual American Association for Cancer Research (AACR) Outstanding Investigator Award for Breast Cancer Re-

search, funded by Susan G. Komen. He receives the award at the 2015 San Antonio Breast Cancer Symposium.

The AACR Outstanding Investigator T:7” Award for Breast Cancer Research recog-

Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)].

8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment.

The elimination of unchanged lenalidomide is predominantly by the renal route.

10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients with MM, MDS, or MCL. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with lenalidomide have not been conducted.

Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindications (4.1)]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

• Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy.

• Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test.

• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy.

Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.

• Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.

• Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy.

• Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

• All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)].

• Patients must sign a Patient-Physician agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)].

• REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product.

Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)].

Venous and Arterial Thromboembolism Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Boxed Warnings and Warning and Precautions (5.4)].

Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)].

Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID [see Warnings and Precautions (5.6)].

Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.7)].

Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens-Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.8)].

Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.9)].

Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.10)].

Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water.

Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.

Manufactured for:

Celgene Corporation Summit, NJ 07901

REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation.

REVLIMID REMS™ is a trademark of Celgene Corporation.

Pat. www.celgene.com/therapies ©2005-2015 Celgene Corporation, All Rights Reserved.

REV_MM_HCP_BS_v020 02_2015

Cosmos Communications

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Mohamed Bentires-Alj, PharmD, PhD

cancer. Such work may involve any discipline across the continuum of biomedical research, including basic, translational, clinical, and epidemiologic studies.

Seminal Discoveries Dr. Bentires-Alj, Senior Staff Scientist at the Friedrich Miescher Institute for Biomedical Research (FMI) in Basel, Switzerland, was honored for his seminal work on normal and neoplastic breast cell plasticity, which found that mutant PI3K induces multipotency and multilineage mammary tumors and that SHP2 promotes breast cancer progression and maintains tumor- initiating cells.

Dr. Bentires-Alj’s research has revealed that cotargeting PI3K/mTOR and JAK2 in triple-negative breast cancer models decreases tumor volume, seeding, and metastasis and increases overall survival. He also discovered that discontinuation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis.

Dr. Bentires-Alj is dedicated to discovering new and more effective cancer treatments and to training the next generation of scientists, in addition to his efforts in building bridges between basic research and the clinic. He is also exploring complementary and interdisciplinary approaches to understanding the mechanisms of cancer. The BentiresAlj lab aims to understand the cellular and molecular mechanisms regulating normal and neoplastic breast stem cells, progression to metastasis, and resistance to targeted therapy.

Dr. Bentires-Alj received his doctorate in pharmaceutical sciences from the University of Liège in Liège, Belgium.

He completed his postdoctoral work at Beth Israel Deaconess Medical Center at Harvard Medical School, where he studied the effects of Gab2 and PTP1B in breast cancer.

In addition, Dr. Bentires-Alj is the Founder and President of the European Network for Breast Development and Cancer and Cofounder of the Basel Breast Consortium. n T:10”

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

nizes an investigator of no more than 50 years of age whose novel and significant work has had or may have a far-reaching impact on the etiology, detection, diagnosis, treatment, or prevention of breast

The ASCO Post | DECEMBER 25, 2015

PAGE 172

Perspective Ronald A. DePinho, MD continued from page 1

by more than half among girls aged 14 to 19 in the United States.1 This may sound encouraging, but we could be doing so much better. Research shows that less than 40% of girls and just over 20% of boys in the United States receive all three doses of this safe and effective vaccine.2 Vaccine uptake is low due to a variety of reasons, but the two most frequently cited by parents are that they didn’t receive a physician recommendation for it and that they lacked knowledge or needed more information about the vaccine.

Missing the Mark The reality is that this cancer vaccine has the potential to prevent the vast majority of HPV-related cancers, including cervical, throat, anal, vaginal, vulvar, and penile cancers. Yet, we’re clearly missing the mark.

Every year in this country, 27,000 people get cancer caused by HPV—that’s one person every 20 minutes of every day.3 The annual disease burden in the United States is significant. In Texas alone, annual HPV-related disease costs for men and women approach $170 million.4 Each year for American women, there are 1.4 million new cases of lowgrade cervical dysplasia,5 1 million new cases of genital warts,6 330,000 new cases of high-grade cervical dysplasia,5 over 12,000 new cases of cervical cancer, and, worst of all, 4,000 cervical cancer deaths each year.7 That’s 3 million HPV-related cases at a cost to our health-care system of $8 billion8 and the cause of significant pain and suffering for patients, most of which could be avoided if the HPV vaccine had been available and properly used in these patients.

Reaching the Goal The National Institutes of Health initiative Healthy People 2020 (healthypeople.gov) has set a goal of achieving an 80% HPV vaccination adherence rate in both boys and girls. So the question is, what can be done to reach that goal?

I believe one key answer is education. Through education, improved early screening, and the development of new and better therapies, we have an opportunity to make these cancers as rare as polio, smallpox, and diphtheria.

As one of the newly announced targets in our Moon Shots Program, dozens of researchers, clinicians, prevention and public health experts, and governmental relations leaders at The University of Texas MD Anderson Cancer Center are working to identify prac-

tical solutions and strategies to enhance awareness, improve vaccination rates, and ultimately reduce the incidence and mortality of HPV-related cancers.

It’s not a simple task, but it’s one that we’re committed to accomplishing through three major flagship projects currently underway, the first of which, public policy and education, is the focus of this column.

The second flagship project focuses on target discovery through our Cancer Genomics Lab and target validation and drug discovery through our Institute for Applied Cancer Science.

The third flagship project aims to build upon our success in immunotherapy treatments and novel clinical trials using peptide vaccines coupled with immune checkpoint inhibitors. In the early phases of this moon shot, we are targeting rare tumors, gynecologic cancers, and head and neck cancers. This

caregivers, and adolescents.

Health-care providers are most successful when they are well versed in the safety and efficacy data and better informed on how to discuss a sometimesdifficult subject with unsure parents and nervous kids. But it must be done, and we must rely on pediatricians and primary care providers to make this a priority.

Just recently, we brought together experts from the National Cancer Institute (NCI), the American Cancer Society, the Centers for Disease Control and Prevention (CDC), and more than 35 of the nation’s NCI-designated cancer centers for a summit titled, “Increasing HPV Vaccination in the U.S.: A Collaboration of NCI-Designated Cancer Centers.” A highlight of the summit was the presentation of findings from recently completed, federally funded environmental scans, which revealed barriers to increasing vaccination rates in pediatric settings

It is our collective responsibility to protect the future health of all children.

The seeds of cancer are often planted during childhood, so we must treat cancer prevention as a serious childcare issue.

—Ronald A. DePinho, MD

project is enabled by MD Anderson’s Center for Co-Clinical Trials, Institute for Applied Cancer Science, and Immunotherapy platform.

But let’s look more closely at our first flagship project, which targets policy, education, and screening through health policy, governmental relations, and professional and public education.

We are committed to increasing HPV vaccination using policy and education to (1) reduce missed clinical opportunities to recommend and administer HPV vaccines and (2) to increase acceptance of HPV vaccines by parents, caregivers, and adolescents.

Engaging Health-Care Providers How do we make that happen? Our multidisciplinary team of experts is an educational army working to share our knowledge with our peers in health care.

We cover all medical disciplines, including pediatricians, primary care providers, nurse practitioners, midlevel providers, nurses, fellows, and beyond and provide helpful tools, like curriculum reviews, continuing medical education videos, and communication training to help inform provider discussion with parents,

as well as successful strategies that might be adapted across the country. Collaboration was another major focus, with centers currently developing a consensus statement of shared endorsement for the HPV vaccine.

From a governmental perspective, Congress made HPV vaccine education a priority through the Prevention and Public Health Fund, created in 2010 as part of the Affordable Care Act. Aimed at providing stable and increased investment in public health activities to prevent disease and promote health and wellness in communities nationwide, this program is proving successful.

From 2011 to 2014, $17.4 million in federal funding was awarded to 18 states and 4 cities to increase HPV vaccination coverage among adolescents through joint initiatives with immunization stakeholders, communication campaigns, and strategies targeted to improve immunization providers’ knowledge, skills, and adherence to current HPV vaccination recommendations. According to data from the CDC’s 2014 National Immunization Survey-Teen, 4 of the 11 public health jurisdictions that received funding in 2013 from the Prevention and Public Health Fund to increase HPV vaccine coverage

demonstrated significant increases in either ≥ 1- or ≥ 3-dose coverage among girls and women.2 These data suggest that the funding is beginning to have an impact, and it is hoped that over time, more jurisdictions will follow suit.

Initiating efforts at the state level, experts in our Cancer Control platform, HPV Moon Shot program, and governmental relations worked with the Texas legislature to raise awareness about the impact of HPV-associated cancers on the state. In collaboration with other stakeholders, we served as the primary resource on legislation requiring the state to develop a statewide strategic plan to address HPV-associated cancers by improving vaccination rates, enhancing and expanding access to screening and treatment, and other evidencebased programs aimed at significantly reducing cancer mortality in Texas.

In the area of screening, we’ve been able to tap into our global, collaborative network to make a broad impact. With our 31 sister institutions in 22 countries, the opportunities are limitless and the desire for information, support, and training is significant.

In the United States, Project ECHO: Extension for Community Healthcare Outcomes (New Mexico), a collaborative model of medical education and care management,9 is allowing experts to provide best-practice care for common and complex diseases in rural and underserved areas through telementoring. This approach involves biweekly, 1-hour teleconferences including case presentations and discussions with specialists. These sessions are supplemented with handson training and instruction to assist local providers in managing their patients with greater confidence.

Using the ECHO model, we partnered with several institutions to educate and support primary care providers and midlevel providers in Texas’ lower Rio Grande Valley, where cervical cancer rates are 31% higher than in other areas of Texas. Coupled with public education regarding cervical cancer screening and HPV vaccination, Project ECHO is already making an impact in the lives of many underserved and often uninsured women in this region.

Protecting the Health of Children A variety of controversies often surround vaccines. However, research has proved that the HPV vaccine is safe and effective. It has also been shown in several large studies that receiving the vaccine does not lead to increased sexual promiscuity. I’ll say it again: This

ASCOPost.com | DECEMBER 25, 2015

PAGE 173

Perspective

is a cancer vaccine that protects against a contagious virus that infects 80% of the world’s adult population, causes more than 400,000 deaths each year, and disfigures millions more. This cancer vaccine is safe and effective, and it has the potential to put an end to many of the hardest-to-diagnose and most difficultto-treat cancers.

I am the parent of three young children, and they have all received the HPV vaccine. There are many things that worry me as a parent, but HPVrelated cancers can now be crossed off my list. Knowledge has prevailed to protect them. It is our collective responsibility to protect the future health of all children. The seeds of cancer are often planted during childhood, so we must treat cancer prevention as a serious child-care issue. n

related disease in Texas. 82nd Annual Texas Public Health Association Conference. Presented February 2007.

5. Schiffman M, Solomon D: Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med 127:946949, 2003.

6. Fleischer AB, Parrish CA, Glenn R, et al: Condylomata acuminata (genital warts):

Patient demographics and treating physicians. Sex Transm Dis 28:643-647, 2001.

7. American Cancer Society: Cancer Facts & Figures 2014. Atlanta, American Cancer Society, 2014.

8. Chesson HW, Ekwueme DU, Saraiya M, et al: Estimates of the annual direct medical costs of the prevention and treatment of disease associated with human papillomavi-

rus in the United States. Vaccine 30:60166019, 2012.

9. Agency for Healthcare Research and Quality: Project ECHO: Extension for Community Healthcare Outcomes (New Mexico). Available at https://healthit. ahrq.gov/ahrq-funded-projects/projectecho-extension-community-healthcareoutcomes. Accessed December 8, 2015.

Disclosure: Dr. DePinho reported no potential conflicts of interest.

References 1. Markowitz LE, Hariri S, Lin C, et al: Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. J Infect Dis 208:385-393, 2013.

2. Centers for Disease Control and Prevention: Teen vaccination coverage: 2014 National Immunization Survey-Teen (NISTeen). Available at cdc.gov/vaccines/who/ teens/vaccination-coverage.html. Accessed December 8, 2015.

3. Centers for Disease Control and Prevention: How many cancers are linked with HPV each year? Available at cdc.gov/ cancer/hpv/statistics/cases.htm. Accessed December 8, 2015.

4. Fonseca V: Cervical cancer and HPV-

The ASCO Post

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In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 cases of progression with firstgeneration EGFR TKIs are related to the T790M mutation1,2

NEARLY 2 OUT OF 3

CASES ARE RELATED TO T790M

T790M is an acquired mutation and has been identified as the most common mechanism of acquired resistance in nearly 2 out of 3 patients with advanced NSCLC.1,2 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).3 Find out how the T790M mutation could affect the future of NSCLC at: EGFRevolution.com.

@ASCOPost

AstraZeneca is conducting ongoing research to understand the science of the T790M mutation

as a driver of resistance.

References: 1. Yu HA, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19: 2240-2247. 2. Arcila ME, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay.

Clin Cancer Res. 2011;17:1169-1180. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. ©2015 AstraZeneca. All rights reserved. 3140405 6/15

The ASCO Post | DECEMBER 25, 2015

PAGE 174

Book Review

Mixing Metaphors to Change the Language of Cancer

By Ronald Piana

Bookmark Title: Malignant Metaphor: Confronting Cancer Myths Author: Alanna Mitchell Publisher: ECW Press Publication date: September 15, 2015 Price: $24.95; hardcover, 184 pages

“I

llness is the night-side of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the kingdom of the well and in the kingdom of the sick.” So begins the small classic Illness as Metaphor, by Susan Sontag. Considered one of the most liberating books of its time, Ms. Sontag, a cancer patient when she was writing the book, shows how the metaphors and myths surrounding certain illnesses, especially cancer, add greatly to the suffering of patients and often inhibit them from seeking proper treatment.

Ms. Sontag’s book was published in 1977, and even though it remains in print and is revered by her large fan base, things have changed for the better in the world of cancer metaphors that she eloquently described. Ms. Sontag died of leukemia at Memorial Sloan Kettering Cancer Center in 2004.

Inevitable Comparisons In a new book, science writer Alanna Mitchell takes a risk with the title: Malignant Metaphor. Once Ms. Mitchell stepped into the cancer metaphor territory that was staked out by Susan Sontag,

she left her book open to inevitable comparisons, at least on its intellectual merit, to the iconic Illness as Metaphor. And she adds fuel to this fire by referencing Illness as Metaphor numerous times.

The title issue aside, Ms. Mitchell, who is touted on the cover as a bestselling, award-winning science writer, informs the reader that she started writing her book because “cancer barged into my life.… First, my beloved brother-in-law, John, got it. Then, my 21-year-old daughter, Calista, was diagnosed and the quest to understand cancer became even more personal.”

The motif of Malignant Metaphor revolves around the author’s brother-in-law, who is diagnosed with malignant melanoma. She throws herself into his world of cancer treatment, which ultimately enters the alternative treatment realm. Along the way, through clinical trials and multiple doctors and cancer quacks, Ms. Mitchell “confronts and debunks cancer myths.”

The subtext is the author’s explorations of the untested waters of cancer treatment, during which she encounters the primal fears people have about cancer. She labors to open a door to new ways of looking at this most feared disease.

Historical Allegories Although this cancer story has been told before with different characters and events, there is always room for a wellwritten human-interest story dealing with the roller-coaster drama of battling a potentially lethal disease. Ms. Mitchell has a friendly writing style and enough compelling characters and plot points that could have raised her story a cut above most in this genre, had she not been so enamored of the metaphor conceit, her unfortunate references to Susan Sontag, and digressions into historical allegories.

For example, Ms. Mitchell writes, “This cultural gloss on cancer, this malignant metaphor, sows immense, widespread blame, shame and fear onto those who are already ill, often fighting for their lives. It spreads to their loved ones and, by osmosis, to a whole society stricken at the thought of getting the disease. Sontag notes that cancer ‘arouses thoroughly old-fashioned kinds of dread,’ and that it felt to be ‘morally, if not literally, contagious.’”

Ms. Sontag made that observation more than 3 decades ago, and by retooling it to somehow make her narrative more elegant, the author seems woefully out of touch with the modern reality of

cancer awareness and how far our society has progressed.

Ms. Mitchell continues: “Let me delve more deeply into the trope of culpability or deservedness, which is tightly linked to the idea that cancer is preventable: cancer has come to be interpreted as a billboard for the sufferer’s secret sins. You did something awful and now you’ve been found out, like the transgressors of the Middle Ages who feared an eternity in hell for a single misstep or mis-thought against the teachings of an inflexible church….”

An acclaimed science writer should know that more than half of all human cancers are preventable. Middle Ages?

essentially told John to go home and wind up his affairs…. They had nothing to offer him. John describes the whole tenor of his appointments with the Canadian doctors as ‘funereal.’”

To her credit, Ms. Mitchell drove John from Canada to Memorial Sloan Kettering Cancer Center in New York, where “the attitude could not have been more different…. The tone was upbeat, relaxed, and totally in control of John’s situation.” John was fortunate enough to have renowned surgeon Daniel G. Coit, MD, take over his care. But the prognosis of stage IIIB was daunting, and John ping-ponged between Memorial and

Ms. Mitchell—when she doesn’t succumb to the sirens of metaphor—has written a well-balanced narrative about a cancer patient’s interesting and provocative journey from diagnosis to monitored survivorship.

Although this book will please many science-loving laypersons, it is not recommended for readers of The ASCO Post, who might bristle at the mixing of metaphors with the serious business of caring for cancer patients.

Ms. Mitchell’s time-traveling analogies back to the days of Torquemada are an insult to cancer patients and the oncologists they partner with to fight their disease.

And we are not yet out of the prologue!

Again, there is some interesting content in Malignant Metaphor, but the author buries it with her purple prose.

Gathering Speed and Interest After some interesting backstory about cancer research and various advances in detection and treatment, Ms. Mitchell arrives at her brother-in-law’s cancer diagnosis, what the reader has been waiting for. She writes, “John hadn’t worried about a mole on his flank.… It bore short, rounded tentacles, like a stunted Hydra, the mythic Greek beast that grew two heads for every one hacked off.… He had it removed the day he turned 66.”

While in Nairobi doing AIDS missionary work, John gets the dreaded call via cell phone that the biopsy was positive; he had very aggressive malignant melanoma. From that point, the book gathers speed and interest. The author becomes a knowledgeable support system for John and his wife, as he moves from his first doctor to a second opinion.

Ms. Mitchell sums up the Canadian experience: “The doctors in Canada had

Canada, where he got involved in alternative therapies such as a macrobiotic diet, juicing, coffee enemas and massive doses of intravenous vitamin C.

Much-Needed Substance John’s quest for a cure, evidencebased or not, is the most interesting part of the book. It drills deep into the vulnerability of cancer patients as they battle their disease, and this is the terrain that Ms. Mitchell is adroit at describing. Ultimately, John severs his ties and treatments with several alternative practitioners, none of whom are doctors, and entrusts his care to “faith based on the best science available to him.” His journey to that point was, indeed, quite interesting, giving the book much-needed substance.

Ms. Mitchell—when she doesn’t succumb to the sirens of metaphor— has written a well-balanced narrative about a cancer patient’s interesting and provocative journey from diagnosis to monitored survivorship. However, although this book will please many science-loving laypersons, it is not recommended for readers of The ASCO Post, who might bristle at the mixing of metaphors with the serious business of caring for cancer patients. n

ASCOPost.com | DECEMBER 25, 2015

PAGE 175

FDA Update

FDA Oncology New Drug/New Indication Approvals for 2015 as of December 20, 2015

T

he following new hematology/ oncology agents and expanded indications were approved by the U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research in 2015: • Alectinib (Alecensa), an ALK inhibitor, for the treatment of patients with anaplastic lymphoma kinase (ALK)positive metastatic non–small cell lung cancer (NSCLC) who have had disease progression on or are intolerant to crizotinib (Xalkori). Approved December 11, 2015.

at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory

agent. Approved November 16, 2015.

• Osimertinib (Tagrisso), a tyrosine kinase inhibitor, for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M muta-

tion–positive NSCLC, as detected by an FDA-approved test, who have had disease progression on or after EGFR tyrosine kinase inhibitor therapy. Apcontinued on page 176

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• Uridine triacetate (Vistogard), for the emergency treatment of adult and pediatric patients following a fluorouracil (5-FU) or capecitabine overdose regardless of the presence of symptoms or who exhibit earlyonset, severe, or life-threatening toxicity affecting the cardiac or central nervous system and/or early-onset, unusually severe adverse reactions within 96 hours following the end of 5-FU or capecitabine administration.

Approved December 11, 2015.

• Elotuzumab (Empliciti), a monoclonal antibody, in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies. Approved November 30, 2015.

• Necitumumab (Portrazza), a monoclonal antibody, in combination with gemcitabine and cisplatin for first-line treatment of patients with metastatic squamous NSCLC. Approved November 24, 2015.

• Nivolumab (Opdivo), a monoclonal antibody, for the treatment of advanced renal cell carcinoma in patients who have received prior antiangiogenic therapy. Approved November 23, 2015.

• Ixazomib (Ninlaro), a proteasome inhibitor, in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approved November 20, 2015.

• Daratumumab (Darzalex), a monoclonal antibody, administered as a single agent for the treatment of patients with multiple myeloma who have received

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Agenda Topics:* Breast Cancer

Early Stage, Hormone Sensitive, and Screening and Risk Assessment

Genitourinary (GU) Cancers

Androgen Deprivation Therapy and Multigene Testing in Prostate Cancer

Gastrointestinal (GI) Cancers

Gastroesophageal, Localized Rectal, Metastatic Colorectal Cancer, and Pancreatic

Hematologic Malignancies

B-Cell Lymphomas, Chronic Myelogenous Leukemia, and Multiple Myeloma

Lung Cancer

EGFR-Mutation Positive Metastatic NSCLC

Survivorship

Sexual Function in Cancer Survivors and Cancer Pain Management

Women’s Health

Cervical and Vulvar Cancers and Hereditary Breast and Ovarian Cancers

Additional Content

Advanced Melanoma, CNS, Hepatocellular Carcinoma, Role of Biosimilars, VTE

This conference is approved for AMA PRA Category 1 Credit™ for physicians and is also certified for nurses, pharmacists, and other oncology professionals. NCCN will also seek approval for case manager and tumor registrar clock hours.

NCCN.org/AC2016 Plan to visit the NCCN Exhibition Hall

Sponsorship and exhibit opportunities are available! For more information, e-mail exhibits@nccn.org. * Subject to change.

JNCCN-N-0214-1215

The ASCO Post | DECEMBER 25, 2015

PAGE 176

FDA Update FDA Approvals for 2015 continued from page 175

proved November 13, 2015.

• Cobimetinib (Cotellic), a MEK inhibitor, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, in combination with vemurafenib (Zelboraf). Approved November 10, 2015.

• Ipilimumab (Yervoy), a monoclonal antibody, for the additional indication of adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. Approved October 28, 2015.

• Trabectedin (Yondelis), a novel anticancer agent, for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have received a prior anthracycline-containing regimen.

Approved October 23, 2015.

• Irinotecan liposome (Onivyde), a liposomal formulation of the topo­ isomerase I inhibitor irinotecan, administered in combination with 5-FU and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas whose disease has progressed following gemcitabine-based therapy. Approved October 22, 2015.

• Idarucizumab (Praxbind), a mono-

clonal antibody, for the treatment of patients treated with dabigatran (Pradaxa) when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding. Approved October 16, 2015.

• Nivolumab (Opdivo), a monoclonal antibody, for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Approved October 9, 2015.

• Pembrolizumab (Keytruda), a monoclonal antibody, for the treatment of patients with metastatic NSCLC whose tumors express programmed death ligand 1 (PD-L1) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Approved October 2, 2015.

• Nivolumab (Opdivo), a monoclonal antibody, in combination with ipilimumab for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma. Approved September 30, 2015.

• Trifluridine/tipiracil (Lonsurf), a nucleoside analog and thymidine phosphorylase inhibitor, respectively, for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an

A Happy, Healthy New Year to All

anti-VEGF biologic product, and an anti-EGFR monoclonal antibody, if their disease is RAS wild-type. Approved September 22, 2015.

• Eltrombopag (Promacta), a c-mpl (TpoR) receptor agonist, for the treatment of thrombocytopenia in pediatric patients aged 1 year and older with chronic idiopathic thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Approved August 24, 2015.

• Brentuximab vedotin (Adcetris), an antibody-drug conjugate for the post–autologous hematopoietic stem cell transplantation consolidation treatment of patients with classical Hodgkin lymphoma at high risk of relapse or disease progression. Approved August 17, 2015.

• Carfilzomib (Kyprolis), a selective proteasome inhibitor, in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy. Approved July 24, 2015.

• Sonidegib (Odomzo), an oral Hedgehog signaling pathway inhibitor, for the treatment of patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy or those who are not candidates for surgery or radiation therapy. Approved July 24, 2015.

• Gefitinib (Iressa) for the treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. This approval of gefitinib was approved concurrently with a labeling expansion of the therascreen EGFR RGQ PCR Kit, a companion diagnostic test for patient selection. Approved July 13, 2015.

• Ramucirumab (Cyramza), a monoclonal antibody, for use in combination with FOLFIRI (leucovorin, 5-FU, irinotecan) for the treatment of patients with metastatic colorectal cancer (whose disease has progressed on a first-line bevacizumab (Avastin)-, oxaliplatin-, and fluoropyrimidine-containing regimen. Approved April 24, 2015.

• Dinutuximab (Unituxin), a monoclonal antibody, in combination with

granulocyte-macrophage colony-stimulating factor (Leukine), interleukin-2 (IL-2, Proleukin), and 13-cis-retinoic acid, for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Approved March 10, 2015.

• Filgrastim-sndz (Zarxio), a human granulocyte colony-stimulating factor, as a biosimilar to U.S.-licensed filgrastim (Neupogen) for the five indications for which U.S.-licensed filgrastim is approved. The formulation of Zarxio differs from that of U.S.-licensed filgrastim in one inactive component.

Approved March 6, 2015.

• Nivolumab (Opdivo), a monoclonal antibody, for the treatment of patients with metastatic squamous NSCLC with disease progression on or after platinum-based chemotherapy. Approved March 4, 2015.

• Panobinostat (Farydak), an oral nonselective histone deacetylase (pan HDAC) inhibitor in combination with bortezomib (Velcade) and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. As a condition of this accelerated approval, the FDA requires the sponsor to conduct a trial to verify and describe the clinical benefit of panobinostat for patients with multiple myeloma. Approved February 23, 2015.

• Lenvatinib (Lenvima), a multikinase inhibitor, for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine–refractory differentiated thyroid cancer. Approved February 13, 2015.

• Palbociclib (Ibrance), a kinase inhibitor, for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for metastatic disease. Approved February 3, 2015.

• Ibrutinib (Imbruvica), a selective and covalent oral Bruton’s tyrosine kinase inhibitor, for the treatment of patients with Waldenström’s macroglobulinemia. Approved January 29, 2015. n

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