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Genetics and Breast Cancer Onset

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| Anaplastic Oligodendroglial Tumors

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| Childhood Cancer Survivors

VOLUME 4, ISSUE 12

104

JULY 25, 2013

Editor-in-Chief, James O. Armitage, MD

ASCO Annual Meeting

Some Successes, Some Failures Reported in Research and Treatment of Pancreatic Cancer By Caroline Helwick

ASCOPost.com

Why Is Stem Cell Transplant So Underused in Follicular Lymphoma? By Timothy S. Fenske, MD

T

he challenge of treating pancreatic cancer inched forward with studies reported at the 2013 ASCO Annual Meeting, though some important studies proved disappointing.

Nab-paclitaxel Improves Overall Survival In treatment-naive metastatic patients, the addition of nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) to gemcitabine improved overall survival vs gemcitabine alone, in MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial), a 151-site international phase III study in which 861 patients were randomly assigned to nabpaclitaxel at 125 mg/m2 followed by gemcitabine, or gemcitabine alone.1 Treatment with the combination extended median overall survival by approximately

2 months—from 6.7 months with gemcitabine to 8.5 months with the combination (hazard ratio [HR]  = 0.72; P = .000015), reported Daniel Von Hoff, MD, of the Translational Genomics Research Institute in Scottsdale, Arizona, who Daniel Von Hoff, MD presented the main results earlier this year at the Gastrointestinal Cancers Symposium.2 Nab-paclitaxel/gemcitabine was favored in all subgroups. Responses by positron-emission tomography (PET) imaging and CA19-9 correlated with overall survival, he reported at the ASCO Annual Meeting. Serious life-threatening toxicity was not incontinued on page 11

ASCO Annual Meeting

continued on page 21

Dr. Fenske is Associate Professor of Medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin, Milwaukee.

Top Five Things Oncologists Need to Know about Cancer in Older Adults By Charlotte Bath

A

F

ollicular lymphoma is the second most common subtype of non-Hodgkin lymphoma (NHL) in the United States. Of the nearly 70,000 new cases of NHL anticipated in 2013,1 approximately 7,000 to 13,000 (10%–19%) will be follicular lymphoma, by recent estimates.2-5 For many years, the median overall survival of patients with follicular lymphoma was 10 years. However, since the introduction of rituximab (Rituxan) and radioimmunotherapy, the survival of patients with follicular lymphoma has significantly improved.6,7 More recently, the addition of rituximab as a maintenance therapy has improved progression-free survival after first-line therapy.8 With ongoing efforts to develop more effective front-line therapies, incorporating agents

MORE IN THIS ISSUE

workforce shortage of geriatricians and other health professionals certified in caring for older patients with cancer is colliding with the aging of the population and the increasing number of older Americans with cancer. After describing factors contributing to these dual challenges, Arti Hurria, MD, outlined how using geriatric assessment tools to guide interventions and technology to integrate geri-

atrics and oncology care can facilitate quality of care for these patients. Dr. Hurria’s comments came during the B.J. Kennedy Lecture entitled “Cancer in Older Adults: The Top Five Things Oncologists Need to Know” that she delivered at the 2013 ASCO Annual Meeting after receiving the B.J. Kennedy Award for Scientific Excellence in Geriatric Oncology.1 Dr. Hurria is Director of the Cancer and Aging Program at the City of Hope Comprehensive Cancer Center in Duarte, By 2030, our largest shift in growth is California, and a founding going to be in the 80-plus population, member of the Cancer and a group where we really have had very Aging Research Group. The following highlimited data in best practices. lights were excerpted from —Arti Hurria, MD Dr. Hurria’s lecture.

Oncology Meetings Coverage ASCO Annual Meeting ��������� 3–5, 7, 19, 38, 40, 58 International Conference on Malignant Lymphoma�������������31–37 ACCC Annual Meeting ����������������������� 75 Expanded Indications for Lenalidomide ������������������������������������ 44 Direct from ASCO �������������������������� 52–54 Brivanib/Cetuximab in Colorectal Cancer ������������������������������� 63 Managing Graft-vs-Host Disease ���������� 87 Pioneers in Oncology: James Watson, PhD ��������������������������������� 95

continued on page 14

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The ASCO Post | JULY 25, 2013

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Harborside Press® Publishing Staff

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E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@ asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2013 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

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Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.


ASCOPost.com | JULY 25, 2013

PAGE 3

ASCO Annual Meeting Genitourinary Oncology

Enzalutamide Monotherapy Highly Active in Patients with Prostate Cancer Who Have Had No Prior Hormone Therapy By Alice Goodman

E

© ASCO/Todd Buchanan 2013

nzalutamide (Xtandi) monotherapy induced striking declines in prostate-specific antigen (PSA) in a majority of patients with hormonenaive prostate cancer in a phase II trial, and this oral agent appears to have little

native to androgen deprivation therapy, and although the drug seems to have little or no effect on bone mineral density, it also appears to be less effective than standard androgen deprivation therapy, Dr. Smith said. “Hormone therapy with a high level of efficacy and fewer adverse events [than androgen deprivation therapy] is an unmet medical need. Enzalutamide is a novel oral androgen receptor inhibitor approved by the FDA for treatment of men with castration-resistant prostate cancer and disease progression after docetaxel therapy. It makes sense

Matthew R. Smith, MD, PhD

effect on bone mineral density. If these findings are confirmed in a phase III III trial, then enzalutamide may be an alternative to androgen deprivation therapy in recurrent and metastatic prostate cancer with fewer side effects.

Effective Monotherapy “Enzalutamide achieved marked PSA responses and PSA declines in men with hormone-naive prostate cancer. We believe the results of this trial compare favorably with [the data for androgen deprivation therapy]. In contrast with [androgen deprivation therapy], patients treated with enzalutamide had stable bone mineral density and only modest changes in serum triglycerides. The beneficial effects seen in this phase II trial are consistent with those seen with potent [androgen deprivation therapy] inhibition, and support the role of enzalutamide as monotherapy in prostate cancer,” reported Matthew R. Smith, MD, PhD, of Massachusetts General Hospital in Boston. Although androgen deprivation therapy is considered the mainstay of treatment for recurrent or metastatic prostate cancer, the side effects can be difficult for men to tolerate. These include hot flashes, fatigue, loss of libido and erectile function, increased risk of bone mineral density loss, decreased muscle mass, and decreased insulin sensitivity that increases the risk of diabetes and cardiovascular disease. Bicalutamide was evaluated as an alter-

“W

to study this drug earlier in the course of disease,” he continued.

Study Details The phase II open-label, multicenter study evaluated enzalutamide as monotherapy in patients with hormone-naive prostate cancer for which androgen deprivation therapy is indicated. All patients had testosterone levels ≥  230 ng/mL, PSA ≥  2 ng/mL, and life expectancy of at least 12 months. Patients were treated with enzalutamide monotherapy for 25 weeks. At that point, a primary efficacy analysis

was performed. Patients deemed eligible could continue on therapy. The study included 67 men, with a median age of 73 years, mean body mass index of 22.6 kg/m2, median baseline PSA of 18.2 ng/mL, and median duration of prostate cancer since diagnosis of 1 year; 50% had Gleason 7 scores and 25% had Gleason 8 to 10 scores at entry. Approximately 38% had metastasis at study entry, and about one-third had had a prior prostatectomy. The primary endpoint was PSA response (at least an 80% decline in continued on page 4

EXPERT POINT OF VIEW

ith the high rate of [prostate-specific antigen (PSA)] decline, the study of enzalutamide (Xtandi) reported by Dr. Smith and colleagues appears to be a positive study,” said formal discussant Michael A. Carducci, MD, AEGON Professor in Prostate Cancer Research at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. “We still need to know about the durability of PSA decline and the long-term clinical benefits.” The side-effect profile of enzalutamide is more favorable than that of androgen deprivation therapy, he noted. “The way forward is novel uses and sequencing of androgen-inhibiting drugs for prostate cancer that improve survival—enzalutamide being one of them,” said Dr. Carducci. “With six new drugs approved for the treatment of metastatic castration-resistant, it is a no-brainer to study them earlier in the course of disease, in sequence and in combination.” Recent paradigm shifts in prostate cancer research include a focus on enhanced therapy at the time of local management and drug development for biochemical recurrence, Dr. Carducci said. “However, studies thus far suggest that monotherapy with a noncastrating drug will not be enough to slow the course of disease and improve survival,” he pointed out. “Biology tells us combination therapy will be the next advance, treating patients earlier in the course of disease. The problem is that when we move to the adjuvant setting, it will take a decade to show cure rates. Drugs approved for advanced dis-

ease are currently used sequentially, but this may not be the best way to treat patients in the adjuvant setting,” he said.

Combination Studies Dr. Carducci said that since the optimal sequence for these new drugs is not known, combination studies should be conducted, and he listed several that are underway or in the planning stages, including the following: The ALLIANCE A031201 study in men with metastatic castrationresistant prostate cancer who have not received docetaxel is evaluating enzalutamide vs enzalutamide plus abiraterone (Zytiga). The primary endpoint is overall survival, and the study will include 1,400 patients. The Southwest Oncology Group (SWOG) 1216 trial is being conducted in men with newly diagnosed metastatic disease, treating them with a luteinizing hormone-releasing hormone (LHRH) antagonist and bicalutamide vs an LHRH antagonist plus the investigational androgen synthesis inhibitor orteronel. The study will enroll 1,600 men and assess overall survival. The Prostate Cancer Clinical Trials Consortium’s AbiCure study is one example of several studies investigating biochemical recurrence. This study includes patients with short PSA doubling times who are randomly assigned to degarelix (Firmagon) alone vs degarelix plus abiraterone vs abiraterone alone. The primary endpoint is proportion of men with an undetectable PSA at 18 months.

Michael A. Carducci, MD

The Radiation Therapy Oncology Group (RTOG) 1115 trial is enrolling men with high-risk prostate cancer, who are undergoing standard dose-escalated radiotherapy plus 2 years of standard androgen deprivation therapy vs androgen deprivation therapy plus orteronel. Planned enrollment is 900 men, and the primary endpoint is overall survival. A proposed adjuvant prostatectomy trial by the ECOG-ACRIN Cancer Research Group—the merger of the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network—will compare placebo plus an LHRH antagonist vs an LHRH antagonist and enzalutamide. The study will enroll men at the highest risk, ie, those with Gleason score > 8, lymph node–positive, seminal vesicle– positive prostate cancer. The standard use of adjuvant radiation for such highrisk men will be incorporated into this study as well. The proposed primary endpoint will be 8-year biochemical relapse-free survival. n

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


The ASCO Post | JULY 25, 2013

PAGE 4

ASCO Annual Meeting Genitourinary Oncology

Shorter Duration of Hormone Therapy Feasible in Localized High-risk Prostate Cancer By Alice Goodman

M

en with localized high-risk prostate cancer treated with adjuvant radiotherapy had similar overall and disease-free survival when treated with

Abdenour Nabid, MD

18 months of androgen deprivation therapy vs 36 months of androgen deprivation therapy, the current standard of care in this setting. These results were reported at the 2013 ASCO Genitourinary Symposium1 and again at the 2013 ASCO Annual Meeting.2

Potential New Standard? “[Androgen deprivation therapy] of 18 months could represent a threshold effect with no further gain in survival compared with 36 months of [androgen deprivation therapy]. Duration of side effects and treatment cost could be significantly reduced with a shorter course of [androgen deprivation therapy] compared with 36 months. With longer follow-up, 18 months of

Enzalutamide in Prostate Cancer continued from page 3

PSA level). Monotherapy with enzalutamide achieved marked and rapid PSA declines in 92.5% of patients. Median PSA decrease was –99.6%. A total of 62 of 67 (92.5%) achieved the pri-

EXPERT POINT OF VIEW

“N

o one likes to give long-term hormonal therapy. I am optimistic that we can give shorter-term androgen deprivation therapy, but I am not sure I can state that with certainty today,” said Anthony V. D’Amico, MD, PhD, Professor of Radiation Oncology at Harvard Medical School and Chief of Genitourinary Radiation Oncology at DanaFarber Cancer Institute and Brigham and Women’s Hospital, Boston. The study by Dr. Nabid and colleagues was not a noninferiority study designed to show whether 18 months of androgen deprivation therapy is not inferior to 36 months of androgen deprivation therapy. The noninferiority design sets a prespecified threshold on the upper limit of increased risk of death that is acceptable and not inferior to 36 months of treatment.

“Because this study was designed as a superiority—not a noninferiority— study, the upper limit was 1.56, which is a high bar to accept—a 56% increase in death,” Dr. D’Amico said. “The study showed that 36 months is not superior to 18 months, but 18 months may be inferior to 36 months. It will take up to 7.5 years of follow-up to determine if the upper limit is under 1.35, a sufficient value to accept 18 months as not inferior to 36 months,” he explained.

Longer Follow-up Needed At present, it appears that 36 months of androgen deprivation therapy is too long, and 6 months is too short [based on European Organisation for Research and Treatment of Cancer data]. “Maybe 18 months is just right. We need longer follow-up,”

[androgen deprivation therapy] may become the standard in this setting,” stated lead investigator Abdenour Nabid, MD, Associate Professor at Sherbrooke University Hospital Center, Sherbrooke, Quebec, Canada. The side effects of long-term androgen deprivation therapy are difficult for men to tolerate, and include depression, loss of sexual function and libido, reduced bone mineral density, reduced insulin sensitivity, increased serum tri-

glycerides and cholesterol, and loss of muscle mass. The optimal duration of androgen deprivation therapy in this setting is unknown, Dr. Nabid told listeners. An earlier European Organisation for Research and Treatment of Cancer study found that the standard 36 months of androgen deprivation therapy improved overall survival compared with 6 months in men with high-risk prostate cancer.3 The present study evaluated an

mary endpoint of PSA decline > 80% at week 25, including patients with and without metastasis at baseline. Four of five patients categorized as nonresponders were actually patients who withdrew from the study before response was evaluable. Among 16 patients evaluable for ob-

jective responses with measurable disease, the complete plus partial response rate was 50%. Dr. Smith said that the data on durability of response will be included in the full publication of the trial’s results, but he did not have those data at the time of the Annual Meeting.

Enzalutamide in Hormone-naive Prostate Cancer ■ A phase II study showed promising results for enzalutamide monotherapy in hormone-naive prostate cancer.

■ Enzalutamide has an improved side-effect profile compared with standard androgen deprivation therapy.

■ Already approved for metastatic castration-resistant prostate cancer,

enzalutamide will move to phase III evaluation earlier in the course of disease.

Adverse Effects The expected rate of decline in bone mineral density is 3% to 5% during the first year of androgen deprivation therapy. In this study, no significant changes in bone mineral density were observed after 25 weeks of treatment with enzalutamide. In fact, bone mineral density increased at the femoral neck by about 0.4%. After 25 weeks of enzalutamide

Anthony V. D’Amico, MD, PhD

Dr. D’Amico emphasized. Comorbidity status is an important consideration, he continued. If a patient has cardiovascular disease, perhaps the 18-month course of androgen deprivation therapy is preferable, whereas if there are no comorbid conditions, 36 months might be the choice.

Disclosure: Dr. D’Amico reported no potential conflicts of interest.

intermediate duration of androgen deprivation therapy—18 months—vs 36 months, which cuts the time on treatment in half. The hope was to achieve similar efficacy with fewer side effects.

Study Design The study was conducted at 10 centers in Quebec, Canada from October 2000 through January 2008 and included 630 men with high-risk prostate continued on page 5

monotherapy, mean body mass index decreased by 4.2%, and body fat increased by 6.9%. Moderate increases were seen in serum triglycerides (6.5%) and total cholesterol levels (+4.6%), and these changes compare favorably with the effect of androgen deprivation therapy on these parameters. n Disclosure: Dr. Smith has served in a consultant or advisory role for Astellas Pharma and has received honoraria from Medivation.

Reference 1. Smith MR, Borre M, Rathenborg P, et al: Efficacy and safety of enzalutamide monotherapy in hormone-naive prostate cancer. 2013 ASCO Annual Meeting. Abstract 5001. Presented June 3, 2013.


ASCOPost.com | JULY 25, 2013

PAGE 5

ASCO Annual Meeting Germ Cell Tumors

Dose-dense Chemotherapy Improves Outcomes in Poor-prognosis Germ Cell Tumors By Caroline Helwick

F

© GMG/Scott Morgan

or poor-prognosis patients with germ-cell tumors, dose intensification of chemotherapy based on slow decline of tumor markers can increase progression-free survival, according

Karim Fizazi, MD, PhD

to the first randomized trial of a “personalized” treatment strategy for this tumor.1 At the 2013 ASCO Annual Meeting, investigators called this approach—which enlists dose-dense chemotherapy for “slow decliners”—a

Hormone Therapy in Prostate Cancer continued from page 4

cancer, defined as having at least one of the following three risk factors: T3–4 stage, prostate-specific antigen (PSA) > 20 ng/mL, and Gleason score > 7. Participants were aged 18 to 80 (median, 71 years), had no evidence of residual disease or distant metastases, and no history of previous malignancy. The primary endpoints were overall survival, disease-specific survival, and quality of life. Secondary endpoints were disease-free survival by chemical failure and site of relapse. Patients were treated with 1 month of bicalutamide and then randomly assigned in a 1:1 ratio to androgen deprivation therapy with goserelin (Zoladex) for 36 vs 18 months. Radiation therapy to the pelvis and prostate was started 4 months after initiation of androgen deprivation therapy and was similar in both arms of the study. “This was a very high-risk population of patients with prostate cancer,” Dr. Nabid emphasized. About 25% had stage T3–4 disease, 44.3%% had PSA > 20  ng/mL, 60% had Gleason scores > 7, 40% had a Gleason score of 8, and 20% had Gleason scores of 9 or 10. Treatment arms were comparable for high-risk features.

game-changer in patients with poorprognosis germ cell tumors. “Dose-dense chemotherapy reduces the risk of progression or death by 34% in young patients with poorrisk germ cell tumors and slow tumor marker decline. An early switch in chemotherapy regimen for patients with slow tumor marker decline is the new standard,” said Karim Fizazi, MD, PhD, Head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France, who presented the late-breaking abstract.

GETUG 13 Study The phase III GETUG 13 trial— conducted in France, the United States, and Slovakia—enrolled 263 patients with poor-prognosis germ cell cancers, defined as advanced nonseminomas associated with elevated serum tumor markers (human chorionic gonadotro-

Major Results At a median follow-up of 78 months (6.5 years), the survival rate was 77.1% in the 36-month group vs 76.2% in the 18-month group, a difference that was not statistically significant. The biochemical failure rate was higher in the 18-month androgen deprivation therapy group (24.7% vs 19.7%), but this difference was not statistically significant. Among 140 patients who received a second course of

Poor-prognosis Germ Cell Tumors ■ When tumor markers decline slowly in patients with germ cell tumors

with poor-prognosis features, switching patients to a dose-dense chemotherapy regimen reduces the risk of disease progression by 34%.

■ GETUG 13 compared two strategies in patients with slow tumor marker

declines at day 21: continuing on standard treatment with BEP or switching to a dose-dense regimen of BEP plus paclitaxel and oxaliplatin (with growth factor support), followed by cisplatin, ifosfamide and bleomycin.

pin [hCG], alpha-fetoprotein [AFP], and lactate dehydrogenase [LDH]), evidence of nonpulmonary visceral metastases or primary mediastinal nonseminomas. For such patients, the 5-year progression-free survival rate is about 40% and 5-year overall survival rate is less than 50%, Dr. Fizazi noted. Four cycles of BEP (bleomycin,

etoposide, platinum) has long been the standard treatment for this cancer, and other attempts to improve upon it have been largely disappointing, Dr. Fizazi said. “In the last 25 years, a number of randomized phase III trials have all been negative,” he said. These studies have evaluated new drugs, alternative regimens, and high-dose chemotherapy plus stem cell transplant.

in both arms, and the rate of bone metastasis was 8% in both arms. “This was very efficient treatment in either arm. This shows that longer duration of [androgen deprivation therapy] does not prevent bone metastases,” Dr. Nabid said.

two treatment arms. A multivariate analysis found that age and Gleason score > 7 were the only factors significantly associated with overall survival. Among participants who were followed for 10 years thus far, overall survival and prostate cancer-specific survival are similar for both groups, he said, and Dr. Nabid expects that this will remain true with additional planned follow-up of 2 to 3 years. The quality-of-life data are extensive but are not yet analyzed. They will be reported later this year. n

Further Analysis No significant differences were found for causes of death between the two arms. Overall, there were 165

Duration of Androgen Deprivation in Prostate Cancer ■ A randomized controlled trial found that 18 months of androgen

deprivation therapy had comparable efficacy to 36 months of treatment in localized high-risk prostate cancer.

■ At 6.5 years of follow-up, overall survival and disease-specific survival were similar in the two treatment arms.

■ Longer follow-up of this study may demonstrate that patients can be safely treated with 18 months of androgen deprivation therapy, reducing the incidence of unwanted side effects and cost of treatment.

androgen blockade, biochemical failure rates were 19.4% for the 18-month group vs 15.5% for the 36-month group. No differences in frequency and site of metastasis were observed between the two treatment arms. The rate of pelvic node metastasis was 1.3%

deaths (26.2%). The most common cause was a second cancer: 6.1% in the 36-month arm vs 8.8% in the 18-month arm. The rate of prostate cancer–related death was similar between the two arms: 5.2% and 5.9%, respectively. There were 25 deaths due to other causes, and these were evenly distributed between the

continued on page 6

Disclosure: Dr. Nabid has received research funding from AstraZeneca.

References 1. Nabid A, Carrier N, Martin A-G, et al: High-risk prostate cancer treated with pelvic radiotherapy and 36 versus 18 months of androgen blockade: Results of a phase III randomized study. 2013 Genitourinary Cancers Symposium. Abstract 3. Presented February 14, 2013. 2. Nabid A, Carrier N, Martin A-G, et al: Duration of androgen deprivation therapy in high-risk prostate cancer: A randomized trial. 2013 ASCO Annual Meeting. Abstract LBA4510. Presented June 4, 2013. 3. Bolla M, de Reijke TM, Van Tienhoven G, et al: Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 360:2516-2517, 2009.


The ASCO Post | JULY 25, 2013

PAGE 6

ASCO Annual Meeting Germ Cell Tumors

EXPERT POINT OF VIEW

continued from page 5

Switch to Different Regimen GETUG 13 evaluated a strategy of early tumor marker assessment, with a switch to a more intensified (dosedense) regimen for patients with slow declines in markers. Tumor markers can be reliably assessed as early as 3 weeks after starting chemotherapy. The scheme was as follows: BEP for one cycle, followed by tumor marker assessment on day 21. In the study, 51 patients had favorable declines and they continued on three more cycles of BEP; 203 patients (80% of the population) had unfavorable declines and were randomly assigned to switch to dose-dense chemotherapy (n = 105) or to continue on BEP for three more cycles. The BEP regimen was bleomycin at 30 U/wk plus etoposide at 100 mg/m2 on days 1 to 5 plus cisplatin at 20 mg/m2 on days 1 to 5. The dose-dense regimen included paclitaxel at175 mg/m2 on day 1 plus BEP plus oxaliplatin at 130 mg/m2 on day 10, with growth factor support; this was given every 3 weeks for two cycles. Patients were then switched to cisplatin at 100 mg/m2 on day 1 plus ifosfamide at 2 g/m2 on days 10, 12, and 14 plus bleomycin at 25 U/d on days 10 to 14. The study was amended to use growth factors in all patients, due to a high incidence of neutropenic fever among the patients (many with poor performance status), and oxaliplatin was deleted from cycles 3 and 4 of the dosedense regimen because of excess neurotoxicity observed in the first 10 patients.

Benefits of Dose-dense Chemotherapy At a median follow-up of 4.1 years, the primary endpoint was met, with

C

arsten Bokemeyer, MD, Professor of Internal Medicine at the University Medical Center Hamburg, Germany, formally discussed the paper by Fizazi et al at the ASCO Annual Meet-

Carsten Bokemeyer, MD

ing. “This is a positive trial. The progression-free survival, the primary endpoint, showed a 10% improvement, though, unfortunately, the overall survival was not significantly positive,” he said. “This is the first randomized trial showing an effect of dose intensifica3-year progression-free survival being 59% in the dose-dense arm, compared to 48% in patients continuing BEP (hazard ratio [HR]  = .66; P = .05). All subgroups benefited from the switch. “At the last follow-up, 63 patients in the dose-dense arm were still alive and free of progression, vs 46 patients in the BEP arm,” Dr. Fizazi announced. Overall survival followed this trend, but the difference was not significant: 73% vs 65%, respectively (HR = .78; P = .34). Toxicities in the dose-dense vs control arm included neutropenic fever

tion in slow marker-declining patients and confirms data from subset analyses of other trials in the poor-risk setting,” Dr. Bokemeyer noted. “I congratulate the investigators for doing this trial. Coming up with these data is extremely important, and was not easy to do,” he acknowledged. “It clearly also shows the importance of marker declines as a prognostic on-treatment factor … The fact that marker declines can be assessed after one cycle of BEP is important, as this allows us to change treatment early.”

Alternative Regimens He noted, however, that the dosedense chemotherapy regimen in this study is unfamiliar to most oncologists, and suggested other options worthy of study: a high-dose regimen that includes carboplatin, etoposide, and cyclophosphamide, which is used (17% each), neurotoxicity ≥ grade 2, mostly reversible (23% vs 4%), toxic deaths (1% each), and secondary cancers (1% vs 4%). Need for salvage high-dose chemotherapy plus transplant was lower in the dose-dense arm (6% vs 16%, P = .015). The study also validated the prognostic value of tumor marker decline, as this was associated with outcomes. Among patients treated with BEP, 3-year progression-free survival was 70% for those with favorable declines but only 48% for those with unfavorable declines (HR = .66; P = .01); overall survival was 84% and 65%, re-

at Memorial Sloan-Kettering Cancer Center; accelerated BEP, which is used in Australia; a regimen known as PEI (cisplatin, etoposide, ifosfamide), as used by the European Organisation for Research and Treatment of Cancer; and one called TIP (paclitaxel, ifosfamide, cisplatin), which showed some promise in another study presented at this year’s ASCO Annual Meeting.1 Considering that treatment intensification approaches are different around the world, Dr. Bokemeyer added, “With regard to guideline inclusion, we need more than one discussant from one country.” n

Disclosure: Dr. Bokemeyer has received honoraria or consultation fees from and is an advisor for Merck Serono, Roche, and GlaxoSmithKline.

Reference 1. Feldman DR, Hu J, Dorff TB, et al: 2013 ASCO Annual Meeting. Abstract 4501. Presented June 1, 2013.

spectively (HR = .65; P = .024). “We believe an early switch in the chemotherapy regimen should become the new standard treatment for these patients,” Dr. Fizazi concluded. n

Disclosure: Dr. Fizazi has had a consulting or advisory role with AstraZeneca.

Reference 1. Fizazi K, Pagliaro LC, Flechon A, et al: A phase III trial of personalized chemotherapy based on serum tumor marker decline in poor-prognosis germcell tumors: Results of GETUG 13. 2013 ASCO Annual Meeting. Abstract LBA4500. Presented June 1, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Jeffrey S. Groeger, MD, and Kathleen N. Cathcart, MD, on Critically Ill Hematology Patients see page 67

Clifford A. Hudis, MD, FACP, on the Affordable Care Act see page 55

Andrew S. Chi, MD, PhD, on Anaplastic Oligodendroglial Tumors see page 84

Melissa Hudson, MD, on Childhood Cancer Survivors see page 104

Visit The ASCO Post online at ASCOPost.com

Jonathan Cotliar, MD, on Graft-vs-Host Disease see page 87


ASCOPost.com | JULY 25, 2013

PAGE 7

ASCO Annual Meeting Genitourinary Oncology

First-line Sunitinib Followed by Everolimus Remains Standard Sequence in Metastatic Renal Cell Carcinoma By Alice Goodman

W

ith the approval of a number of different drugs for the treatment of metastatic renal cell carcinoma, a major issue is how to sequence these drugs to optimize outcome. A large, randomized phase II study called RECORD-3 shows that the standard sequence of the

Robert J. Motzer, MD

multitargeted tyrosine kinase inhibitor sunitinib (Sutent) followed by the mTOR inhibitor everolimus (Afinitor) extended survival compared with the reverse sequence of first-line everolimus followed by sunitinib. “The study failed to meet the prespecified level for noninferiority between the two strategies. The sequence of sunitinib followed by everolimus is supported by overall survival and progression-free survival results. The standard first-line paradigm remains first-line sunitinib followed by everolimus at progression,” stated lead author Robert J. Motzer, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York. Dr. Motzer presented results of the study at the 2013 ASCO Annual Meeting.1

Study Details RECORD-3 was an international, randomized, open-label study that enrolled 471 patients from 83 sites in 19 countries between October 2009 and June 2011. All patients had metastatic renal cell carcinoma of clear cell or nonclear cell histology and had had no prior systemic therapy. Patients were randomly assigned

to first-line therapy with everolimus vs sunitinib and treated until progression. After a 2- to 6-week washout period, they could switch to the alternative drug. More than 50% of patients were unable to cross over to the second-line therapy, but they were followed anyway, Dr. Motzer explained. The primary endpoint was progression-free survival on first-line therapy, and the study was designed to show noninferiority of everolimus followed by sunitinib to the standard sequence. The data cutoff was in September 2012. At the time of the progression-free survival analysis of first-line therapy, 201 patients in the everolimus arm and 192 in the sunitinib arm discontinued treatment, mainly due to progressive disease. Crossover to second-line therapy was possible in less than 50% of patients—108 assigned to first-line everolimus and 99 assigned to first-line sunitinib.

Survival Analysis Median progression-free survival on first-line therapy was superior with sunitinib: 7.85 months for everolimus vs 10.71 months for sunitinib. The hazard ratio favoring sunitinib was 1.43, and the study failed to meet the primary objective of a 1.1 hazard ratio for the noninferiority margin. Sunitinib as first-line therapy achieved longer progression-free survival regardless of risk group or histology. Results of the primary progression-free survival analysis were consistent in all three prespecified risk groups: poor, intermediate, and favorable risk according to Memorial Sloan-Kettering criteria. Progression-free survival results in clear cell vs non–clear cell histology were consistent with the primary analysis. An analysis of combined progressionfree survival for first- and second-line therapy was censored for patients who did not cross over to second-line therapy.

Sequencing of Therapies in Metastatic Kidney Cancer ■ Sunitinib as first-line therapy followed by everolimus extended survival and progression-free survival compared with everolimus followed by sunitinib.

■ Progression-free survival was consistent in subgroup analyses according to risk group and histology type.

■ First-line sunitinib followed by everolimus remains the standard of care for patients with metastatic renal cell carcinoma.

EXPERT POINT OF VIEW

F

ormal discussant of the RECORD-3 trial, Toni K. Choueiri, MD, Associate Professor of Medicine at Harvard Medical School and Director of the Kidney Cancer Center at Dana-Farber Cancer Institute, Boston, said that the focus of the research concerns how to move forward in the treatment of metastatic renal cell carcinoma. The trial by Motzer et al addresses an important question on the sequential use of tyrosine kinase inhibitors and mTOR inhibitors. “The study did not Toni K. Choueiri, MD meet its primary endpoint, and therefore, for the average metastatic renal cell carcinoma patient, I would not start with everolimus [Afinitor] as first-line therapy,” he stated. Another important finding of the trial is that less than 50% of patients are unable to cross over to second-line treatment, he noted. Dr. Choueiri had several reservations about the study results. “The analysis assumes patients were able to cross over, and I would strongly argue that the [combined progression-free survival data for first-line and second-line therapy] may not be relevant for patient care, because of the high number of censored patients, the uncertainty of how [progression-free survival] was calculated after second-line therapy, and the [progression-free survival] from start of secondline therapy was not presented,” he commented.

Major Implication The major clinical implication of RECORD-3 is that first-line vascular endothelial growth factor (VEGF)-targeted therapy remains the standard of care in metastatic renal cell carcinoma. A potential use of first-line mTOR inhibition includes temsirolimus (Torisel) in poor-risk disease and in patients with cardiovascular disease. “In my practice, I may use an mTOR inhibitor as first-line therapy in some patients with poor-risk disease and patients with recent acute arterial vascular events or cardiomyopathy, after consultation with my cardiologist,” he said. Future research directions should include identification of tumors addicted to mTOR pathway signaling and evaluation of results from the ongoing phase III SWITCH-1 and SWITCH-2 sequencing trials of sunitinib followed by sorafenib or vice versa and pazopanib (Votrient) followed by sorafenib and vice versa. “However, the small percentages of patients able to go on second-line therapy in the same clinical trial may limit applicability of all of these trials,” he cautioned. n

Disclosure: Dr. Choueiri has served in a consultant/advisory role for AVEO, GlaxoSmithKline, Novartis, Pfizer, and Exelixis, and has received research funding from Pfizer.

A trend was seen in the combined progression-free survival analysis favoring the standard paradigm of sunitinib followed by everolimus. Median progression-free survival for first-line everolimus followed by sunitinib was 21.13 months vs 29.79 months for sunitinib followed by everolimus. The final analysis of overall survival will be available in a year or so. Deaths were similar: 45% for the firstline everolimus sequence and 41% for the first-line sunitinib sequence. Median overall survival was 22.4 and 32.4 months,

respectively, for the two sequences. The adverse event profiles of both drugs were similar to what has been previously described. The incidence of noninfectious pneumonitis was lower than reported previously, Dr. Motzer said. n

Disclosure: Dr. Motzer has had a consultant or advisory role with Pfizer and has received research funding from Astellas Pharma, AVEO, GlaxoSmithKline, Novartis, and Pfizer.

Reference 1. Motzer RJ, Barrios CH, Kim TM, et al: 2013 ASCO Annual Meeting. Abstract 4504. Presented June 1, 2013.


Important Safety Information

Additional Important Safety Information

Boxed WARNING: Embryo-Fetal Toxicity • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception — Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant — Encourage women who may be exposed to PERJETA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 — Monitor patients who become pregnant during PERJETA therapy for oligohydramnios

Left Ventricular Dysfunction • Left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) and decreases in left ventricular ejection fraction (LVEF), occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution’s normal limits • Withhold PERJETA and Herceptin and repeat LVEF assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if the LVEF has not improved or has declined further Infusion‑Associated Reactions, Hypersensitivity Reactions/Anaphylaxis • PERJETA has been associated with infusion and hypersensitivity reactions • When all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting


F O R T H E F I R S T‑ L I N E T R E AT M E N T O F H E R 2 +* M E TA S TAT I C B R E A S T C A N C E R

STRENGTHEN HER DEFENSE

Indication: PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2‑positive metastatic breast cancer who have not received prior anti‑HER2 therapy or chemotherapy for metastatic disease.

Extend progression‑free survival (PFS) with an FDA‑approved HER2 dimerization inhibitor1,2 were observed across several • Consistent PFS results 1

Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

100 90

HR = 0.62‡ 95% CI [0.51‑0.75] P<0.0001

80 70

18.5 MONTHS

60 PFS (%)

patient subgroups At the time of analysis, there were 191 (47.5%) and 242 (59.6%) patients with a PFS event in the PERJETA + Herceptin + docetaxel and placebo + Herceptin + docetaxel arms, respectively1 The most common adverse reactions (ARs) (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy1

6.1-Month Improvement in Median IRF†-Assessed PFS1

50

12.4 MONTHS

40 30 20 10 0

* HER2+ = human epidermal growth factor receptor 2 positive. † IRF = independent review facility. ‡ Stratified by prior treatment status and geographic region.

0

5

10

15

402 406

345 311

267 209

139 93

20

25

30

35

40

32 17

10 7

0 0

0 0

MONTHS P+H+D Pl+H+D

83 42 Patients at risk

• In the randomized trial, the overall frequency of hypersensitivity reactions/anaphylaxis

was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown Most Common Adverse Reactions • The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. You may report side effects to the FDA at (800) FDA‑1088 or www.fda.gov/ medwatch. You may also report side effects to Genentech at (888) 835‑2555. For more information, scan the QR code or visit www.PERJETA.com.

© 2013 Genentech USA, Inc.

All rights reserved.

PER0001010502

References: 1. PERJETA Prescribing Information. Genentech, Inc. June 2012. 2. Baselga J, Cortés J, Kim S‑B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109‑119.

Printed in USA.

(01/13)


PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In the randomized trial, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebotreated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in the randomized trial as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETAtreated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In the randomized trial, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2% in the PERJETAtreated group and 2.5% in the placebo-treated group according to National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by

Dako Herceptest™ or FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis [see Warnings and Precautions (5.3)] 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 clinical practice. In clinical trials, PERJETA has been evaluated in more than 1400 patients with various malignancies and treatment with PERJETA was predominantly in combination with other anti-neoplastic agents. The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in the randomized trial. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients on the PERJETA-treated group. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in the Randomized Trial PERJETA Placebo Body System/ + trastuzumab + trastuzumab Adverse Reactions + docetaxel + docetaxel n=407 n=397 Frequency rate % All Grades %

Grades 3-4 %

Frequency rate % All Grades %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 Asthenia 26.0 2.5 30.2 Edema peripheral 23.1 0.5 30.0 Mucosal inflammation 27.8 1.5 19.9 Pyrexia 18.7 1.2 17.9 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 Rash 33.7 0.7 24.2 Nail disorder 22.9 1.2 22.9 Pruritus 14.0 0.0 10.1 Dry skin 10.6 0.0 4.3 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 Nausea 42.3 1.2 41.6 Vomiting 24.1 1.5 23.9 Constipation 15.0 0.0 24.9 Stomatitis 18.9 0.5 15.4 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 Anemia 23.1 2.5 18.9 Leukopenia 18.2 12.3 20.4 Febrile neutropenia* 13.8 13.0 7.6 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 Headache 20.9 1.2 16.9 Dysgeusia 18.4 0.0 15.6 Dizziness 12.5 0.5 12.1 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 Arthralgia 15.5 0.2 16.1 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

Grades 3-4 %

3.3 1.5 0.8 1.0 0.5 0.3 0.8 0.3 0.0 0.0 5.0 0.5 1.5 1.0 0.3 45.8 3.5 14.6 7.3 2.0 0.5 0.0 0.0 0.8 0.8 0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in <  10% of patients in the PERJETA-treated group: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the

PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebotreated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebotreated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In the randomized trial, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in the randomized trial were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/ hypersensitivity reactions that were clearly related to the antitherapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in the randomized trial, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA.

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

PERJETA is a registered trademark of Genentech, Inc. 01/13 PER0000999401 © 2013 Genentech, Inc. 10139000


ASCOPost.com | JULY 25, 2013

PAGE 11

ASCO Annual Meeting Gastrointestinal Oncology

Pancreatic Cancer continued from page 1

creased with nab-paclitaxel/gemcitabine, but more grade 3/4 adverse events were observed with the combination—most commonly neutropenia (38% vs 27%), fatigue (17% vs 7%), and peripheral neuropathy (17% vs 1%). “This is a new standard for the treat-

ment of metastatic pancreatic cancer that could become the backbone for new regimens,” Dr. Von Hoff concluded.

S-1 Outperforms Gemcitabine Updated findings for the phase III JASPAC-01 trial, also presented at the 2013 Gastrointestinal Cancers Symposium,3 confirmed the overall survival benefit of the oral fluoropyrimide S-1,

a drug currently used in Asia but not approved in the United States. In the study of 385 patients, adjuvant treatment with S-1 (80–120 mg/d every 6 weeks for four courses) led to a 46% reduction in mortality, compared to gemcitabine.4 Two-year overall survival was 70% with S-1 vs 53% for gemcitabine (P  �  .0001 for noninferiority and su-

periority); median overall survival has not been reached with S-1 but was 25.9 months with gemcitabine. Median relapse-free survival was 23.2 months vs 11.2 months, respectively, with 2-year rates of 49% vs 29%, respectively (HR = 0.67; P � .0001 � .0001 .0001 for superiority), reported Akira Fukutomi, MD, of Shizuoka Cancer Center Hospital. continued on page 12

EXPERT POINT OF VIEW

H

edy Lee Kindler, MD, Associate Professor of Medicine at the University of Chicago, the invited discussant of three of these presentations, emphasized the persistent lethality of advanced pancreatic cancer. She predicted that within this decade, pancreatic cancer will become the second

Hedy Lee Kindler, MD

leading cause of cancer death in the United States. “It still has the briefest survival of any solid tumor. Five-year survival is just 6%,” she noted. “There has been a long-standing, well-deserved therapeutic nihilism regarding chemotherapy for advanced pancreatic cancer. In countless trials over several decades, many drugs and combinations have been tested, with minimal to no activity observed,” she said.

Nab-paclitaxel/Gemcitabine Offers New Option One of the few milestones has now come in the form of nab-paclitaxel, she said, which, in combination with gemcitabine, improved overall survival over gemcitabine alone in the MPACT trial. Response rate, disease control rate, and median progression-free survival were all superior to the single agent, though “this came at the cost of increased grade 3 and 4 toxicity,” including neutropenia (38% vs 27%), thrombocytopenia (13% vs 9%), and neuropathy (17% vs � 1%). “This is an important practicechanging study. It is the first random-

ized trial to demonstrate that a cytotoxic agent added to gemcitabine prolongs survival in pancreatic cancer,” she emphasized. “This is wonderful. We are not accustomed to having good treatment choices in advanced pancreatic cancer.” Dr. Kindler acknowledged, however, that while the results achieved with nab-paclitaxel plus gemcitabine are certainly better than with gemcitabine alone, they are not as good as those for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin), as illustrated in Table 1.1,2 FOLFIRINOX is “superior in all metrics” to nab-paclitaxel/gemcitabine, and was shown to improve quality of life and to be cost-effective; for nabpaclitaxel/gemcitabine, these data are still lacking. In the absence of a head-to-head comparison of the two effective regimens, she suggested, “We need to understand the data that we have.” Clinicians may simply need to accept that “it’s nice to finally have choices,” she concluded.

Chemoradiotherapy, Current Immunotherapy Less Promising The results of LAP 07 may also “change practice,” she said, by showing a lack of benefit for the addition of radiation to chemotherapy in patients who respond to induction. “The authors conclude that the standard of care should remain chemotherapy, though chemoradiation is an option, and I agree,” she said. Among the potential explanations for “these somewhat surprising results” is that the treatment may have been inadequate, she suggested. “Could we do better with intensity-modulated radiotherapy or stereotactic body radiation therapy? Could we do better with induction FOLFIRINOX or nab-paclitaxel/

gemcitabine? Can we use better radiosensitizers?” Dr. Kindler questioned. Two upcoming cooperative group trials may help answer these questions: the three-arm randomized phase II RTOG 1201 study, which is evaluating standard vs intensified local or systemic therapy, and the proposed ALLIANCE/ECOG randomized phase  II trial evaluating induction FOLFIRINOX followed by either chemoradiotherapy (with capecitabine) or additional FOLFIRINOX. Also disappointing were the “clearly negative” results of TeloVac, one of the largest studies ever conducted in pancreatic cancer. While TeloVac is “one of a long line of negative phase III trials in pancreatic cancer,” Dr. Kindler maintained that the immune system does play a critical role in the development, progression, and eradication of pancreatic tumors. She suggested that the optimal pancreatic immunotherapy will

incorporate the best possible antigen and optimal adjuvant agent, and will aim to uncouple the tolerance mechanism by blocking immune checkpoints or manipulating the tumor microenvironment. n

Disclosure: Dr. Kindler has served as a consultant or advisor for Abraxis Bioscience, Amgen, AstraZeneca, Bristol-Myers Oncology, Clovis Oncology, Genentech, GlaxoSmithKline, Merck, Otsuka, Roche, and Verastem, and has received research funding from AB Science, Aduro Biotech, Astellas/OSI, CanBas, Genentech, Infinity, Lilly, Merck, and Morphotek.

References 1. Conroy T, Desseigne F, Ychou M, et al: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817-1825, 2011. 2. Von Hoff DD, Ervin TJ, Arena FP, et al: Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA 19-9 correlates. 2013 ASCO Annual Meeting. Abstract 4005. Presented June 3, 2013.

Table 1: FOLFIRINOX vs nab-Paclitaxel/Gemcitabine in Advanced Pancreatic Cancer: Efficacy in Experimental Arms FOLFIRINOX

nab-Paclitaxel/ Gemcitabine

Patients

342

861

Objective response

32%

23%

Disease control (partial response + stable disease)

70%

48%

Median survival

11.1 mo (HR = 0.57)

8.5 mo (HR = 0.72)

1-yr survival

48.4%

35%

Progression-free survival

6.4 mo (HR = 0.47)

5.5 mo (HR = 0.69)

Quality of life better than with gemcitabine

Yes

?

More cost-effective than gemcitabine

Yes

?

FOLFIRINOX = leucovorin, fluorouracil, irinotecan, oxaliplatin; HR = hazard ratio. Courtesy of Hedy Lee Kindler, MD, based on data from Conroy T, et al,1 and Von Hoff, et al.2


The ASCO Post | JULY 25, 2013

PAGE 12

ASCO Annual Meeting Pancreatic Cancer continued from page 11

Chemoradiotherapy Lacks Benefit Chemoradiotherapy provided no benefit over chemotherapy alone in locally advanced pancreatic cancer, and erlotinib (Tarceva) in the induction phase added no benefit over gemcitabine alone, according to the international phase III LAP 07 study, presented by Pascal Hammel, MD, PhD, of the Hopital Beaujon in Clichy, France.5 LAP 07 compared chemoradiotherapy to chemotherapy in patients with locally advanced pancreatic cancer controlled after 4 months of chemotherapy induction. Dr. Hammel noted that previous prospective studies have provided conflicting results as to the role of front-line chemoradiotherapy, while two retrospective studies found that induction chemotherapy may select for patients who will derive benefit from subsequent chemoradiotherapy. Questions have lingered, therefore, regarding the true benefit of chemoradiotherapy. The study first randomly assigned 442 patients to gemcitabine alone or gemcitabine plus erlotinib for 4 months of induction chemotherapy; the 269 who achieved disease control were then randomized to an additional 2 months of the previous chemotherapy or to a chemoradiotherapy (54 Gy plus capecitabine [Xeloda]). Patients receiving erlotinib in the first randomization received erlotinib as maintenance after protocol completion while gemcitabine was stopped. The primary endpoint was overall survival. After a median follow-up of 36 months and 221 deaths, no significant difference was observed in median overall survival between the chemotherapy arm (16.4 months) and chemoradiotherapy arm (15.2 months; HR = 1.03; P = .8295). .8295). Median progression-free survival was

11.8 months for chemotherapy compared with 12.5 months with chemoradiotherapy (HR = .9; P = .2161). “It was clear that to continue the study would not change the final results, and futility was declared at the second interim analysis,” Dr. Hammel announced. When analyzed according to chemotherapy induction arm, median overall survival was 13.6 months for gemcitabine compared with 11.9 months for gemcitabine plus erlotinib (HR = 1.19; P = .0930). .0930). The The combination also produced more toxicity. “Erlotinib was not beneficial in locally advanced pancreatic cancer, and it in-

prove overall survival in patients with locally advanced or metastatic pancreatic cancer.6 TeloVac randomized 1,062 patients from 51 centers to one of three treatment arms: gemcitabine/capecitabine alone; sequential gemcitabine/capecitabine followed by GV1001, and, for patients with stable disease at week 8, treatment with gemcitabine/capecitabine; or concurrent administration of gemcitabine/capecitabine plus GV1001. At a median follow-up of 6.1 months, median overall survival in the GV1001 arms was not significantly different from that derived from chemotherapy alone: 7.89 months

Experimental Treatments in Pancreatic Cancer ■ As a first-line treatment for metastatic pancreatic cancer, weekly nabpaclitaxel plus gemcitabine significantly reduced mortality by 28% compared with gemcitabine alone, in the MPACT study.

■ In the adjuvant JASPAC 01 trial, the oral fluoropyrimidine drug S-1

significantly reduced mortality by 46% compared with gemcitabine.

■ In the LAP 07 trial, chemoradiotherapy did not improve survival or

progression-free survival over chemotherapy alone in patients with locally advanced pancreatic cancer who responded to induction chemotherapy; erlotinib added no benefit over gemcitabine alone in the induction phase.

■ In the TeloVac trial, the telomerase vaccine GV1001 given in combination with gemcitabine/capecitabine did not improve overall survival over chemotherapy alone.

creased the toxicity. There was no advantage to adding erlotinib to better control tumor and thus push a higher rate of patients into the second randomization,” he said. “In locally advanced pancreatic cancer, the standard of care should remain chemotherapy, with chemoradiotherapy being an option after tumor control by chemotherapy,” Dr. Hammel concluded.

Chemoimmunotherapy Falls Short In the phase III TeloVac trial, the addition of GV1001, a telomerase vaccine, to standard gemcitabine/ capecitabine treatment did not im-

New from The ASCO Post

for the control arm, 6.94 months for sequential GV1001 treatment (P = .0466), and 8.36 for concurrent GV1001 treatment (P = .6378). “Overall survival with concurrent [gemcitabine/capecitabine]/GV1001 was not different from that of [gemcitabine/capecitabine] alone, and overall survival with sequential GV1001 was not statistically different from [gemcitabine/capecitabine] alone, as it did not meet the criterion for statistical significance (P � .0175),” said Gary W. Middleton, MD, of the University of Birmingham in the United Kingdom. “The addition of a T-helper epitope vaccine to [gemcitabine/capecitabine] did not improve outcome.” n

Disclosure: Dr. Von Hoff has been a consultant/advisor for and received honoraria and research funding from Celgene Corporation. Dr. Fukutomi has received honoraria from Lilly and Taiho Pharmaceuticals. Dr. Hammel received financial support from Roche for the study. Dr. Middleton reported no potential conflicts of interest.

References 1. Von Hoff DD, Ervin TJ, Arena FP, et al: Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA 19-9 correlates. 2013 ASCO Annual Meeting. Abstract 4005. Presented June 3, 2013. 2. Von Hoff DD, Ervin TJ, Arena FP, et al: Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 Gastrointestinal Cancers Symposium. Abstract LBA148. Presented January 25, 2013. 3. Uesaka K, Fukutomi A, Boku N, et al: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer ( JASPAC-01 study). 2013 Gastrointestinal Cancers Symposium. Abstract 145. Presented January 25, 2013. 4. Fukutomi A, Uesaka K, Boku N, et al: JASPAC 01: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer. 2013 ASCO Annual Meeting. Abstract 4008. Presented June 3, 2013. 5. Hammel P, Huguet F, van Laethem J-L, et al: Comparison of chemoradiotherapy and chemotherapy in patients with a locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. 2013 ASCO Annual Meeting. Abstract LBA4003. Presented June 3, 2013. 6. Middleton GW, Valle JW, Wadsley J, et al: A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer. 2013 ASCO Annual Meeting. Abstract LBA4004. Presented June 3, 2013.


(trametin (trametinib) 0.5 mg, 1 mg, 2 mg tablets tab

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MEKINIST is a trademark of the GlaxoSmithKline group of companies. ©2013 GlaxoSmithKline group of companies. All rights reserved. Printed in USA. MEK012R0 May 2013


The ASCO Post | JULY 25, 2013

PAGE 14

ASCO Annual Meeting Cancer in Older Adults continued from page 1

Increasing Number of Older Adults with Cancer “We know that cancer is a disease associated with aging,” Dr. Hurria said, pointing out that 60% of cancers and almost 70% of cancer deaths occur in people over the age of 65. By 2030, she continued, “our largest shift in growth is going to be in the 80-plus population, a group where we really have had very limited data in best practices.”

Shortage of Health-care Professionals Crediting ASCO for leading the way in helping us understand the workforce needs in oncology, Dr. Hurria said that in 7 years there is going to be “a clear discrepancy between supply and demand.” Currently, in the United States, there is one geriatrician for every 2,620 patients over the age of 75, but by the year 2030, the number of patients per geriatrician is expected to increase to 3,798. “This is going to have clear implications during our time as oncologists in terms of our workforce, and it is going to lead to evolving models of care,” Dr. Hurria said. “We are going to be partnering with our allied health professionals, physician assistants, and nurses. We’ll be involving rehab, pharmacists, and social workers to help us with this care. And probably most importantly, we are going to be partnering at home, with families, family caregivers, and home care aides,” Dr. Hurria said. “If we are all going to be caring for this population, there is a clear need for education and for training,” Dr. Hurria continued. “The health-care workforce receives very little geriatric training and is not prepared to deliver the best possible care to older patients,” she added. According to the Institute of Medicine workforce report, only 1% to 2% of physicians, less than 1% of nurses, less than 1% of physician assistants, less than 1% of pharmacists, and about 4% of social workers are certified in geriatrics.2

Heterogeneous Aging Process Dr. Hurria enumerated the lessons of pediatrics—that treating a young

population requires a unique skill set, that these patients have age-related changes in physiology, are vulnerable to toxicity, dependent in their daily activities, and that the long-term effects of treatment raise concerns in this very vulnerable population. “These are the same things that make our geriatric population potentially vulnerable,” Dr. Hurria said. “In fact, it might be even a bit more complicated because in pediatrics there are clear milestones,” and for that population, chronological age generally equals functional age. Aging is a more heterogeneous process, and for older adults, chronological age doesn’t equal functional age. Aging is, however, “associated with a linear decline in organ reserve,” which might not be obvious when you look at patients or their laboratory values. But the decline in organ reserve

ological age that predict the risk of morbidity and mortality. It evaluates functional status, comorbid medical conditions, nutritional status, cognitive function, psychological state, social support, and whether the patient is taking other medications and if those could interfere with cancer treatment. The model was internally validated, and Dr. Hurria reported that she and her colleagues are now working on externally validating it. “I hope to be able to share those results with you next year at ASCO,” she said.

Moving Beyond Prediction Dr. Hurria acknowledged that a major research need she heard expressed at the Annual Meeting was moving beyond prediction and using the assessment tools to guide practical intervention. She walked the audience

Top Five Take-home Points in Geriatric Oncology ■ Cancer is a disease associated with aging, and the number of older adults with cancer is on the rise.

■ There is a shortage of health-care professionals to meet the needs of the next generation of older adults, and innovative models are needed to enhance the geriatric competence of the workforce.

■ The aging process is heterogeneous, and chronological age does not equal functional age.

■ Tools are available to identify at-risk patients, and geriatric assessments can guide practical interventions.

■ Technology can be used to integrate geriatrics and oncology care. becomes apparent when you stress the patient, and “chemotherapy is the perfect physiological stressor that can unmask the decline in physiological reserve,” Dr. Hurria noted. The good news, she said, is that patients can build this reserve at any age, through lifestyle changes and physical activity. “This is a really important lesson for us to share with our patients,” she added.

Geriatric Assessment Tools Developing a geriatric assessment for oncologists began about a decade ago and represents a melding of the fields of geriatrics and oncology. The assessment takes into account factors that identify individuals at risk for toxicity and factors other than chron-

through different domains of geriatric assessment to demonstrate how it might influence oncology practice and interventions. For example, asking questions about functional status could help determine upfront whether a visiting nurse or social worker is needed to engage family members and help them prepare for anticipated toxicity. Being able to perform basic activities, such as shopping, managing finances, and taking medications at the right times and doses, allows patients to maintain independence. “Once they lose the ability to perform these activities, the need for either 24-hour care or increased levels of care go up,” Dr. Hurria said. Another domain involves comorbidities and whether they will impact

the ability of patients to tolerate cancer treatments. “We as oncologists actually do a really good job of thinking about these other comorbidities. So if they have neuropathy, maybe we won’t use the taxane,” she said. “But I think where we struggle is how do we put these medical conditions together and try to understand what is the impact of these on life expectancy.” Tools that are currently available can predict toxicity of treatments and survival of older patients with cancer and can uncover problems that might go undetected in a routine history and physical. These findings can lead to practical interventions, Dr. Hurria said. “What the question really comes down to is: Is it feasible to incorporate these tools into oncology practice?”

Using Technology to Integrate Geriatrics and Oncology Care Dr. Hurria asserted that geriatric assessment is feasible in oncology practice. “We can utilize technology to capture the information, predict the risk of chemotherapy toxicity, and pinpoint areas of vulnerability in order to guide practical interventions that we can implement ahead of time.” Dr. Hurria’s colleagues at City of Hope have developed touch screen technology and have helped incorporate the geriatric assessment into this technology, she said. This technology can be utilized to show summaries of results or risk prediction tools to start a conversation with patients about preparing together for high-risk situations. n

Disclosure: Dr. Hurria has received research support from Abraxis Oncology, Celgene, and GlaxoSmithKline. She has served as a consultant to GTX and Seattle Genetics.

References 1. Hurria A: Cancer in older adults: The top five things oncologists need to know. B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology. 2013 ASCO Annual Meeting. Presented June 3, 2013. 2. Committee on the Future Health Care Workforce for Older Americans, Institute of Medicine: Retooling for an aging America: Building the health care workforce. Washington, DC: The National Academies Press, 2008.


In the treatment of myelofibrosis What does

REGULATING JAK mean for your patients?


Jakafi® (JAK-ah-fye)—First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated

Jakafi is a registered trademark of Incyte Corporation. © 2013, Incyte Corporation. All rights reserved. RUX-1245a 06/13

• Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary • Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. Advise patients about early signs and symptoms of herpes zoster and to seek early treatment


Jakafi demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2,a,b Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

150

40 20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

80

-100

50% Improvement Upper 50th Percentile

Placebo (n = 153)

Upper 50th Percentile

Jakafi (n = 145)

In these charts, each bar represents an individual patient’s response.

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

At Week 24, significantly more patients receiving Jakafi vs placebo had — A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a — A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive patients and JAK2 V617F-negative patients, relative to placebo2

Visit www.jakafi.com/regulate

for more information on Jakafi and MF, plus valuable educational resources.

• Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed

a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT). A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom

scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1,2

Please see Brief Summary of Full Prescribing Information for Jakafi on the following page. References: 1. Jakafi Prescribing Information. Incyte Corporation. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

JAK targeted to make a difference


Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pretreatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting therapy with Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions]. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see Warnings and Precautions] 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. The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discontinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; however, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi Placebo (N=155) (N=151) Adverse All All Grade 3 Grade 4 Grades Grade 3 Grade 4 Reactions Gradesa (%) (%) (%) (%) (%) (%) Bruisingb 23.2 0.6 0 14.6 0 0 Dizzinessc 18.1 0.6 0 7.3 0 0 Headache 14.8 0 0 5.3 0 0 Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 Weight Gaine 7.1 0.6 0 1.3 0.7 0 Flatulence 5.2 0 0 0.7 0 0 Herpes Zosterf 1.9 0 0 0.7 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Grade 4 (%) 0 3.3 1.3

a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations. DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Jakafi is a registered trademark of Incyte Corporation. All rights reserved. U.S. Patent No. 7,598,257 © 2011-2013 Incyte Corporation. All rights reserved. Issued: June 2013 RUX-1216


ASCOPost.com | JULY 25, 2013

PAGE 19

ASCO Annual Meeting Breast Cancer

Head-to-head Matchup Shows Adjuvant Taxane Schedules Equally Effective By Caroline Helwick

I

n the treatment of early breast cancer, outcomes are equivalent whether paclitaxel is delivered weekly or every 2 weeks, though the weekly schedule may

G. Thomas Budd, MD

be better tolerated, according to the results of a phase III trial presented at the 2013 ASCO Annual Meeting.1 “The progression-free survival curves lie right on top of each other. With either schedule you get equivalent outcomes, but weekly paclitaxel is less toxic for most patients,” said G. Thomas Budd, MD, a staff physician at the Cleveland Clinic’s Taussig Cancer Institute. “The findings provide reassurance that women can choose the lower-dose weekly therapy without sacrificing their chance of survival.” In the Southwest Oncology Group (SWOG) S0221 trial—the first to directly compare the two common taxane regimens— patients with nodepositive or high-risk node-negative operable breast cancer were initially randomly assigned in a 2�2 �22 factorial design to one of two different regimens of doxorubicin and cyclophosphamide. All patients were also randomized to one of two different regimens of paclitaxel. In the taxane comparison, patients received paclitaxel at 80 mg/m2 weekly for 12 cycles or 175 mg/m2 every 2 weeks plus pegfilgrastim (Neulasta) for six cycles. The latter group received six cycles, not four, to achieve the same overall duration of treatment as the weekly patients, he explained. The doxorubicin/cyclophosphamide randomization was halted for futility, and the results were presented at ASCO 2011.2 The study closed in January 2012, having accrued 3,294 patients, and at the third interim analysis, the futility boundary was crossed for the paclitaxel comparison.

Outcomes Similar At a median follow-up of 4.4 years, the estimated 5-year disease-free survival rates for weekly and every-2-week paclitaxel were equivalent—82% and 81%, respectively. There was similarly no difference in overall survival; median survival has not been reached. “Our comparison did not show that weekly paclitaxel had superior efficacy.” Dr. Budd announced. “Since this was not conducted as a noninferiority study, we cannot make a statistical conclusion about the lack of difference. However, the Kaplan-Meier curves and the computed hazard ratio (HR = 1.05) suggest little difference in efficacy.” In a subset analysis, patients with HER2-positive tumors tended to derive somewhat more benefit with ev-

A

Adjuvant Taxane Schedules ■ SWOG 0221 was the first comparison of adjuvant paclitaxel given every 2 weeks vs weekly.

■ Outcomes were equivalent, with about 80% of patients disease-free at 5 years.

■ Weekly paclitaxel was associated with less musculoskeletal pain, peripheral neuropathy, and allergic reaction.

ery-2-week paclitaxel, but the hazard ratio of 1.40 was within the 95% confidence interval, he noted. “The major difference was seen in HER2-positive patients treated without trastuzumab [Herceptin] (HR = 1.71), but given the small number of patients in this subset and the lack of a biological explanation, it’s unclear whether this observation is of any significance,” he added.

Toxicity Profiles Different There were, however, differences in toxicities between the arms. About one-third of each arm experienced some type of grade 3 or 4 toxicity. While overall and dermatologic toxicities did not differ, there was more hematologic toxicity with weekly paclitaxel, especially leukopenia (6% vs continued on page 20

EXPERT POINT OF VIEW

number of breast cancer specialists commented on the value of the Southwest Oncology Group (SWOG) 0221 data. Charles Vogel, MD, Professor of Medicine at the University of Miami Health System, commented after the presentation, “This is a potentially important abstract because of the wide variety of schedules and dosages of paclitaxel used in the adjuvant setting. This is the first time we have seen a good head-to-head comparison, other than for every-3-week vs weekly paclitaxel, and we know the 3-weekly schedule isn’t as good. Here, you show equivalence in efficacy with lower-dose paclitaxel, with less toxicity. I think these implications are important.” Larry Norton, MD, Deputy Physician-in-Chief for Breast Cancer Programs; Medical Director, Evelyn H. Lauder Breast Center; and Norna S. Sarofim Chair in Clinical Oncology at Memorial Sloan-Kettering Cancer Center, agreed that the data are reassuring for individualizing treatment. “For patients coming from some distance, treatment every 2 weeks can be advantageous,” he noted. Dr. Norton also reminded listeners that both regimens were actually dose-dense and are superior to a standard every3-week schedule.

Charles Vogel, MD

Andrew D. Seidman, MD, a medical oncologist at Memorial Sloan-Kettering, who moderated a press briefing where the results were presented, commented, “It’s remarkable that after 2 decades we are still teaching an old dog new tricks. The differences in terms of safety and tolerability, in the absence of differences in efficacy, were very meaningful.” Dr. Seidman, who led the study of weekly paclitaxel vs every-3-week paclitaxel in metastatic patients,1 said he had long believed that more frequent dosing was best but these data confirmed that. “This will change my practice,” he said. ‘The data suggest I can get the same benefit with less toxicity using weekly paclitaxel, and possibly at lower cost, since the expense of growth factor support is not trivial.” G. Thomas Budd, MD, a staff physician at the Cleveland Clinic’s

Larry Norton, MD

Andrew D. Seidman, MD

Taussig Cancer Institute, who presented the SWOG 0221 study at the Annual Meeting, responded that while no formal pharmacoeconomic analysis has been conducted on the data, “a back-of-the-envelope analysis does show lower treatment costs with weekly paclitaxel.” n

Disclosure: Dr. Vogel reported no potential conflicts of interest. Dr. Seidman reported no potential conflicts of interest. Dr. Budd served on an advisory board for Amgen, though not for more than 2 years. Within the past year he has served on advisory boards for and received research funding from Genentech. Dr. Norton reported no potential conflicts of interest.

Reference 1. Seidman AD, Berry D, Cirrincione C, et al: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: Final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642-1649, 2008.


The ASCO Post | JULY 25, 2013

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ASCO Annual Meeting Adjuvant Taxane Schedules continued from page 19

1%, P � .001) and neutropenia (11% vs 2%, P � .001). However, patients in this arm had complete blood counts performed more often and did not receive hematopoietic growth factors routinely, he pointed out. “Importantly, this did not result in more infectious complications, which were uncommon in both,” he noted. In contrast, with every-2-week paclitaxel there was a higher incidence of allergic reactions (1.4% vs 0.6%, P = .035), musculoskeletal pain (11% vs 3%; P � .001), and peripheral neuropathy (17% vs 10%, P = .001). At a press briefing, Dr. Budd did acknowledge that the incidence of neuropathy is a bit lower when the every-2-week

schedule is given for four cycles rather than for six, as was done in this study. “These findings tell me that we have a choice. Either schedule can be recommended based on efficacy. We can discuss the side effects with patients and individualize treatment,” Dr. Budd concluded. “I do believe there will be a move to more weekly paclitaxel, since

hematopoietic growth factors are not required.” n

Disclosure: Dr. Budd served on an advisory board for Amgen, though not for more than 2 years. Within the past year he has served on advisory boards for and received research funding from Genentech.

References 1. Budd GT, Barlow WE, Moore HCF,

et al: S0221: Comparison of two schedules of paclitaxel as adjuvant therapy for breast cancer. 2013 ASCO Annual Meeting. Abstract CRA1008. Presented June 3, 2013. 2. Budd GT, Barlow WE, Moore HCF, et al: First analysis of SWOG S0221: A phase III trial comparing chemotherapy schedules in high-risk early breast cancer. ASCO 2011 Annual Meeting. Abstract 1004. Presented June 6, 2011.

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Boxed Warning And Additional Boxed Warning And Additional Important Safety Information Important Safety Information

• Immediately report exposure to Erivedge during • Immediately report exposure to Erivedge during pregnancy and encourage women who may have been pregnancy encourage who may been exposed to and Erivedge duringwomen pregnancy, eitherhave directly Embryo-Fetal Death and Severe Birth Defects exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge Embryo-Fetal Deathcan andcause Severe Birth Defects • Erivedge capsule fetal harm when or through pharmacovigilance seminal fluid, to participate Erivedge pregnancy program in by the contacting • administered Erivedge capsule causewoman fetal harm when to acan pregnant based on its pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555 administeredoftoaction a pregnant woman based on its mechanism the Genentech Blood Donation Adverse Event Line at (888) 835-2555 mechanism of action • Verify pregnancy status prior to the initiation of Blood Donation • Erivedge. Verify pregnancy statusand prior to thepatients initiation Advise male female ofof these • Advise patients not to donate blood or blood products • Advise patients Erivedge not to donate blood or blood products while receiving and for at least 7 months Erivedge. Advise male and female risks. Advise female patients of thepatients need of these while receiving Erivedge and for at least 7 months after the last dose of Erivedge risks. Advise female patients of the need for contraception during and after treatment after the last dose of Erivedge for during and after treatment andcontraception advise male patients of the potential risk Nursing Mothers andErivedge advise male patients of the potential risk Nursing Mothers of exposure through semen • Inform female patients of the potential for serious Erivedge exposure through semen patients of theinfants potential forErivedge, serious • of Advise patients to contact their healthcare provider • Inform adversefemale reactions in nursing from • immediately Advise patients to contact provider adverseinto reactions nursing infants of from if they suspecttheir theyhealthcare (or, for males, their taking accountinthe importance theErivedge, drug to immediately if they they (or, for males, their taking into account the importance of the drug to female partner) maysuspect be pregnant the mother female partner) may be pregnant the mother


ASCOPost.com | JULY 25, 2013

PAGE 21

Perspective

Follicular Lyphoma continued from page 1

such as bendamustine (Treanda) and bortezomib (Velcade), there is hope for even further improvement.9 For patients with relapsed/refractory follicular lymphoma, outcomes are not nearly as favorable. Using various regimens such as rituximab, bortezo-

mib/rituximab, bendamustine, bendamustine/bortezomib/rituximab, or radioimmunotherapy, the median progression-free survival in several important studies of relapsed/refractory follicular lymphoma has generally been in the vicinity of 1 year.10-15 In some older studies of rituximab-naive patients, results were more favorable, but today

nearly all relapsed/refractory follicular lymphoma patients have had some prior exposure to rituximab. Many will even have rituximab-resistant disease at the time of relapse or progression.

Autologous Transplantation Autologous hematopoietic cell transplantation has been utilized in fol-

TRANSFORM TRANSFORM THE THE TREATMENT TREATMENT OF OF DIFFICULT DIFFICULT ADVANCED ADVANCED BASAL BASAL CELL CELL CARCINOMA CARCINOMA ((aBCC) ((aBCC) (Not actual size)

• • • • • •

ERIVEDGE IS A UNIQUE ORAL THERAPY ERIVEDGE IS A UNIQUE ORAL THERAPY

Due to the nature of aBCC and its clinical factors (ie, lesion recurrence, location/size, 1,2 Due to the nature of aBCC and itsmay clinical factors (ie, lesion location/size, and invasiveness), some patients not be candidates for recurrence, surgery or radiation 1,2 and invasiveness), some patients may not be candidates for surgery or radiation Erivedge is an oral treatment option dosed as a 150-mg capsule once daily until 3 Erivedge is an oral treatment option dosed disease progression or unacceptable toxicityas a 150-mg capsule once daily until 3 disease progression or unacceptable toxicity Erivedge reduced lesions in patients with aBCC1,3 Erivedge reduced lesions in patients with aBCC1,3

(Not actual size)

Objective response rates (ORR) by IR from ERIVANCE1,3* Objective response rates (ORR) bylaBCC IR from ERIVANCE1,3* (n=63) mBCC (n=33) laBCC (n=63) mBCC (n=33) ORR 43% (n=27) 30% (n=10) (95% CI) (30.5-56.0) (15.6-48.2) ORR 43% (n=27) 30% (n=10) (95% CI) (30.5-56.0) (15.6-48.2) Complete response 21% (n=13) 0% Complete response 21% (n=13) Partial response 22% (n=14) 30%0% (n=10)

Partial response Median duration of response (months) (95% CI)duration of response (months) Median (95% CI)

Indication Indication ®

22%7.6 (n=14) (5.7-9.7) 7.6 (5.7-9.7)

30%7.6 (n=10) (5.6-NE) 7.6 (5.6-NE)

Erivedge (vismodegib) capsule is a hedgehog pathway inhibitor indicated for the treatment Erivedge (vismodegib) is a carcinoma, hedgehog pathway inhibitor indicated for the of adults®with metastaticcapsule basal cell or with locally advanced basal celltreatment carcinoma of adults with metastatic cell or carcinoma, or with locally for advanced that has recurred followingbasal surgery who are not candidates surgery,basal and cell who carcinoma are not that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. candidates for radiation.

*Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. Response in laBCC: of diseaseatprogression either ≥30% in lesion size (sum ofrmed the longest diameter) baseline in target *absence Patients received least 1 doseand of Erivedge with reduction independent pathologist-confi diagnosis of BCC.from Response in laBCC: lesions or in externally visible dimension (including scar orthe complete ulceration in in alltarget absencebyofradiography disease progression and either ≥30% reduction in lesion sizetissue); (sum of longestresolution diameter)offrom baseline target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all sampling biopsy. Response in mBCC:also assessed the Response Criteriaand in Solid (RECIST) version 1.0. target lesions. Complete responders had noby residual BCC onEvaluation sampling biopsy partialTumors responders had residual BCC on sampling biopsy. Review; Response in mBCC: assessed byBCC; the Response Evaluation Criteria in CI=confi Solid Tumors IR=Independent laBCC=locally advanced ORR=objective response rate; dence(RECIST) interval; version NE=not1.0. estimable; mBCC=metastatic BCC. IR=Independent Review; laBCC=locally advanced BCC; ORR=objective response rate; CI=confidence interval; NE=not estimable; mBCC=metastatic BCC.

Adverse Reactions Adverse Reactions • The most common adverse reactions (≥10%) were • The most common adversedysgeusia, reactions weight (≥10%)loss, were muscle spasms, alopecia, muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, fatigue, nausea, diarrhea,vomiting, decreased appetite, constipation, arthralgias, and ageusia constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal • women In clinical trials, aamenorrhea total of 3 ofwhile 10 premenopausal developed receiving Erivedge developed amenorrhea while receiving Erivedge • women Treatment-emergent grade 3 laboratory abnormalities • observed Treatment-emergent grade were 3 laboratory abnormalities in clinical trials hyponatremia in observed clinical trials wereinhyponatremia in 6 patientsin(4%), hypokalemia 2 patients (1%), 6 patients (4%), in 2 patients (1%), and azotemia in 3hypokalemia patients (2%) and azotemia in 3 effects patientsto(2%) You may report side the FDA at You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech You(888) may 835-2555. also report side effects to Genentech at at (888) 835-2555. Please see Brief Summary of Prescribing Information on Please seepage. Brief Summary of Prescribing Information on following following page.

See what you can offer your patients with See what you can offer your patients with aBCC at www.Erivedge.com aBCC at www.Erivedge.com

References: 1. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012;366:2171-2179. 2.Migden Walling MR, HW, Oro et al. Cancer Rev. References: 1. Sekulic A, AE, et al. Metastasis N Engl J Med. ® 2004;23:389-402. 3. Erivedge capsule Prescribing 2012;366:2171-2179. 2. Walling(vismodegib) HW, et al. Cancer Metastasis Rev. ® Information. Genentech, Inc. January 2012. capsule Prescribing 2004;23:389-402. 3. Erivedge (vismodegib) Information. Genentech, Inc. January 2012. © 2013 Genentech USA, Inc. All rights reserved. HED0001655400 in USA. © 2013 GenentechPrinted USA, Inc. All rights reserved. HED0001655400 Printed in USA.

licular lymphoma for decades. While autologous hematopoietic cell transplantation is not currently recommended as consolidation of first remission for follicular lymphoma, the situation is quite different for those with relapsed/ refractory follicular lymphoma. One prospective randomized continued on page 22


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Perspective

Follicular Lymphoma

motherapy alone.16 In that study, the standard therapy arm had a median progression-free survival of about 1  year, and the autologous hematopoietic cell transplantation arms had a median progression-free survival in excess of 4 years. Several single-center and multi-

continued from page 21

trial in relapsed/refractory disease showed a clear benefit in progression-free survival and a nearly significant improvement in overall survival in favor of autologous hematopoietic cell transplantation vs standard che-

center retrospective studies have evaluated autologous hematopoietic cell transplantation for follicular lymphoma. Eight studies of more than 100 patients have been published since 2003; they collectively include over 2,500 patients.17,31 In most of these studies, the progression-free survival curve shows

Safety:7" Table 1: Adverse Reactions Occurring in ≥  10% of Advanced BCC Patients (cont)

MedDRA Preferred Term

Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].

All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

-

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

-

All aBCC1 Patients (N = 138) Grade 3 Grade 4 All Grades 3 (%) (%) (%)

35 (25.4%)

3 (2.2%)

-

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

-

76 (55.1%) 15 (10.9%)

-

-

88 (63.8%)

-

-

aBCC = Advanced Basal Cell Carcinoma. 2 MedDRA = Medical Dictionary for Regulatory Activities. 3 Grading according to NCI-CTCAE v3.0. Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)]. Laboratory Abnormalities: Treatment-emergent Grade  3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. 7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE 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 embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)]. In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). 8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7  months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540  mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). • Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. • Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7  months after the last dose of ERIVEDGE. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. • Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. • Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

ERIVEDGE ® [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2013 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832301

Allogeneic Transplantation

Safety:10"

1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150  mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 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 clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138  patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10  months (305  days; range 0.7  to  36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥  10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥  10% of Advanced BCC Patients

2

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, 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 The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)]

a plateau at around 5 years, with 30% to 50% of patients achieving long-term (5- to 15-year) remissions. In the three most recent studies, progression-free survival was in the 48% to 56% range at 3 to 5 years.18,19,31 Importantly, in the National Comprehensive Cancer Network (NCCN) study by Evens et al, results were similar in an analysis restricted to patients who had prior rituximab exposure.18 The range of treatment-related mortality in the eight studies since 2003 was 2% to 14%, but only 2% to 3% in the three most recent studies. While treatment-related myelodysplastic syndromes and acute myeloid leukemia can occur after autologous hematopoietic cell transplantation for follicular lymphoma, the risk is relatively low: 3% to 8% at 5 to 15 years post-transplant using conditioning regimens that do not employ total-body irradiation.20 Importantly, three separate studies suggest improved survival for follicular lymphoma patients who undergo autologous hematopoietic cell transplantation in second or third remission, vs later in the disease course, indicating that early referral for transplantation consideration is prudent.18,21,22 With allogeneic hematopoietic cell transplantation, recent results are also quite encouraging. A shift has occurred such that the majority of allogeneic hematopoietic cell transplantation procedures now performed utilize nonablative or reduced-intensity conditioning regimens. Results from five recent studies, including one multicenter study, show that treatment-related mortality with reduced-intensity conditioning is now in the 8% to 17% range at 1 year. In addition, progression-free survival in these studies was in the 57% to 85% range with median follow-up between 3 and 11 years.23-26,31

Underused Strategy Given the low treatment-related mortality, favorable rates of long-term remission, and better results than expected with conventional therapy, one might expect that hematopoietic cell transplantation would be commonly utilized for follicular lymphoma. However, this is not the case. According to a recent analysis of the National LymphoCare Study, fewer than 3% of patients undergoing second-line therapy for follicular lympho-


ASCOPost.com | JULY 25, 2013

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Perspective

ma were treated with a strategy that included hematopoietic cell transplantation.27 Even if one assumes that only 30% to 50% of patients considered for second-line therapy would be hematopoietic cell transplantation candidates, this would still indicate that 10% or fewer of potential hematopoietic cell transplantation candidates are referred to a transplant center during secondline therapy. Similarly, data from the Center for International Blood and Marrow Transplant Research (CIBMTR) shows that over the past 10 years, approximately 370 hematopoietic cell transplantations occur in the United States for follicular lymphoma each year (240 autologous and 130 allogeneic hematopoietic cell transplantations).28,29 Assuming that only 80% of U.S. hematopoietic cell transplantations are captured by the CIBMTR (a conservative estimate), as many as 460 to 470 patients may actually undergo hematopoietic cell transplantation yearly. Now, let’s assume there are about 10,000 new cases of follicular lymphoma in the United States each year.1-5 Since the median age at diagnosis is 63, let’s further assume that about 40% of follicular lymphoma patients will, by the time they need second- or thirdline therapy, remain candidates for hematopoietic cell transplantation by age alone. Let’s further assume that 40% of these age-eligible patients will be found to be poor transplant candidates (due to comorbid conditions, or problems with stem cell collection and/or donor availability). This leaves approximately 2,400 follicular lymphoma patients each year who should be hematopoietic cell transplantation candidates. Yet, the number who actually undergo transplantation is less than 20% of that figure.

Potential Explanations So, how can we explain the relatively low use of hematopoietic cell transplantation in follicular lymphoma? There are several potential explanations. In a general sense, (a) patients may be referred but then be found to be poor transplantation candidates, (b) patients may decline transplantation, or (c) patients may not be referred for transplantation evaluation at all. In scenarios (a) and (b), the dropout occurs predominantly at the transplant center after an initial evaluation.

We certainly have patients like this at our center. In my experience, however, this occurs very infrequently. It seems likely that the major factor is that patients are not being referred in the first place. Why might this be? As a physician working at a transplant center, I cannot be sure. My suspicion is that many community oncologists are reluctant to refer patients for hematopoietic cell transplantation evaluation. In rare cases, this may stem from a concern about potentially losing a patient to the tertiary care center. However, among the community oncologists that I know and collaborate with, I sense a deep

niques, high-resolution HLA typing, and breakthroughs in supportive care. These developments, collectively, have led to a decrease in treatment-related mortality after both autologous and allogeneic hematopoietic cell transplantation, and an ability to offer transplantation to a much wider range of patients.

Nontransplant Options At the same time, the past 15 years have seen an ever-expanding arsenal of non-transplant therapies for lymphoma such as rituximab, bendamustine, radioimmunotherapy, bortezomib, lenalidomide (Revlimid), and

For now, there is no therapy besides hematopoietic cell transplantation with as impressive a track record for relapsed/refractory follicular lymphoma, and we should not ignore that when recommending treatments to our patients. —Timothy S. Fenske, MD

commitment to doing what is best for the patient. So why are patients not referred? I believe that, for many community oncologists, their primary exposure to hematopoietic cell transplantation was during fellowship training. These experiences tended to be heavily weighted toward inpatient work, which involved dealing with patients suffering from complications of transplantation. In some cases, this exposure occurred in an era when our ability to prevent and treat complications was more limited. They saw many fewer patients doing well after hematopoietic cell transplantation, since those patients spend much less time as inpatients. This experience, consciously or subconsciously, may lead to a perception that hematopoietic cell transplantation should be a treatment of “last resort,” and, in turn, to a reluctance to refer until late in the disease course. Additionally, depending on where or when they trained, a practicing community oncologist may not have witnessed the important strides made in hematopoietic cell transplantation in the past 10 to 15 years, including less toxic conditioning regimens, more effective stem cell mobilization tech-

emerging agents such as the Bruton’s tyrosine kinase inhibitors, PI3-kinase inhibitors, mTOR inhibitors, new monoclonal antibodies, and antibody-drug conjugates. The availability of multiple nontransplant therapies makes it easier to put off the transplant referral. Many of these nontransplant therapies are marketed aggressively. Hematopoietic cell transplantation does not get marketed in the same way and so may not come to mind as readily when considering treatment options.

‘Selection Bias’ Another possible reason for patients not being referred for hematopoietic cell transplantation is that transplant studies are often criticized for being subject to patient selection bias. It is certainly true that retrospective studies and single-arm phase  II trials are subject to bias, especially when comparing across trials or using historical controls. I fully agree that we need more high-quality prospective randomized phase III trials evaluating hematopoietic cell transplantation in various settings. So one may pessimistically look at the transplantation studies I have cited above and think, “patient selection bias.” My response would be, “Send us

the patients, and let us select!” Transplant physicians spend their days trying to identify those patients most likely to benefit from, and least likely to be harmed by, a transplant procedure. Whatever thought process went into selecting patients for the studies cited above, a very similar thought process will be applied to the patients you send to a transplant center. After a discussion of the risks and benefits, I believe that many follicular lymphoma patients would be pleased to be “selected” to have a treatment that gives them the best chance for long-term remission and survival.

Educational Efforts Those of us who work in transplant centers should strive to ensure that graduating hematology/oncology fellows have a balanced exposure to hematopoietic cell transplantation. We should also make a stronger effort to keep our community oncology colleagues informed of the advances and current state of our field, so that patients can be offered all options available, including hematopoietic cell transplantation. Currently, based on available evidence, I recommend that follicular lymphoma patients under age 70, in first or second relapse, be referred for a transplant evaluation. Comorbidity can now be quantified using the well-validated Hematopoietic Cell Transplant Comorbidity Index (HCT-CI). Patients with an HCT-CI score of 3 or higher have increased risk of treatment-related mortality30 and may be found to be poor transplant candidates. As new, more “targeted” therapies become available, the role of hematopoietic cell transplantation may evolve. However, despite the great enthusiasm for new and emerging agents in follicular lymphoma, their ability to produce long-term remission remains uncertain. For now, there is no therapy besides hematopoietic cell transplantation with as impressive a track record for relapsed/refractory follicular lymphoma, and we should not ignore that when recommending treatments to our patients. n Disclosure: Dr. Fenske reported no potential conflicts of interest. References available at www.ASCOPost.com


A treatment strategy built for your patients PARAMOUNT trial: Overall survival Overall survival following randomization* in advanced nonsquamous† NSCLC patients (n=539)1,2

* Only patients with stable disease or better were eligible for continuation maintenance with ALIMTA single agent. †

Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA/cisplatin followed by continuation maintenance with ALIMTA + BSC met its primary endpoint of investigator-assessed PFS as compared to ALIMTA/cisplatin followed by placebo + BSC.

a

OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy.

b

An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Limitations of Use: ALIMTA® (pemetrexed for injection) is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.


PARAMOUNT trial: Safety profile of ALIMTA continuation maintenance compared with placebo1,2 CTCAE drug-related toxicities

CTCAE=Common Terminology Criteria for Adverse Events. a

Refer to NCI CTCAE version 3.0.

b

Adverse reactions of any severity (all grades) occurring more frequently (竕・5%) or grades 3/4 adverse reactions occurring more frequently (竕・2%) in ALIMTA-treated patients compared to those receiving placebo.

See the complete data at ALIMTAhcp.com/data ALIMTAツョ (pemetrexed for injection) is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. Myelosuppression is usually the dose窶人imiting toxicity with ALIMTA therapy. Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. See the Important Safety Information and Brief Summary for ALIMTA on the following pages. References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Paz-Ares L, et al. Lancet Oncol. 2012;13(3):247-255.


Indications for ALIMTA® (pemetrexed for injection) ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Important Safety Information for ALIMTA Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy. Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. Warnings and Precautions Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities. Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment. ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities. ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function. Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. Drug Interactions See Warnings and Precautions for specific information regarding NSAID administration in patients with renal insufficiency. Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother. Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information. Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC) The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%). Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%). Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinumbased induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%). Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/desquamation (10% vs 3%). Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%). Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/ stomatitis (5% vs 2.4%); and edema (5% vs 3.6%). For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Brief Summary of Prescribing Information on the adjacent page. PM_HCP_ISI_NSCLC1M_17OCT2012 PM84635

07/2013 PRINTED IN USA © 2013, Lilly USA, LLC. ALL RIGHTS RESERVED. ALIMTA® is a registered trademark of Eli Lilly and Company.


ASCOPost.com | JULY 25, 2013

PAGE 27

FDA Update

New Drug Application Submitted for Ibrutinib in the Treatment of Two B-cell Malignancies

P

harmacyclics, Inc, recently announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration

(FDA) for the investigational oral Bruton’s tyrosine kinase inhibitor ibrutinib, for two relapsed/refractory B-cell malignancy indications: mantle cell

ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information. 1

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity

INDICATIONS AND USAGE

Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.1

1.2

Nonsquamous Non-Small Cell Lung Cancer – Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.5

Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information]. 2

DOSAGE AND ADMINISTRATION

2.1

Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information. 2.2

Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. 2.3

Premedication Regimen and Concurrent Medications Vitamin Supplementation Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)]. Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)]. Corticosteroids Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)]. 2.4

Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)]. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin. Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets 75% of previous dose (pemetrexed ≥50,000/mm3. and cisplatin). 75% of previous dose (pemetrexed Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC. and cisplatin). Nadir platelets <50,000/mm3 with bleedinga, 50% of previous dose (pemetrexed regardless of nadir ANC. and cisplatin). a

These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding. If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2. Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicitiesa,b Dose of ALIMTA Dose of Cisplatin (mg/m2) (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous 75% of previous dose dose Any diarrhea requiring hospitalization (irrespective 75% of previous 75% of previous of Grade) or Grade 3 or 4 diarrhea dose dose Grade 3 or 4 mucositis 50% of previous 100% of previous dose dose

a b

NCI Common Toxicity Criteria (CTC). Excluding neurotoxicity (see Table 3).

ALIMTA® (pemetrexed for injection)

PV 8926 AMP

lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The submission was based on data from phase

CTC Grade 0-1 2

Dose of ALIMTA (mg/m2) 100% of previous dose 100% of previous dose

Dose of Cisplatin (mg/m2) 100% of previous dose 50% of previous dose

Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

II studies in patients with relapsed/ refractory MCL and in patients with relapsed/refractory CLL/SLL. continued on page 28

6 6.1

Clinical Trials Experience Because clinical trials are conducted under widely varying condit cannot be directly compared to rates in other clinical trials and may n in clinical practice. In clinical trials, the most common adverse reactions (incide with ALIMTA as a single-agent were fatigue, nausea, and anorexia. reactions (incidence ≥20%) during therapy with ALIMTA when used i included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyn constipation. Non-Small Cell Lung Cancer (NSCLC) – ALIMTA in Combination w Table 4 provides the frequency and severity of adverse reaction >5% of 839 patients with NSCLC who were randomized to study and re and 830 patients with NSCLC who were randomized to study and receive All patients received study therapy as initial treatment for locally advanc patients in both treatment groups were fully supplemented with folic ac

Table 4: Adverse Reactions in Fully Supplemented Receiving ALIMTA plus Cisplatin in NSCLC Reactionb

3

DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

All Adverse Reactions Laboratory   Hematologic    Anemia    Neutropenia    Leukopenia    Thrombocytopenia   Renal    Creatinine elevation Clinical   Constitutional Symptoms    Fatigue   Gastrointestinal    Nausea    Vomiting    Anorexia    Constipation    Stomatitis/Pharyngitis    Diarrhea    Dyspepsia/Heartburn   Neurology    Neuropathy-sensory    Taste disturbance   Dermatology/Skin    Alopecia    Rash/Desquamation

4

CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. 5

WARNINGS AND PRECAUTIONS

5.1

Requirement for Premedication and Concomitant Medication to Reduce Toxicity Vitamin Supplementation Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin  B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin  B12  prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0]. Corticosteroids Administer dexamethasone the day before, the day of, and the day after ALIMTA administration [see Dosage and Administration (2.3)]. 5.2

Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the doselimiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)]. Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)]. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.3

5.4

Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)]. 5.5

Required Laboratory Monitoring Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)]. 5.6

Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA 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. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)]. ALIMTA® (pemetrexed for injection)

PV 8926 AMP

ADVERSE REACTIONS

a

ALIMTA/cisplatin (N=839) All Grades Grade 3-4 Toxicity (%) Toxicity (%) 90 37

33 29 18 10

6 15 5 4

10

1

43

7

56 40 27 21 14 12 5

7 6 2 1 1 1 0

9 8

0 0c

12 7

0c 0

A T

For the purpose of this table a cut off of 5% was used for inclusion of considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term Grade 1 or 2. No clinically relevant differences in adverse reactions were histology. In addition to the lower incidence of hematologic toxicity on the A of transfusions (RBC and platelet) and hematopoietic growth factors w cisplatin arm compared to the gemcitabine and cisplatin arm. The following additional adverse reactions were observed in pati cancer randomly assigned to receive ALIMTA plus cisplatin. Incidence 1% to 5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — creatinine clearance decrease, renal failure Special Senses — conjunctivitis Incidence Less than 1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Non-Small Cell Lung Cancer (NSCLC) – Maintenance ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum

ALIMTA® (pemetrexed for injection)


The ASCO Post | JULY 25, 2013

PAGE 28

FDA Update

NDA for Ibrutinib continued from page 27

With this submission, Pharmacyclics is also requesting Priority Review. If approved, ibrutinib would be the first available agent in a class of oral Bruton’s tyrosine kinase inhibitors. Pharmacyclics is jointly developing ibrutinib with Janssen.

xicity, the recommended dose adjustments for ALIMTA and cisplatin are should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

: Dose Reduction for ALIMTA (single-agent or combination) and Cisplatin - Neurotoxicity Dose of ALIMTA (mg/m2) 100% of previous dose 100% of previous dose

Dose of Cisplatin (mg/m2) 100% of previous dose 50% of previous dose

mmendation uld be discontinued if a patient experiences any hematologic or 4 toxicity after 2 dose reductions or immediately if Grade 3 or

nts atients with creatinine clearance ≥45 mL/min required no dose e recommended for all patients. Insufficient numbers of patients with 5 mL/min have been treated to make dosage recommendations for this al Pharmacology (12.3) in the full Prescribing Information]. Therefore, nistered to patients whose creatinine clearance is <45 mL/min [see Dose Reduction/Discontinuation Recommendations (2.4) in the full tion should be exercised when administering ALIMTA concurrently with atinine clearance is <80 mL/min [see Drug Interactions (7.1)].

The NDA submission follows the receipt of a Breakthrough Therapy designation from the FDA in February 2013 for ibrutinib as a monotherapy for the treatment of patients with relapsed/refractory MCL, and receipt of a second Breakthrough Therapy designation for the treatment of patients with CLL/SLL with 6

deletion of the short arm of chromosome 17 (del 17p). Ibrutinib has also been granted a Breakthrough Therapy designation for the treatment of patients with Waldenström’s macroglobulinemia. “We are very excited having achieved this major milestone. This first NDA for ibrutinib was made

ADVERSE REACTIONS

6.1

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Small Cell Lung Cancer (NSCLC) – ALIMTA in Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table  5 provides the frequency and severity of adverse reactions reported in >5% of the 438 patients with NSCLC who received ALIMTA maintenance and the 218 patients with NSCLC who received placebo following a platinum-based induction therapy. All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12. Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa Following Platinum-Based Induction Therapy ALIMTA Placebo (N=438) (N=218) Reactionb All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 66 16 37 4 Laboratory   Hematologic 1 6 3 15     Anemia 0 0 3 6     Neutropenia 1 1 2 6     Leukopenia   Hepatic     Increased ALT 10 0 4 0     Increased AST 8 0 4 0 Clinical   Constitutional Symptoms     Fatigue 25 5 11 1   Gastrointestinal 1 6 1 19     Nausea 0 5 2 19     Anorexia 0 1 0 9     Vomiting 0 2 1 7     Mucositis/stomatitis 0 3 1 5     Diarrhea   Infection 5 2 2 0   Neurology     Neuropathy-sensory 9 1 4 0   Dermatology/Skin     Rash/Desquamation 10 0 3 0

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa Reactionb

STRENGTHS or injection, is a white to either light-yellow or green-yellow lyophilized gle-use vials containing 100 mg or 500 mg pemetrexed.

All Adverse Reactions Laboratory   Hematologic    Anemia    Neutropenia    Leukopenia    Thrombocytopenia   Renal    Creatinine elevation Clinical   Constitutional Symptoms    Fatigue   Gastrointestinal    Nausea    Vomiting    Anorexia    Constipation    Stomatitis/Pharyngitis    Diarrhea    Dyspepsia/Heartburn   Neurology    Neuropathy-sensory    Taste disturbance   Dermatology/Skin    Alopecia    Rash/Desquamation

S ated in patients who have a history of severe hypersensitivity reaction

CAUTIONS

medication and Concomitant Medication to Reduce Toxicity ion with ALIMTA, initiate supplementation with oral folic acid and reduce the severity of hematologic and gastrointestinal toxicity of ministration (2.3)]. Do not substitute oral vitamin B12 for intramuscular s, the incidence of the following Grade 3-4 toxicities were higher in who were never supplemented as compared to patients who were c acid and vitamin  B12  prior to and throughout ALIMTA treatment: 23%], thrombocytopenia [9% versus 5%], febrile neutropenia on with neutropenia [6% versus. 0].

ALIMTA/cisplatin (N=839) All Grades Grade 3-4 Toxicity (%) Toxicity (%) 90 37

Gemcitabine/cisplatin (N=830) All Grades Grade 3-4 Toxicity (%) Toxicity (%) 91 53

33 29 18 10

6 15 5 4

46 38 21 27

10 27 8 13

10

1

7

1

43

7

45

5

56 40 27 21 14 12 5

7 6 2 1 1 1 0

53 36 24 20 12 13 6

4 6 1 0 0 2 0

9 8

0 0c

12 9

1 0c

12 7

0c 0

21 8

1c 1

possible in record time because of the continuous support and consultations we received from the FDA,” said Urte Gayko, PhD, Senior Vice President of Global Regulatory Affairs, Pharmacyclics. “We look forward to continuing to work with the FDA as they review the application for ibrutinib through the new Break-

a

D sm of action, ALIMTA can cause fetal harm when administered to a ed administered intraperitoneally to mice during organogenesis was ratogenic in mice at greater than 1/833rd the recommended human ng pregnancy, or if the patient becomes pregnant while taking this apprised of the potential hazard to the fetus. Women of childbearing o avoid becoming pregnant. Women should be advised to use effective revent pregnancy during treatment with ALIMTA [see Use in Specific

For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. No clinically relevant differences in adverse reactions were seen in patients based on histology. In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm. The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin. Incidence 1% to 5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — creatinine clearance decrease, renal failure Special Senses — conjunctivitis Incidence Less than 1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Non-Small Cell Lung Cancer (NSCLC) – Maintenance ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction Therapy

For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity. No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%). Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen. Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%). The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA. Incidence 1% to 5% Dermatology/Skin — alopecia, pruritus/itching Gastrointestinal — constipation General Disorders — edema, fever (in the absence of neutropenia) Hematologic — thrombocytopenia Renal — decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate Special Senses — ocular surface disease (including conjunctivitis), increased lacrimation Incidence Less than 1% Cardiovascular — supraventricular arrhythmia Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity Neurology — motor neuropathy Renal — renal failure Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum Induction Therapy Table  6 provides the frequency and severity of adverse reactions reported in >5% of the 500 patients with non-squamous NSCLC who received at least one cycle of ALIMTA maintenance (n=333) or placebo (n=167) on the continuation maintenance trial. The median of maintenance cycles administered to patients receiving one or more doses of maintenance therapy was 4 on both the pemetrexed and placebo arms. Dose reductions for adverse events occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose delays for adverse events occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm. Patients in both study arms were supplemented with folic acid and vitamin B12.

r injection)

ALIMTA® (pemetrexed for injection)

ALIMTA® (pemetrexed for injection)

sone the day before, the day of, and the day after ALIMTA administration n (2.3)].

ession bone marrow function, as manifested by neutropenia, thrombocytopenia, ) [see Adverse Reactions (6.1)]; myelosuppression is usually the doseons for subsequent cycles are based on nadir ANC, platelet count, and xicity seen in the previous cycle [see Dosage and Administration (2.4)].

nction eliminated unchanged by renal excretion. No dosage adjustment is nine clearance ≥45 mL/min. Insufficient numbers of patients have been ance <45 mL/min to give a dose recommendation. Therefore, ALIMTA o patients whose creatinine clearance is <45 mL/min [see Dosage and

ere renal impairment (creatinine clearance 19 mL/min) who did not n B12 died of drug-related toxicity following administration of ALIMTA

dal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate

ed when administering NSAIDs concurrently with ALIMTA to patients insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug

Monitoring od count and renal function tests at the beginning of each cycle and as e of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is atinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

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a

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ASCOPost.com | JULY 25, 2013

PAGE 29

FDA Update

through Therapy designation process,” he added. “The FDA submission is another important milestone for ibrutinib since we formed our strategic partnership with Pharmacyclics just 18 months ago,” said Peter F. Lebowitz, MD, PhD, Global Oncology Head, Janssen. “Both companies

recognize that there is great unmet need among these patient populations, and together in close collaboration with the FDA, as part of its Break-

Table 6: Selecteda Adverse Reactionsb Occurring in ≥5% of Patients Receiving ALIMTA in Nonsquamous NSCLC Following ALIMTA Plus Cisplatin Induction Therapy Adverse Reaction Organ System and Term All Adverse Reactions Laboratory   Hematologic     Anemia     Neutropenia Clinical   Constitutional Symptoms     Fatigue   Gastrointestinal     Nausea     Vomiting     Mucositis/stomatitis   General Disorders     Edema

ALIMTA (N=333) All Gradesa Grade 3-4a Toxicity (%) Toxicity (%) 53 17

Placebo (N=167) All Gradesa Grades 3-4a Toxicity (%) Toxicity (%) 34 4.8

15 9

4.8 3.9

4.8 0.6

0.6 0

18

4.5

11

0.6

12 6 5

0.3 0 0.3

2.4 1.8 2.4

0 0 0

5

0

3.6

0

Adverse reactions of any severity (all grades) occurring more frequently (≥5%) or Grade 3-4 adverse reactions occurring more frequently (≥2%) in ALIMTA-treated patients compared to those receiving placebo b NCI CTCAE Criteria version 3.0 Administration of RBC (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0) were higher in the ALIMTA arm compared to the placebo arm. The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm. Incidence 1% to 5% Blood/Bone Marrow — thrombocytopenia General Disorders — febrile neutropenia Incidence Less than 1% Cardiovascular — ventricular tachycardia, syncope General Disorders — pain Gastrointestinal — gastrointestinal obstruction Neurologic — depression Renal — renal failure Vascular — pulmonary embolism No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%). Additional Experience Across Clinical Trials Sepsis, which in some cases was fatal, occurred in approximately 1% of patients. Esophagitis occurred in less than 1% of patients. 6.2

Postmarketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. 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. These reactions occurred with ALIMTA when used as a single-agent and in combination therapies. Blood and Lymphatic System – Immune-mediated hemolytic anemia Gastrointestinal — colitis, pancreatitis General Disorders and Administration Site Conditions — edema Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy. Respiratory — interstitial pneumonitis Skin — Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal. DRUG INTERACTIONS

7.1

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function [see Clinical Pharmacology (12.3)]. Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. ALIMTA® (pemetrexed for injection)

7.2

Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)]. Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/ m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA 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. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3

a

7

through Therapy designation pathway, we have been able to accelerate the ibrutinib development program for the benefit of patients,” he said. “Thus far, more than 1,600 patients have been treated in our studies with ibrutinib and we are making excellent progress in the development and preparation for commer-

PV 8926 AMP

Nursing Mothers It is not known whether ALIMTA or its metabolites are 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 ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother. 8.4

Pediatric Use Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a  Phase  2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea. The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults. 8.5

Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions  to this drug may be greater in patients with impaired renal function. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)]. Of 3,946 patients (34.0% ≥65) studied across the five clinical trials [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in patients <65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia. 8.6

Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7

Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment. 8.8

Gender Of 3,946 patients (Male 70.5% ) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients. 8.9

Race Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients. 10

OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, ALIMTA® (pemetrexed for injection)

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cialization of this investigational drug,” noted Bob Duggan, CEO and Chairman of Pharmacyclics. “As of today, we have initiated seven phase III studies together with our partner Janssen and have currently registered with the U.S. National Institute of Health 31 clinical trials using ibrutinib.” n


The ASCO Post | JULY 25, 2013

PAGE 30

FDA Update

Roche Files for Cervical Cancer Primary Screening Indication for cobas HPV Test

R

oche recently announced it has submitted a Premarket Approval (PMA) supplement to the FDA seeking the addition of a cervical

cancer primary screening indication for the cobas HPV Test. Approval of the expanded indication would mean the cobas HPV Test could be

used as the first-line test rather than Pap cytology as part of a cervical cancer screening strategy. The filing includes new 3-year follow-up

infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days. The ability of ALIMTA to be dialyzed is unknown. 13

data from the ATHENA study, the landmark U.S.-based registration trial, including more than 47,000 women screened for cervical disease with Pap and human papillomavirus (HPV) tests. The cobas HPV Test is the only FDA-approved test that provides pooled results for known high-risk genotypes and simultaneously provides individual results for the two

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. 17

PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (PPI) Instruct patients to read the patient package insert before initiating ALIMTA. • Instruct patients on the need for folic acid and vitamin B12 supplementation to reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. • Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia. • Instruct patients to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear. • Instruct patients to inform their physician of all concomitant prescription or over-thecounter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

highest-risk genotypes, HPV 16 and HPV 18. Data from the ATHENA study show strategies that incorporate high-risk HPV DNA testing with simultaneous detection of genotypes 16 and 18 as an initial screening test can detect more cervical disease than strategies that use Pap alone. The cobas HPV Test received FDA approval in April 2011 to screen patients aged 21 years and older with abnormal Pap test results and to co-test with Pap in women aged 30 to 65 to assess the presence or absence of high-risk HPV genotypes. n

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/Safety/MedWatch. Additional information can be found at www.AlimtaHCP.com Literature revised: May 1, 2013

The ASCO Post

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Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved. PV 8926 AMP PM HCP BS NSCLC1M 14May 2013 ALIMTA® (pemetrexed for injection)

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ASCOPost.com | JULY 25, 2013

PAGE 31

12th International Conference on Malignant Lymphoma Hematology

New Research on Combination Chemotherapy, Prognostic Biomarkers, and PET-guided Radiation Therapy in B-cell Malignancies By Matthew Stenger

T

he 12th International Conference on Malignant Lymphoma was held June 19-22, 2013, in Lugano, Switzerland. Over 3,000 hematologists, clinical oncologists, pathologists, and leading researchers attended the meeting, which featured new research on B-cell malignancies, follicular lymphoma, as well as updated data on ibrutinib in chronic lymphocytic leukemia. The ASCO Post has selected several key abstracts for summary in the following roundup.

Biomarkers in Diffuse Large B-cell Lymphoma In studies to identify prognostic factors in diffuse large B-cell lymphomas, Thierry J. Molina, MD, PhD, of Paris Descartes University, and colleagues assessed expression of MYC, BCL2, MYC/BCL2, IgM, and germinal center B-cell–like and non–germinal center B-cell–like subtypes in a large series of patients with de novo disease treated with rituximab (Rituxan) and anthracycline-based chemotherapy. Multivariate analysis showed that BCL2 overexpression and the non–germinal center B-cell–like subtype were significantly associated with poorer progression-free survival and overall survival.1 The study involved 670 patients with de novo CD20-positive diffuse large B-cell lymphoma enrolled in six GELA (Groupe d’Etudes des Lymphomes de l’Adulte) LNH-03 trials and stratified according to age and age-adjusted international prognostic index (IPI). Of these, 237 had received intensive R-ACVBP (doseintensive rituximab plus doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) and 433 had received R-CHOP/Rmini-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Tumor samples were analyzed by immunohistochemistry using CD10, BCL6, MUM1, MYC (40% threshold), BCL2 (70% threshold), and IgM an-

tibodies on tissue microarrays. Overall, 304 patients (45.4%) were classified as germinal center Bcell–like subtype and 366 (54.6%) as non–germinal center B-cell–like subtype according to the Hans algorithm. Tumors were positive for IgM in 52.4% of cases, 29.5% of cases were MYC-positive, 55.3% were BCL2-positive, and 21% were positive for BCL2/MYC coexpression. Progression-free survival and overall survival were significantly worse among patients with high IPI score (P < .0001 for both progression-free and overall survival), non– germinal center B-cell–like subtype (P < .0001 for both), and IgM-positive (P < .0001 for progression-free survival, P = .02 for overall survival), MYC-positive (P < .001, P  < .01), BCL2-positive (P < .001 for both), and MYC/BCL2-positive (P = .003, P = .005) tumors.

The investigators concluded, “Our study confirmed the relevance of immunohistochemistry to identify significant prognostic biomarkers for clinical use. Above all, we fully validated the strong and independent prognostic value of the Hans algorithm, daily used by the pathologists to subtype diffuse large B-cell lymphoma, as well as BCL2 overexpression.”

Vitamin D Deficiency in B-cell Lymphoma Vitamin D deficiency recently was shown to be associated with worse outcome in patients with nonHodgkin lymphoma. To determine whether such an association exists in patients with aggressive B-cell lymphoma, Jörg T. Bittenbring, MD, of Saarland University Medical School, Germany, and colleagues in the German High-Grade Non-

Key Findings from Lugano ■ Progression-free survival and overall survival were significantly worse

among patients with diffuse large B-cell lymphoma with high IPI score, non–germinal center B-cell–like subtype, and IgM-positive, MYC-positive, BCL2-positive, and MYC/BCL2-positive tumors.

■ In elderly patients with diffuse large B-cell lymphoma, vitamin D deficiency (< 10 ng/mL) was associated with poorer event-free survival and overall survival in patients receiving R-CHOP and poorer overall survival in those receiving CHOP without rituximab.

■ Chlorambucil plus rituximab significantly prolonged event-free and

progression-free survival compared with either agent alone in patients with extranodal marginal zone B-cell lymphoma.

On multivariate analysis, in addition to IPI score, only BCL2 overexpression and non–germinal center B-cell–like subtype predicted significantly worse progression-free survival (P = .0002 and P = .002, respectively) and significantly worse overall survival (P = .03 and P = .002, respectively). The prognostic values of BCL2 (P = .002 for progression-free survival and P = .02 for overall survival) and non–germinal B-cell–like subtype (P = .002 for both progression-free survival and overall survival) were confirmed when analysis was limited to patients treated with R-CHOP.

Hodgkin Lymphoma Study Group analyzed the relationship between serum vitamin D levels and outcome in elderly patients with diffuse large B-cell lymphoma receiving CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or RCHOP.2 The results were also reported earlier at the 2013 ASCO Annual Meeting in Chicago.3 Vitamin D deficiency was associated with significantly reduced event-free survival and overall survival in patients receiving R-CHOP and significantly reduced overall survival in those receiving CHOP. In the study, 25-OH vitamin  D

serum levels were measured by chemoluminescence immunoassay in elderly patients receiving six or eight cycles of CHOP with or without rituximab. Of 359 patients, 193  (54%) had vitamin D deficiency (<  10 ng/mL) and 165 (46%) had vitamin D insufficiency (10–30 ng/mL). Among patients receiving R-CHOP, those with vitamin D deficiency had 3-year event-free survival of 59% and 3-year overall survival of 70% compared with 79% and 82%, respectively, in patients without vitamin D deficiency. In a multivariate analysis adjusting for IPI risk factors, these differences were significant for both event-free survival (hazard ratio [HR] = 2.1, P = .008) and overall survival (HR = 1.9, P = .040). In multivariate analysis among patients receiving CHOP without rituximab, those with vitamin D deficiency had a significantly poorer overall survival (HR = 1.8, P = .025) but not event-free survival (HR = 1.2, P = .388) compared with those with higher vitamin D levels. The results were confirmed in an independent validation set of 63 patients in the prospective RICOVER-no-Rx study. As stated by the investigators, “Vitamin D deficiency is associated with a significantly worse outcome of patients with diffuse large B-cell lymphoma treated with R-CHOP. The stronger adverse effect of vitamin D deficiency in patients receiving rituximab suggests that vitamin D deficiency interferes with the mechanisms of action of this antibody. A prospective study evaluating the effects of vitamin D [supplementation] on outcome of patients receiving R-CHOP is warranted.”

Chlorambucil plus Rituximab in Extranodal Marginal Zone B-cell Lymphoma The International Extranodal Lymphoma Study Group (IELSG)-19 trial is the largest randomized trial in extranodal marginal zone B-cell lymphoma conducted continued on page 32


The ASCO Post | JULY 25, 2013

PAGE 32

12th International Conference on Malignant Lymphoma B-cell Malignancies continued from page 31

to date. As reported by Emanuele Zucca, MD, of the Oncology Institute of Southern Switzerland, and colleagues, preliminary final results of the trial indicate that the combination of chlorambucil (Leukeran) and rituximab resulted in improved event-free and progression-free survival compared with either agent alone although no differences in overall survival were observed.4 In the trial, patients with disseminated lymphoma or localized disease not suitable for local therapy were randomized to receive daily chlorambucil 6 mg/m2 for 6 weeks, with patients with response or stable disease receiving 6 mg/m2 daily for 14 consecutive days every 28 days for four cycles; intravenous rituximab 375 mg/m2 on days 1, 8, 15, 22, 56, 84, 112, and 140; or both. The preliminary analysis included 393 patients with complete data, consisting of 130 patients in the chlorambucil group, 132 in the rituximab group, and 131 in the combination group. The primary site of lymphoma was the stomach in 43% of patients, lymph nodes were involved in 34%, 81% had low or low-intermediate International Prognostic Index scores, and 8% of patients had received prior local therapy. With a median follow-up of 67 months, 5-year event-free survival, the primary endpoint of the trial, was 70% in the combination group compared with 52% in the chlorambucil group (P = .0005) and 51% in the rituximab group (P = .0015). Progression-free survival was also significantly longer in the combination group compared with the chlorambucil group (P = .0128) and the rituximab group (P = .0058). Overall survival was 90% at 5 years in the total population, with no significant differences between treatment arms. No unexpected severe side effects were reported. Hematologic toxicity was more pronounced in the combination group. The investigators concluded, “This is the largest randomized study ever conducted in extranodal marginal zone B-cell lymphoma and is the first trial to compare chemotherapy vs rituximab and vs the combination of both. Longer eventfree survival and progression-free survival were attained in the combi-

nation arm but this did not translate into improved overall survival.”

PET-guided Radiation in Patients with Advanced B-cell Lymphoma Residual masses are often detected on post-therapy computed tomography (CT) scans in patients with diffuse large B-cell lymphoma, and the potential role of consolidative radiation therapy in such cases remains undefined. An analysis of the use of PET-guided radiation therapy presented by Laurie H. Sehn, MD, and colleagues from the British Columbia Cancer Agency indicated favorable outcomes with

with curative-intent R-CHOP who underwent a post-therapy PET scan. Patients in complete remission on CT, HIV-infected patients, and patients with primary progressive disease, primary mediastinal large B-cell lymphoma, or transformed lymphoma were not included in the analysis. A total of 262 patients were included in the analysis. Patients had a median age of 65 years, 60% were male, 69% had stage III/IV disease, 42% had a bulky site > 10 cm, and 48% had International Prognostic Index scores of 3 to 5. Of these patients, 167 (64%) were PET-negative, 82 (31%) were PET-positive,

tients with PET-negative residual CT abnormalities also have a favorable outcome and should be spared unnecessary toxicity.”

Ibrutinib in CLL with 17p Deletion The 17p deletion in chronic lymphocytic leukemia (CLL) is associated with worse outcome in patients receiving standard chemotherapy. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has shown durable antitumor activity in high-risk CLL.

Key Findings from Lugano ■ Four-year overall survival in PET-positive patients receiving radiation

therapy (85%) was similar to that in PET-negative patients (83%) not receiving radiation therapy and better than that in PET-positive patients not receiving radiation therapy (30%).

■ Ibrutinib produced rapid and durable control of disease in both treatmentnaive and relapsed/refractory patients with 17p deletion chronic lymphocytic leukemia.

PET-guided radiation therapy in select patients.5 A policy has been in place in British Columbia (BC) since 2005 that recommends post-therapy PET evaluation for patients with advancedstage diffuse large B-cell lymphoma who have residual masses > 2 cm on CT, with radiation therapy being administered to PET-positive sites

Laurie H. Sehn, MD

when feasible. Patients with a negative PET scan are observed irrespective of initial or residual bulk, and patients who are PET-positive but not suitable for radiation therapy are treated according to physician discretion. The BC Cancer Agency Lymphoid Cancer Database was used to identify all newly diagnosed patients with advanced-stage diffuse large B-cell lymphoma between January 2005 and February 2012 treated

and 13 (5%) had indeterminate PET findings. Of the PET-positive patients, 60 (73%) received radiation therapy (30-45 Gy, 56 in single and four in multiple fields); of the 21 not receiving radiation therapy, 13 were not amenable to treatment, physicians decided against treatment in 7, and 2 had negative biopsy. One PET-negative patient received radiation therapy. The median follow-up for living patients was 45 months. Relapse occurred in 10 of 60 PET-positive patients receiving radiation therapy, with in-field relapse occurring in 6. Four-year rates of freedom from progression and overall survival in PETpositive patients receiving radiation therapy (81% and 85%) were similar to those in PET-negative patients not receiving radiation therapy (74% and 83%) and better than those in PETpositive patients not receiving radiation therapy (33% and 30%). The investigators concluded, “Patients with advanced-stage diffuse large B-cell lymphoma with residual CT abnormalities after RCHOP who receive consolidative radiation therapy to sites of PET positivity have an unexpectedly favorable outcome, strongly supporting the rationale for the use of PET-guided radiation therapy. Pa-

Adrian Wiestner, MD, PhD

In a phase II study of ibrutinib in patients who had CLL with 17p deletion, Adrian Wiestner, MD, PhD, of the National Institutes of Health, and colleagues found that that ibrutinib achieves rapid and durable control over disease and is associated with an acceptable safety profile.6 Findings were available for the first 29 patients in the trial, with a median follow-up of 9 months. In the trial, treatment-naive patients (n = 15, age range 33–82 years) and patients with relapsed/refractory CLL (n = 14, age range 56–79 years) received oral ibrutinib 420 mg daily until disease progression. High-risk disease (Rai stage III/IV) was present in 66% of patients. At 6 months, 88% of 25 evaluable patients had a nodal response (70% median reduction in lymph node size), 48% had a partial response by International Workshop on CLL (IWCLL) criteria, and 40% had a partial response with lymphocytosis. One patient had progressive disease (presumed transformation). Nodal response was observed in 93% of the patients with relapsed/ refractory disease and in 82% of treatment-naive patients. The estimated event-free survival at 12 months was 90%. All patients exhibited a reduction in splenomegaly, with a median reduction in spleen volume of 446 mL (46%) from baseline. Bone marrow continued on page 36


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The first antibody-drug conjugate (ADC) for HER2-positive (HER2+) metastatic breast cancer

Indication KADCYLA™ (ado-trastuzumab emtansine) injection, for intravenous use, as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

Important Safety Information Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY • Do Not Substitute KADCYLA for or with Trastuzumab • Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function • Embryo- Fetal Toxicity: Exposure to KADCYLA can result in embryo- fetal death or birth defects. Advise patients of these risks and the need for effective contraception Please see brief summary of full Prescribing Information on following pages for additional important safety information, including Boxed WARNINGS.


NOW APPROVED Additional Important Safety Information Pulmonary Toxicity • Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in clinical trials with KADCYLA. In EMILIA the overall frequency of pneumonitis was 1.2% • Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis Infusion-Related Reactions, Hypersensitivity Reactions • Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the overall frequency of IRRs in patients treated with KADCYLA was 1.4% • KADCYLA treatment should be interrupted in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR

HER2 Testing • Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA approved tests by laboratories with demonstrated proficiency Extravasation • In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration Nursing Mothers • Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother Pregnancy Registry • Encourage women who may be exposed to KADCYLA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720

• Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate

Adverse Reactions • The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue

Neurotoxicity • In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group

You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/ medwatch or calling 1-800-FDA-1088.

Thrombocytopenia • In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group

• Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2

© 2013 Genentech USA, Inc. All rights reserved. TDM0001176100 Printed in USA. (02/13)


In the Phase III EMILIA trial (N=991) versus lapatinib + capecitabine:

Single-agent KADCYLA significantly 1 improved survival PRIMARY ENDPOINT: OVERALL SURVIVAL (OS) 100

30.9 months

90

Proportion surviving (%)

80

HR=0.682 95% CI: 0.55, 0.85 P=0.0006

70 60 50

25.1 months

40 30 20

KADCYLA (n=495) No. of events: 149 lapatinib + capecitabine (n=496) No. of events: 182

10 0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

32

34

36

164 133

136 110

111 86

86 63

62 45

38 27

28 17

13 7

5 4

Months No. at risk: 495 KADCYLA lapatinib + 496 capecitabine

485 471

474 453

457 435

439 403

418 368

349 297

293 240

242 204

197 159

Patients received KADCYLA (3.6 mg/kg IV, q3w) or lapatinib (1250 mg po qd, Days 1-21) + capecitabine (1000 mg/m2 po bid, Days 1-14) until disease progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) assessed by independent review committee, OS, and safety.1,2

• KADCYLA increased median OS by 5.8 months vs lapatinib + capecitabine1 • 50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.55, 0.77; P<0.0001)1 • The most common NCI-CTCAE (version 3) adverse reactions (ARs) Grades ≥3 (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

References: 1. KADCYLA Prescribing Information. Genentech, Inc. February 2013. 2. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.

Please see brief summary of full Prescribing Information on following pages for additional important safety information, including Boxed WARNINGS. For more information on KADCYLA, please visit KADCYLA.com


The ASCO Post | JULY 25, 2013

PAGE 36

12th International Conference on Malignant Lymphoma B-cell Malignancies continued from page 32

biopsy at 6 months in 23 patients showed a median 76% reduction from baseline in tumor burden as assessed by immunohistochemistry for CD79a. Fluorescence in situ hybridization measurement of percent of tumor cells with the 17p deletion

at 6 months in 18 patients showed a reduction from baseline in 15 patients (median reduction, 55%), no change in 1, and an increase in 3 patients. Treatment was well tolerated, with nonhematologic toxicities of grade 3 or higher observed in 14% of patients. Two deaths occurred dur-

ing the study and were not considered treatment-related. The investigators concluded, “Ibrutinib as a single agent is effective in both treatment-naïve and relapsed/refractory patients with 17p deletion CLL, S:6.875” achieving rapid control over disease in blood, nodes, spleen, and marrow that is durable with an acceptable safety

KADCYLA™ (ado-trastuzumab emtansine) Injection for intravenous use Initial U.S. Approval: 2013 This is a brief summary of information about KADCYLA. Before prescribing, please see full Prescribing Information. Do Not Substitute KADCYLA for or with Trastuzumab WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action. If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of KADCYLA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. (2.2, 5.1) • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. (2.2, 5.2) • Embryo-Fetal Toxicity: Exposure to KADCYLA can result 5.4 Pulmonary Toxicity in embryo-fetal death or birth defects. Advise patients Cases of interstitial lung disease (ILD), including pneumonitis, of these risks and the need for effective contraception. some leading to acute respiratory distress syndrome or fatal (5.3, 8.1, 8.6) outcome have been reported in clinical trials with KADCYLA. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) 1 INDICATIONS AND USAGE has been reported, with one case of grade 3 pneumonitis. Signs KADCYLA™, as a single agent, is indicated for the treatment and symptoms include dyspnea, cough, fatigue, and pulmonary of patients with HER2-positive, metastatic breast cancer who infiltrates. These events may or may not occur as sequelae of previously received trastuzumab and a taxane, separately or in infusion reactions. In the randomized trial (Study 1), the overall combination. Patients should have either: frequency of pneumonitis was 1.2% [see Adverse Reactions (6.1)]. • Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. completing adjuvant therapy. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies (14.1)]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2)]. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment. In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension but with normal transaminases and no manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued. 5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution’s normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2)]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies (14.1)].

profile. Ibrutinib will be further investigated as a strategy for these high-risk patients.” n Disclosure: Drs. Molina, Bittenbring, Zucca, Sehn, and Wiestner reported no potential conflicts of interest.

References 1. Molina TJ, Briere J, Copie-Bergman C, et al: Overexpression of MYC,

and 13.5% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2)]. 5.8 HER2 Testing Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 5.9 Extravasation In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

Patients with dyspnea at rest due to complications of advanced 6 ADVERSE REACTIONS malignancy and co-morbidities may be at increased risk of The following adverse reactions are discussed in greater detail in other sections of the label: pulmonary toxicity. • Hepatotoxicity [See Warnings and Precautions (5.1)] 5.5 Infusion-Related Reactions, Hypersensitivity Reactions • Left Ventricular Dysfunction [See Warnings and Precautions (5.2)] Treatment with KADCYLA has not been studied in patients who • Embryo-Fetal Toxicity [See Warnings and Precautions (5.3)] had trastuzumab permanently discontinued due to infusion-related • Pulmonary Toxicity [See Warnings and Precautions (5.4)] reactions (IRR) and/or hypersensitivity; treatment with KADCYLA is • Infusion-Related Reactions, Hypersensitivity Reactions [See not recommended for these patients. Warnings and Precautions (5.5)] Infusion-related reactions, characterized by one or more of • Thrombocytopenia [See Warnings and Precautions (5.6)] the following symptoms − flushing, chills, pyrexia, dyspnea, • Neurotoxicity [See Warnings and Precautions (5.7)] hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In the randomized 6.1 Clinical Trials Experience trial (Study 1), the overall frequency of IRRs in patients treated with Because clinical trials are conducted under widely varying KADCYLA was 1.4% [see Adverse Reactions (6.1)]. In most patients, conditions, adverse reaction rates observed in the clinical trials of these reactions resolved over the course of several hours to a day a drug cannot be directly compared to rates in the clinical trials of after the infusion was terminated. KADCYLA treatment should be another drug and may not reflect the rates observed in practice.

In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, One case of a serious, allergic/anaphylactic-like reaction has been musculoskeletal pain, thrombocytopenia, headache, increased observed in clinical trials of single-agent KADCYLA. Medications to transaminases, and constipation. treat such reactions, as well as emergency equipment, should be The ADRs described in Table 6 were identified in patients with HER2positive metastatic breast cancer treated in a randomized trial available for immediate use. (Study 1) [see Clinical Studies (14.1)]. Patients were randomized 5.6 Thrombocytopenia to receive KADCYLA or lapatinib plus capecitabine. The median Thrombocytopenia, or decreased platelet count, was reported in duration of study treatment was 7.6 months for patients in the clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade KADCYLA-treated group and 5.5 months and 5.3 months for patients 3; 283 of 884 treated patients with any Grade). The majority of these treated with lapatinib and capecitabine, respectively. Two hundred patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the and eleven (43.1%) patients experienced ≥ Grade 3 adverse events nadir occurring by day 8 and generally improving to Grade 0 or in the KADCYLA-treated group compared with 289 (59.2%) patients 1 (≥ 75,000 /mm3) by the next scheduled dose. In clinical trials of in the lapatinib plus capecitabine-treated group. Dose adjustments KADCYLA, the incidence and severity of thrombocytopenia were for KADCYLA were permitted [see Dosage and Administration higher in Asian patients. Independent of race, the incidence of (2.2)]. Thirty-two patients (6.5%) discontinued KADCYLA due to an severe hemorrhagic events in patients treated with KADCYLA was adverse event, compared with 41 patients (8.4%) who discontinued low. lapatinib, and 51 patients (10.5%) who discontinued capecitabine In the randomized trial (Study 1), the overall frequency of due to an adverse event. The most common adverse events leading thrombocytopenia was 31.2% in the KADCYLA-treated group and to KADCYLA withdrawal were thrombocytopenia and increased 3.3% in the lapatinib plus capecitabine-treated group [see Adverse transaminases. Eighty patients (16.3%) treated with KADCYLA had Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was adverse events leading to dose reductions. The most frequent 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus adverse events leading to dose reduction of KADCYLA (in ≥ 1% of capecitabine-treated group. In Asian patients, the incidence of patients) included thrombocytopenia, increased transaminases, ≥ Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated and peripheral neuropathy. Adverse events that led to dose delays occurred in 116 (23.7%) of KADCYLA treated patients. The most group and 1.3% in the lapatinib plus capecitabine-treated group. Monitor platelet counts prior to initiation of KADCYLA and prior frequent adverse events leading to a dose delay of KADCYLA (in to each KADCYLA dose [see Dosage and Administration (2.2)]. ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, KADCYLA has not been studied in patients with platelet counts fatigue, increased transaminases and pyrexia. interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR [see Dosage and Administration (2.2)]. Patients should be observed closely for IRR reactions, especially during the first infusion.

<100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm3) [see Dosage and Administration (2.2)]. Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

5.7 Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any 5.3 Embryo-Fetal Toxicity Grade). In the randomized trial (Study 1), the overall frequency of KADCYLA can cause fetal harm when administered to a pregnant peripheral neuropathy was 21.2% in the KADCYLA-treated group

Table 6 reports the ADRs that occurred in patients in the KADCYLAtreated group (n=490) of the randomized trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

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12th International Conference on Malignant Lymphoma BCL2, MYC/BCL2, IgM, and nongerminal centre B cell-like immunophenotype predicts a worse progression-free survival and overall survival in a series of 670 de novo diffuse large B-cell lymphomas: S LYSA study. 12th International Conference on Malignant Lymphoma. Abstract 178. Presented June 19, 2013. 2. Bittenbring JT, Achenbach M,

Table 6 Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA Treatment Arm in the Randomized Trial (Study 1)

Adverse Drug Reactions (MedDRA) System Organ Class

KADCYLA (3.6 mg/kg) n=490 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) n=488 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Blood and Lymphatic System Disorders Neutropenia

6.7

2.0

9.0

4.3

Anemia

14.3

4.1

10.5

2.5

Thrombocytopenia

31.2

14.5

3.3

0.4

1.8

0.2

3.3

0.4

Lacrimation increased

3.3

0

2.5

0

Dry eye

3.9

0

3.1

0

Vision blurred

4.5

0

0.8

0

Conjunctivitis

3.9

0

2.3

0

Cardiac Disorders Left ventricular dysfunction Eye Disorders

Gastrointestinal Disorders Dyspepsia

9.2

0

11.5

0.4

Stomatitis

14.1

0.2

32.6

2.5

Dry Mouth

16.7

0

4.9

0.2

Abdominal pain

18.6

0.8

17.6

1.6

Vomiting

19.2

0.8

29.9

4.5 20.7

Diarrhea

24.1

1.6

79.7

Constipation

26.5

0.4

11.1

0

Nausea

39.8

0.8

45.1

2.5 0.2

General Disorders and Administration 8.2

0

3.1

0

Pyrexia

18.6

0.2

8.4

0.4

Asthenia

17.8

0.4

17.6

1.6

Fatigue

36.3

2.5

28.3

3.5

Nodular regenerative hyperplasia*

0.4

ND

0

0

Portal hypertension*

0.4

0.2

0

0

0

0.8

0

0

0.2

0

9.4

0.6

3.9

0

Blood alkaline phosphatase increased

4.7

0.4

3.7

0.4

Increased transaminases

28.8

8.0

14.3

2.5

2.7

9.4

4.7 0

Hepatobiliary Disorders

Immune System Disorders Drug hypersensitivity

2.2

Injury, Poisoning, and Procedural Infusion-related reaction

1.4

Infections and Infestations Urinary tract infection Investigations

Metabolism and Nutrition Disorders Hypokalemia

10.2

Musculoskeletal and Connective Tissue Disorders Myalgia

14.1

0.6

3.7

Arthralgia

19.2

0.6

8.4

0

Musculoskeletal pain

36.1

1.8

30.5

1.4

Nervous System Disorders Dysgeusia

8.0

0

4.1

0.2

Dizziness

10.2

0.4

10.7

0.2

Peripheral neuropathy

21.2

2.2

13.5

0.2

Headache

28.2

0.8

14.5

0.8

12.0

0.4

8.6

0.2

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and Mediastinal Disorders Pneumonitis

1.2

0

0

0

Dyspnea

12.0

0.8

8.0

0.4

Cough

18.2

0.2

13.1

0.2

Epistaxis

22.5

0.2

8.4

0

Skin and Subcutaneous Tissue Disorders Pruritus

5.5

0.2

9.2

0

Rash

11.6

0

27.5

1.8

5.1

1.2

2.3

0.4

Vascular Disorders Hypertension

* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient. ND = Not determined

All Grade %

Grade 3 %

Grade 4 %

All Grade %

Grade 3 %

Grade 4 %

Increased bilirubin

17

<1

0

57

2

0

Increased AST

98

7

<1

65

3

0

Increased ALT

82

5

<1

54

3

0

8.3 Nursing Mothers It is not known whether KADCYLA, specifically, is excreted in Decreased human milk, but IgG is known to be excreted in human milk. In 83 14 3 21 <1 <1 platelet count lactating monkeys, trastuzumab was excreted in small amounts Decreased (about 0.3% of maternal serum concentrations) in breast milk after 60 4 1 64 3 <1 hemoglobin post-partum doses of 25 mg/kg (about 7 times the clinical dose of Decreased KADCYLA). Because many drugs are excreted in human milk and 39 3 <1 38 6 2 neutrophils because of the potential for serious adverse reactions in nursing Decreased 33 3 0 31 6 <1 infants from KADCYLA, a decision should be made whether to potassium discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see Warnings and 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune Precautions (5.3)]. response to KADCYLA. 8.4 Pediatric Use A total of 836 patients from six clinical studies were tested at Safety and effectiveness of KADCYLA have not been established in multiple time points for anti-therapeutic antibody (ATA) responses pediatric patients. to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients 8.5 Geriatric Use tested positive for anti-KADCYLA antibodies at one or more post- Of 495 patients who were randomized to KADCYLA in the randomized dose time points. The presence of KADCYLA in patient serum at trial (Study 1) [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 the time of ATA sampling may interfere with the ability of this assay years of age and 11 patients (2%) were ≥ 75 years of age. In patients to detect anti-KADCYLA antibodies. As a result, data may not ≥ 65 years old (n=138 across both treatment arms) the hazard ratios accurately reflect the true incidence of anti-KADCYLA antibody for progression-free survival (PFS) and Overall Survival (OS) were development. In addition, neutralizing activity of anti-KADCYLA 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. antibodies has not been assessed. Population pharmacokinetic analysis indicates that age does not Immunogenicity data are highly dependent on the sensitivity and have a clinically meaningful effect on the pharmacokinetics of specificity of the test methods used. Additionally, the observed ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)]. incidence of a positive result in a test method may be influenced 8.6 Females of Reproductive Potential by several factors, including sample handling, timing of sample KADCYLA can cause embryo-fetal harm when administered during collection, drug interference, concomitant medication and the pregnancy. Counsel patients regarding pregnancy prevention and underlying disease. Therefore, comparison of the incidence of planning. Advise females of reproductive potential to use effective antibodies to KADCYLA with the incidence of antibodies to other contraception while receiving KADCYLA and for 6 months following products may be misleading. Clinical significance of anti-KADCYLA the last dose of KADCYLA. antibodies is not yet known. If KADCYLA is administered during pregnancy or if the patient 7 DRUG INTERACTIONS becomes pregnant while receiving KADCYLA, immediately report No formal drug-drug interaction studies with KADCYLA have exposure to the Genentech Adverse Event Line at 1-888-835-2555. been conducted. In vitro studies indicate that DM1, the cytotoxic Encourage women who may be exposed during pregnancy to enroll component of KADCYLA, is metabolized mainly by CYP3A4 and to in the MotHER Pregnancy Registry by contacting 1-800-690-6720 a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 [see Patient Counseling Information (17)]. inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 8.7 Renal Impairment telithromycin, and voriconazole) with KADCYLA should be avoided No dedicated renal impairment trial for KADCYLA has been due to the potential for an increase in DM1 exposure and toxicity. conducted. Based on the population pharmacokinetics, as well Consider an alternate medication with no or minimal potential to as analysis of Grade 3 or greater adverse drug reactions and dose inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is modifications, dose adjustments of KADCYLA are not needed in unavoidable, consider delaying KADCYLA treatment until the strong patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) CYP3A4 inhibitors have cleared from the circulation (approximately or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose 3 elimination half-lives of the inhibitors) when possible. If a strong adjustment can be recommended for patients with severe renal CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot impairment (CLcr less than 30 mL/min) because of the limited data be delayed, patients should be closely monitored for adverse available [see Clinical Pharmacology (12.3)]. reactions. 8.8 Hepatic Impairment In vitro studies in human liver microsomes indicates that DM1 is 8 USE IN SPECIFIC POPULATIONS metabolized by CYP3A4/5. The influence of hepatic impairment on 8.1 Pregnancy the pharmacokinetics of ado-trastuzumab emtansine conjugate has Pregnancy Category D [see Warnings and Precautions (5.3)] not been determined. Risk Summary 10 OVERDOSAGE KADCYLA can cause fetal harm when administered to a pregnant There is no known antidote for overdose of KADCYLA. In clinical woman. There are no adequate and well-controlled studies of trials, overdose of KADCYLA has been reported at approximately KADCYLA in pregnant women. No reproductive and developmental two times the recommended dose which resulted in Grade 2 toxicology studies have been conducted with ado-trastuzumab thrombocytopenia (resolved 4 days later) and one death. In the fatal emtansine. Nevertheless, two components of KADCYLA case, the patient incorrectly received KADCYLA at 6 mg/kg and died (trastuzumab and DM1) are known or suspected to cause fetal harm approximately 3 weeks following the overdose; a cause of death and or death when administered to a pregnant woman. If KADCYLA is a causal relationship to KADCYLA were not established. administered during pregnancy, or if a patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus. Patients should be advised to use effective contraception during treatment with KADCYLA and for 6 months following the last dose of KADCYLA. If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

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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Human Data In the post-marketing setting, treatment with trastuzumab during pregnancy has resulted in cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped. In one case, trastuzumab therapy resumed after the amniotic fluid index improved, and oligohydramnios recurred.

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0

7.6

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2)

KADCYLA (3.6 mg/kg)

Parameter

component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant monkeys at doses up to 25 mg/kg (about 7 times the clinical dose), trastuzumab crossed the placental barrier during the early and late phases of gestation. The resulting concentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings.

4. Zucca E, Concini A, Martinelli G, et al: Chlorambucil plus rituximab produces better event-free and progression-free survival in comparison with chlorambucil or rituximab alone in extranodal marginal zone B-cell lymphoma (MALT lymphoma): Final results of the IELSG-19 study. 12th International Conference on Malignant Lymphoma. Abstract 007. Presented June 19, 2013. 5. Sehn LH, Klasa R, Shenkier T, et al: Long-term experience with PETguided consolidative radiation therapy in patients with advanced-stage diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP. 12th International Conference on Malignant Lymphoma. Abstract 123. Presented June 21, 2013. 6. Wiestner A, Farooqui M, Valdez J, et al: Single agent ibrutinib (PCI32765) is highly effective in chronic lymphocytic leukaemia patients with 17p deletion. 12th International Conference on Malignant Lymphoma. Abstract 008. Presented June 19, 2013.

T:10.5”

7.1

Chills

Table 7 Selected Laboratory Abnormalities

Altmann B, et al: Association of 25OH vitamin D deficiency with worse outcome for elderly patients with aggressive B-cell lymphomas treated with CHOP plus rituximab (R): An analysis of the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). 2013 ASCO Annual Meeting. Abstract 8569. Presented June 2, 2013.

S:9.875”

Peripheral edema

Altmann B, et al: Inferior Outcome of elderly DLBCL patients with 25-OH vitamin D deficiency treated with CHOP plus rituximab: Results of the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). 12th International ConS:6.875” ference on Malignant Lymphoma. Abstract 103. Presented June 20, 2013. 3. Bittenbring JT, Achenbach M,

KADCYLA™ (ado-trastuzumab emtansine)

Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way Animal Data South San Francisco, CA There were no reproductive and developmental toxicology studies 94080-4990 conducted with ado-trastuzumab emtansine. DM1, the cytotoxic U.S. License No: 1048

4862200 Initial U.S. Approval: 02/13 KADCYLA is a trademark of Genentech, Inc. 02/13 TDM0001661000 © 2013 Genentech, Inc.


The ASCO Post | JULY 25, 2013

PAGE 38

ASCO Annual Meeting Targeted Therapy

Genomic Heterogeneity Can Lead to the Selection of ‘Incorrect’ Targeted Inhibitors By Charlotte Bath

G

enomic heterogeneity within tumors and among lesions varies widely, and “discordance among lesions could lead to the selection of the ‘incorrect’ targeted inhibitor,” according to David B. Solit, MD, of Memorial Sloan-Kettering Cancer Center, who spoke at the ASCO/American Association for Cancer Research (AACR) Joint Session during the 2013 ASCO Annual Meeting.1 In some cases, where a targeted inhibitor is given “in the wrong genetic context,” Dr. Solit explained, it can actually harm patients. For example, while BRAF mutation is known to predict response to vemurafenib (Zelboraf ) in patients with melanoma, patients with BRAF wild-type melanoma do not respond. Not only might they not benefit, “they actually might see acceleration of their tumor growth, which could be very harmful,” Dr. Solit said.

Key Questions “There are a lot of key questions for targeted therapy drug development that have to do with tumor heterogeneity, such as what samples should be profiled, is it adequate to profile the primary vs metastases, should we be performing more biopsies at time of progression, or relying on older samples that were collected at the time of diagnosis,” Dr. Solit stated. Another important question is whether tumor heterogeneity is “going to be an issue in one type of cancer more so than in another.” These questions are important, he said, “because it is already a reality in the clinic that we profile our patients molecularly and actually use that information to guide therapy.”

As an example, he cited patients with colorectal cancer who have KRAS mutations. “We don’t treat those patients with anti-EGFR therapies because they don’t respond,” Dr. Solit said. He referred to a 2008 study by Amado et al comparing panitumumab (Vectibix) monotherapy vs best supportive care in patients

metastatic samples in addition to about 800 unmatched samples “to see what the heterogeneity is within tumors and among primary and metastatic pairs,” Dr. Solit explained. The results showed “incredible concordance” for the genes studied (including RAS, BRAF, PIK3CA, and TP53) and the copy number alterations.

If we can understand the type of variability and the downstream pathways that are activated, we may be able to prevent the emergence of these drug-resistant clones. —David B. Solit, MD

with metastatic colorectal cancer.2 “The patients who had KRAS mutations had no benefit. All the benefit of the panitumumab was in patients with KRAS wild-type tumors,” in terms of response rates and progression-free survival. “This is an example of where, if we have the KRAS status wrong, because the tumor is heterogeneous, it is possible we are going to deny a patient effective therapy that they could otherwise have benefitted from,” Dr. Solit stated.

Discordance in KRAS Mutations In laboratory work at Memorial Sloan-Kettering, Dr. Solit and his colleagues looked at the “issue of potential heterogeneity between primary and metastatic disease very carefully in colorectal tumors,” he said. That work included profiling more than 100 matched pairs of frozen primary and

Genomic Heterogeneity in Tumors ■ Genomic heterogeneity within tumors and among lesions varies widely. ■ Discordance among lesions could lead to the selection of an inappropriate

targeted inhibitor, which in some cases could lead to acceleration of tumor growth.

■ Discordance in KRAS and BRAF between primary and metastatic colorectal tumors is due to multiple primary colorectal cancers in some patients, and metastatic sites should be biopsied to determine KRAS and BRAF status.

On the other hand, the discordance in KRAS is likely due to multiple primary colorectal cancers in some of these patients.  “The one example where we really are seeing dramatic discordance between primary and metastatic with things like BRAF and KRAS are these tumors in patients who have had a history of multiple primaries. I think we can make a clear clinical recommendation in those cases that if you have a colorectal cancer patient with a history of a polyp resection or a second primary, you probably should be biopsying the metastatic sites to determine KRAS and BRAF status,” Dr. Solit said. He emphasized that findings are very different from tumor to tumor. “In colorectal cancer, we are seeing incredible concordance among these potential drivers used as predictors of drug response. In melanoma, we’ve only looked at a small number of tumors so far, and there has been a very disquieting amount of discordance among those lesions.”

Self-seeding Phenomenon One possible explanation for “this incredible concordance in colorectal cancer between primary and metastatic cells,” Dr. Solit said, is the “self-seeding phenomenon,” initially demonstrated in breast cancer mod-

els and also seen in melanoma and colon cancer models. “It may be true that newer mutations are occurring in a metastasis, but it is possible that those mutations are now seeding back into the primary and into other tumors, thus minimizing the amount of discordance between primary and metastatic or different tumors than we otherwise would have seen or expected based upon a sequence of new mutations that were occurring over time,” he explained. “It is possible that tumor seeding of primary and metastatic, which is ongoing, will actually minimize this issue in the clinic. But it is also possible that while it is a minimal issue in colorectal cancer, it is going to be more of an issue in other tumor types,” Dr. Solit said. Another consideration to take into account is that, so far, the investigators have been looking at untreated tumors. “Under the stress of a targeted agent or other therapy, we may see a more distinct selection for clones that will cause greater heterogeneity over time than we see in the primary situation,” Dr. Solit said.

Cetuximab Resistance To address the issue of the selection of clones following exposure to drug therapy, Dr. Solit described a study looking at mechanisms of resistance to cetuximab (Erbitux). The investigators developed a resistant cell line and several different resistance models. “If you look at those resistant models, in terms of the ability of the drug to inhibit the pathway, you will find that cetuximab fairly effectively inhibits EGFR activation in both the parental and resistant cell lines, but in the resistant cell lines we don’t see the same degree of ERK inhibition that we see in the parental cell line,” Dr. Solit said. “Notably, that inability to inhibit ERK is accompanied by activation of RAS, and it is known that the finding of a RAS mutation causes de novo resistance. We suspected that maybe these tumors with acquired resistance to these cells that were selected also had RAS mutations.” The investigators profiled both cell lines and found that continued on page 40


Leaders in antibody-drug conjugate development Extending the reach of our technology through collaboration Company AbbVie Agensys, a subsidiary of Astellas Pharma Bayer Celldex Therapeutics Daiichi Sankyo Genentech, a member of the Roche Group Genmab GlaxoSmithKline Millennium: The Takeda Oncology Company Pfizer Progenics Pharmaceuticals There are more than a dozen collaborator antibody-drug conjugates (ADCs) in clinical development using Seattle Genetics’ technology, including 8 from Genentech.

Empowering antibodies by linking precision with potency Seattle Genetics has developed proprietary, industry-leading technology that employs a monoclonal antibody specific for a tumor-associated antigen, plus potent cytotoxic agents connected by stable linker systems designed to securely bind the cytotoxic agent to the antibody and then release the agent within the targeted cell.

Cytotoxic agent Designed to kill target cells when internalized and released.1,2

Linker Antibody Specific for a tumorassociated antigen that has restricted expression on normal cells.1,2

Attaches the cytotoxic agent to the antibody. Seattle Genetics’ linker system is designed to be stable in circulation and release the cytotoxic agent inside targeted cells.1-3

In addition to licensing its ADC technology, Seattle Genetics is developing 7 proprietary ADCs. The company’s robust pipeline of empowered antibody-based therapies and one approved ADC are designed to address significant unmet medical needs.

For more information about our ADC technology and to download an educational slide deck, please visit seattlegenetics.com/technology. REFERENCES: 1. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3):154-169. 2. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235-244. 3. Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the treatment of non–Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6):2358-2364.

Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2013 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA USP/COR/2013/0001(1)


The ASCO Post | JULY 25, 2013

PAGE 40

ASCO Annual Meeting Genitourinary Oncology

Surveillance Sufficient Follow-up for Most Patients with Stage I Seminoma By Alice Goodman

S

urveillance appears to be sufficient for men with stage  I seminoma treated with orchiectomy, sparing patients from side effects of adjuvant radiation or chemotherapy.

Mette Saksø Mortensen, MD

In a long-term study presented at the ASCO Annual Meeting,1 99.5% of men followed by surveillance alone were disease-free and alive 15 years postdiagnosis. The researchers identified prognostic factors associated with relapse, as well, which should help to identify high-risk patients who require a more intensive follow-up program.

Largest Stage I Seminoma Study “To our knowledge, this is the largest study with the longest follow-up of surveillance for stage I seminoma ever performed. In this series, 80% of patients avoided unnecessary adjuvant treatment after orchiectomy, and only 19% relapsed. We believe surveillance is a safe strategy for stage I patients,” stated Mette Saksø Mortensen, MD, a PhD student from the Department

Genomic Heterogeneity continued from page 38

“in both cases, as we treat with increasing passages of cetuximab, you find the emergence of these KRAS mutant clones,” Dr. Solit reported. With deep-sequencing techniques, the investigators found that they were selecting out preexisting mutations under selective pressure

Visit

of Oncology at Copenhagen University Hospital, Denmark. Seminoma is a common form of testicular cancer, and approximately 80% of seminoma patients present with stage I. The primary treatment for stage I disease is orchiectomy. In many countries this is followed by adjuvant radiotherapy or adjuvant chemotherapy. Only a few countries offer surveillance instead of adjuvant treatments after orchiectomy. The retrospective study included 1,822 men with stage I seminoma diagnosed between 1984 and 2007 and followed by a 5-year surveillance program after surgery. Surveillance was defined as 5 years of scheduled physical exams, chest x-ray exams, CT scans, and blood tests to measure tumor markers. Data from patients’ medical records were linked to national registries that recorded inpatient and outpatient clinic visits, relapses, and deaths.

Key Data Median follow-up was 15.4 years

EXPERT POINT OF VIEW

“T

hese patients are mainly young men,” stated Clifford A. Hudis, MD, ASCO President, commenting on a cohort study of surveillance for stage I seminoma at a press conference held before the Annual Meeting. “For these selected patients, neither chemotherapy nor radiation therapy is necessary, sparing them from the harmful side effects of these treatments without diminishing their chances for a long and healthy life. With surveillance alone Clifford A. Hudis, MD as a strategy, only 4 out of every 1,000 patients will die over a decade,” he noted. “The study suggests that more treatment is probably not necessary for stage I seminoma patients. These data should encourage doctors and patients to opt for surveillance and avoid unnecessary treatment,” Dr. Hudis commented. n Disclosure: Dr. Hudis reported no potential conflicts of interest.

(range, 0–28 years). Over that time, 355 relapses (19.5%) occurred; relapse was treated with radiotherapy in 216 patients, chemotherapy in 136 patients, and surgery in 3 patients. Only 10 patients (0.55%) died from testicular cancer or treatment-related causes. Median time to relapse was 13.7 months (range, 1.2–173.3 months); 72.4% relapsed within the first 2

Treatment of Stage I Seminoma ■ In the largest and longest study of patients with stage I seminoma, surveillance appeared to be sufficient for almost all of the study population.

■ Factors associated with risk of relapse included tumor size, vascular invasion, and elevated levels of human chorionic gonadotropin.

with the drug. “But I don’t think that is the whole story. I think that de novo mutations are just as critical in this situation,” Dr. Solit added. “I don’t think it is completely inevitable that all patients will develop resistance to targeted agents,” he concluded. “If we can understand the type of variability and the downstream pathways that are activated, we may be

able to prevent the emergence of these drug-resistant clones.” n

Disclosure: Dr. Solit has served in a consultant or advisory role for Abbott Laboratories, ArQule, AstraZeneca, Endo Pharmaceuticals, OrthoBiotech, Pfizer, Quintiles, and Roche. He has received research funding from AstraZeneca.

References 1. Solit DB: Genomic heterogeneity

years, 20.3% within years 2 to 5, and 7.3% relapsed after 5 years of followup. Prognostic factors associated with relapse were tumor size > 1.5 inches, invasion of blood or lymphatic vessels, and elevated levels of human chorionic gonadotropin. Dr. Mortensen said that these factors were also associated with a higher risk of relapse in previous smaller studies. n

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

Reference 1. Mortensen MS, Gundgaard MG, Lauritsen J, et al: A nationwide cohort study of surveillance for stage I seminoma. ASCO Annual Meeting. Abstract 4502. Presented June 1, 2013.

as a barrier to the development of targeted inhibitors. 2013 ASCO Annual Meeting. ASCO/AACR Joint Session. Presented June 2013. 2. Amado RG, Wolf M, Peeters, M, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634, 2008.

website at ASCOPost.com


ASCOPost.com | JULY 25, 2013

PAGE 41

Expert’s Corner Breast Cancer

Examining the Role Genetics Plays in Breast Cancer Onset A Conversation with Olufunmilayo I. Olopade, MD, FACP By Jo Cavallo The ASCO Post spoke with Dr. Olopade about her research in tumorsuppressor genes, the treatment of breast cancer in women at high risk— especially young women—and the development of better strategies for earlier detection and prevention of breast and ovarian cancers.

African–African American Connection Olufunmilayo I. Olopade, MD, FACP

I

nternationally known for her research in the molecular genetics of cancer, Olufunmilayo I. Olopade, MD, FACP, first became interested in oncology during medical school in Nigeria, where she cared for patients with Burkitt’s lymphoma. After moving to Chicago in 1983 to continue her medical education, Dr. Olopade became interested in the fundamental biology of cancer, especially solid tumors, and in finding ways to translate research in genetics to the development of more effective therapies for patients. In the early 1980s, Dr. Olopade was the recipient of ASCO’s Conquer Cancer Foundation Young Investigator Award, which she used to study chromosomal abnormalities in brain tumors. She later concentrated her research on the molecular genetics of breast cancer in diverse populations, cancer risk assessment, personalized approaches to prevention, and disparities in health outcomes. In 2005, she received a MacArthur Foundation Genius Grant, and the following year, was the recipient of the American Association for Cancer Research–Minorities in Cancer Research Jane Cooke Wright Memorial Lectureship Award. Dr. Olopade is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, Associate Dean for Global Health, and Director of the Center for Clinical Cancer Genetics at the University of Chicago Medicine. Her current laboratory research is focused on using whole-genome technologies and bioinformatics to develop novel approaches to risk assessment and precision cancer medicine.

Why did you become interested in studying the genetics of breast cancer? I’ve been fortunate to work in an area of the South Side of Chicago where the population is predominantly African American, and I was able to look at how genetics can be distributed across populations. I realized how much we know about cancer in majority populations and how little we know about cancers in minority and underserved populations. And as far back as

en, but more Hispanic women as well. If you look at the global distribution of cancer in women, the disease affects greater numbers of younger women in populations that have a lower incidence of breast cancer in general. So anywhere around the world where populations have not adopted a Western lifestyle, you are going to see that the face of breast cancer is that of a young woman. How do genetic mutations like BRCA1 and BRCA2 contribute to earlyonset breast cancer? We really haven’t had the tools to determine both the genetic contribution and the role of lifestyle and other environmental factors in the development of breast cancer. But we know that genes are influenced by lifestyle, culture, what you eat, and the environment. So as much as we need to study how these factors interact with one

We hear about the celebrities having prophylactic mastectomies, but what’s missing in the media reports are stories of regular women who are going about their lives and asking their doctors to help them manage their risk factors. This is where ASCO can come into the discussion and help doctors give women good information regarding their specific risks. —Olufunmilayo I. Olopade, MD, FACP

1997, when we started thinking about the role of genetics in the clinic, I felt that until we could get in-depth knowledge about minority populations, we would not know what to do with all the genetic variations that could potentially impact cancer outcomes. So part of my interest in researching the genetics of breast cancer came from the connection I was making between early-onset breast cancer in the young women coming into my clinic in Chicago and the women I saw in Nigeria. I asked a simple question: Were these cancers due to inherited gene mutations?

Early-onset Breast Cancer Does early-onset breast cancer affect more African American women than Caucasian women? Yes, early-onset breast cancer affects not only more African American wom-

another, we also need to ask, What is driving this cancer, is it the genetic mutation that is acquired, and how are those mutations acquired? Is it that the genetic mutations you were born with predispose you to getting cancer? We are finally now in a position to understand these questions, because we can do testing on the germ line and testing on the tumors and figure out which one is driving the development of the cancer.

Sequencing the Genome What led to the development of BROCA, the genetic screening panel that now includes BRCA1 and BRCA2 (since the Supreme Court ruling that human genes may not be patented)? After investigators found the BRCA1 gene mutation in 1994 and BRCA2 mutation in 1995, we began looking for the un-

explained inherited factors that contributed to breast cancer. We were expecting to find BRCA3, but we didn’t. What we did find were other altered genes that contributed to breast cancer risk. We now know there are about 18 genes that can be altered and thereby contribute to breast cancer risk, but we may learn about more genes in the future. BROCA, which was developed by Mary-Claire King, PhD, Tom Walsh, PhD, and their colleagues at the University of Washington School of Medicine, is a new way of sequencing the genome to find out how these genes can be altered and lead to cancer. The test currently detects mutations in about 40 genes, with a focus on mutations associated with breast and ovarian cancers.

Genetic Screening When should oncologists recommend genetic testing for their patients with breast cancer or ovarian cancer? ASCO has issued recommendations for when genetic counseling and testing should be offered to patients.1 In general, there are three reasons why oncologists may want to offer their patients genetic screening: To predict the risk of cancer for the patient and to help family members understand their own risk factors, because now we can actually do something about managing those risks. Increasingly, genetic test results can also influence choice of treatment after a cancer diagnosis. For example, a study we presented at this year’s ASCO Annual Meeting showed that magnetic resonance imaging (MRI) surveillance of women at high risk for breast cancer every 6 months is effective in early detection of aggressive breast cancer by detecting tumors less than 1 cm in diameter.2 Moreover, using MRI imaging eliminates exposing young women to excessive amounts of radiation in mammography screenings. This makes me much more optimistic that for many of these aggressive cancers, we can now do better risk assessments and use genetics to identify women at high risk for specific subtypes of breast cancer. We can then tailor strategies to manage that risk.

Prophylactic Mastectomy Are more women coming to your practice asking about prophylactic mastectomies since the actress Angelina Jolie went public continued on page 42


The ASCO Post | JULY 25, 2013

PAGE 42

News Breast Cancer

ASCO Releases Updated Guideline on Interventions for Women at Increased Risk for Breast Cancer

T

he American Society of Clinical Oncology (ASCO) recently issued a newly updated clinical practice guideline on pharmacologic prevention interventions for premenopausal and postmenopausal women who are at increased risk for breast cancer. Compared to the previous version of the guideline, this third update, published today in the Journal of Clinical Oncol-

Kala Visvanathan, MBBS, FRACP, MHS

ogy,1 strongly recommends discussing the use of tamoxifen with premenopausal women and tamoxifen and raloxifene (Evista) with postmenopausal women at increased risk. There is also a recommendation for discussing the option of exemestane as an alternative option for postmenopausal women. The update also stresses the need for ongoing research on approaches to increase tamoxifen and raloxifene use in breast cancer prevention among women

Genetics in Breast Cancer continued from page 41

with her decision to have a bilateral mastectomy? How are you advising those patients? Even before Ms. Jolie’s announcement, we had been seeing an epidemic of women coming into our clinic and asking to have a prophylactic mastectomy. Everybody still has a fear of getting cancer, and that’s why I’m excited about our research—because we know that having a genetic mutation doesn’t mean that the person will get cancer. A lot of work we are doing gives women more options, including regular MRI surveillance. We hear about the celebrities having prophylactic mastectomies, but what’s missing in the media reports are stories of regular women who are going about their lives and asking their doctors to help them manage their risk factors. This is where ASCO can come into the discussion and help doctors give

who are at higher risk of developing invasive breast cancer. Currently, only a small percentage of eligible women have the discussion of breast cancer risk reduction with their doctors.

Key Recommendations The key recommendations of the guideline are as follows: • Tamoxifen (20 mg per day orally for 5 years) should be discussed as an option to reduce the risk of invasive, estrogen receptor (ER)-positive breast cancer in premenopausal or postmenopausal women. • Raloxifene (60 mg per day orally for 5 years) should also be discussed as an option to reduce the risk of invasive, ER-positive breast cancer in postmenopausal women. • Exemestane (25 mg per day orally for 5 years) should be discussed as an alternative to reduce the risk of invasive, ER-positive breast cancer in postmenopausal women. This recommendation is based on encouraging data from a single clinical trial that showed up to a 70% reduction in overall and ER-positive invasive breast cancer incidence with exemestane compared to placebo over a 3-year period. All three agents should be discussed (including risks and benefits) with women aged 35 years or older without a personal history of breast cancer who are women good information regarding their specific risks, so they are not getting their information from the media.

Aggressive Treatment A study presented at the ASCO Annual Meeting showed that most women 40 or younger diagnosed with breast cancer are choosing mastectomy rather than lumpectomy plus radiation, and most of those choosing mastectomy also elect to have their noncancerous breast removed.3 Why do you think more women are choosing such aggressive treatment? We have failed in presenting these patients with alternative viewpoints. Women come to my clinic after being told by their oncologist, “If you don’t want to get cancer, why don’t you have both breasts removed?” At our cancer genetics education presentation at the ASCO meeting, we said it is important that we tell these patients they have options and that hav-

at increased risk of developing invasive breast cancer, based on risk factors such as the woman’s age, race, and medical and reproductive history. “Not every woman should use these preventive agents, but we believe women who are at increased risk for breast cancer should be given the option, because in some cases the magnitude of the risk reduction is large. For some women, these therapies can reduce the risk of breast cancer by up to 50%,” said Kala Visvanathan, MBBS, FRACP, MHS, Co-Chair of the Guideline Panel and Associate Professor of Epidemiology and Oncology at the Johns Hopkins Bloomberg School of Public Health and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

Risks and Benefits of Therapy The guideline provides new insight on the risks and benefits for tamoxifen and raloxifene use in postmenopausal women. The risk and benefit profile for both agents varies by age, race, level of breast cancer risk, and history of hysterectomy. The guideline emphasizes that women should discuss both the risks and benefits of these drugs with their doctors before deciding whether to take these drugs for prevention. “We now have a better understanding of the net health benefits of these interventions. This knowledge will help ing a genetic mutation doesn’t mean they will definitely get cancer. We want women to know about their risk for breast cancer and how to manage that risk. Cancer prevention is going to be increasingly emphasized, because we can’t tell every woman to remove every body part. Let’s give women options and tell them that cancer is curable when picked up early and cancer is preventable. As ASCO members, all of us have to make sure that women get that message.

Supreme Court Decision What was your reaction to the Supreme Court ruling in June that human genes could not be patented? It was a victory for genetic justice. And now the price for genetic testing will be less expensive and available to more people. As someone who is interested in health disparities, I feel that the

us identify those women in which the benefit is greater than the risk,” Dr. Visvanathan said. The guideline specifies that tamoxifen and raloxifene are not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or during prolonged immobilization. In addition, tamoxifen is not recommended for use in women who are pregnant, may become pregnant, or nursing mothers, and should not be used in combination with hormone therapy. ASCO has also developed clinical tools and resources to help doctors implement this guideline. The resources include a decision aid tool, which uses straightforward charts to explain the risks and benefits of breast cancer chemoprevention. ASCO has also developed a companion patient guide and graphic, available on ASCO’s cancer information website, www.cancer.net. More information on the new guideline and clinical tools and resources can be found at www.asco.org/guidelines/ bcrr. n Reference 1. Visvanathan K, Hurley P, Bantug E, et al: Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. July 8, 2013 (early release online).

Supreme Court got it right by supporting the most vulnerable of all. People with a genetic burden who need our help should not face unnecessary emotional and financial burden because they can’t afford the genetic test. n

Disclosure: Dr. Olopade reported no potential conflicts of interest

References 1. Robson ME, Storm CD, Weitzel J, et al: American Society of Clinical Oncology policy statement update: Genetic and genomic testing for cancer susceptibility. J Clin Oncol 28:893-901, 2010. 2. Guindalini RSC, Huang Y-C, Obeid E, et al: Breast cancer surveillance in high-risk women with magnetic resonance imaging every 6 months. 2013 ASCO Annual Meeting. Abstract 1506. Presented June 3, 2013. 3. Rosenberg SM, Sepucha K, Ruddy KJ, et al: Choosing mastectomy over lumpectomy. 2013 ASCO Annual Meeting. Abstract 6507. Presented June 3, 2013.


In the research of advanced cancers

What if the PD-1 checkpoint pathway played an important role in tumor growth? The programmed death 1 (PD-1) checkpoint pathway plays a key role in modulating the immune system. However, some tumors exploit this pathway to evade the bodyâ&#x20AC;&#x2122;s protective immune response to cancer1-5 In a normal state, the immune system recognizes tumors and can mount an active antitumor response6,7 Antigen-presenting cell

Step 1:

Tumor releases antigen8 T cells

Through tumor-immune surveillance, activated T cells can eradicate tumor cells from the body 6,7

Step 2:

Antigen-presenting cells activate T cells that proliferate, migrate to, and attack the tumor8

Tumor

One way that tumors can evade normal immune attack is by exploiting the PD-1 immune checkpoint pathway via the PD-1 receptor1,2,5

PD-L1 ligand

Tumor cell

PD-L2 ligand

PD-1 receptor

Inhibited T cell

Both PD-L1 and PD-L2 on the tumor cells bind to the PD-1 receptor on T cells to exploit the immune checkpoint pathway. This inhibits activated T cells and suppresses T-cell attack1,2,4,5

PD-1 receptor

By exploiting the PD-1 checkpoint pathway, cancer cells evade the immune response and continue to proliferate1,2,6,8 PD-L1=programmed death 1 ligand 1; PD-L2=programmed death 1 ligand 2. References: 1. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptopic receptor on cancer cells. Blood. 2008;111(7):3635-3643. 2. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 3. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 4. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. 5. Dong H, Strome SE, Salomao DR, et al.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 6. Hanahan D,Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 7. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 8. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489.

Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology. Learn more at www.bmsimmunooncology.com. Š2013 Bristol-Myers Squibb Company. All rights reserved. ONCUS13UB01112-02-01 06/13 Printed in USA.


The ASCO Post | JULY 25, 2013

PAGE 44

In the Clinic Hematology

Lenalidomide in Relapsed/Progressed Mantle Cell Lymphoma after Two Prior Therapies Including Bortezomib 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.

Indication On June 5, 2013, lenalidomide (Revlimid) was approved for treatment of patients with mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib (Velcade).1,2 Approval was based on overall response rate and duration of response in a single-arm, multicenter trial in 134 patients with mantle cell lymphoma who had relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. Patients were required to have received prior treatment with an anthracycline or mitoxantrone, cyclophosphamide, rituximab (Rituxan), and bortezomib, alone or in combination. Patients had to have an absolute neutrophil count ≥ 1,500/µL, platelet count ≥ 60,000/ µL, serum AST or ALT ≤ 3 × upper limit of normal unless there was documented evidence of liver involvement by lymphoma, serum total bilirubin

OF NOTE Lenalidomide carries boxed warnings for embryo-fetal toxicity, hematologic toxicity, and venous thromboembolism. ≤ 1.5 × upper limit of normal except in cases of Gilbert’s syndrome or documented liver involvement by lymphoma, and calculated creatinine clearance > 30 mL/min. Patients with creatinine clearance > 60 mL/min received lenalidomide at 25 mg once daily for 21 days every 28 days, and those with creatinine clearance ≥ 30 mL/min and < 60 mL/ min received 10 mg once daily for 21 days every 28 days. Patients had a median age of 67 years, 96% were Caucasian, 81% were male, and 86% had an ECOG performance status of 0 or

1. Furthermore, 61% had mantle cell lymphoma for at least 3 years, 72% had stage IV disease, 67% had a high or intermediate mantle cell lymphoma Prognostic Index Score, 57% had high tumor burden, 33% had bulky disease, 75% had extranodal disease. Approximately 53% had at least four prior systemic therapies, 29% had prior autologous bone marrow or stem cell transplantation, and 60% were demonstrated to be bortezomib-refractory. In the 133 patients evaluable for efficacy, overall response rate was 26%, including complete response or complete response–unconfirmed in 9 patients (7%) and partial response in

pairment, and 5 mg once daily following dialysis in patients requiring dialysis. Lenalidomide should be taken at about the same time each day, either with or without food. Treatment should be continued until disease progression or unacceptable toxicity. Treatment should be interrupted in patients developing thrombocytopenia or neutropenia, and complete blood counts should be followed weekly. Upon recovery, the lenalidomide dose should be reduced by 5 mg to no lower than 5 mg/d. Treatment should be discontinued in patients with a suspected allergic reaction to lenalidomide.

Expanded Indications for Lenalidomide in Mantle Cell Lymphoma ■ Lenalidomide (Revlimid) was approved for treatment of patients with

mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

■ The recommended starting dose of lenalidomide is 25 mg/d orally on

days 1 to 21 of repeated 28-day cycles, adjusted for renal impairment, and continued until disease progression or unacceptable toxicity.

25 (19%). The median duration of response among the 34 patients with a response was 16.6 months.

How It Works Lenalidomide is a thalidomide (Thalomid) analog with immunomodulatory, antiangiogenic, and antineoplastic properties. It inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells, mantle cell lymphoma, multiple myeloma, and del(5q) myelodysplastic syndromes in vitro. Immunomodulatory properties of the agent include activation of T cells and natural killer cells, increased numbers of natural killer T cells, and inhibition of proinflammatory cytokines (eg, tumor necrosis factor-α and interleukin-6) by monocytes.

How It Is Given The recommended starting dose of lenalidomide is 25 mg/d orally on days 1 to 21 of repeated 28-day cycles. Starting doses should be 10 mg once daily for moderate renal impairment, 15 mg every 48 hours for severe im-

Periodic monitoring of digoxin plasma levels is recommended in patients receiving lenalidomide, since digoxin exposure is increased with concomitant treatment. Patients taking such agents as erythropoietin-stimulating agents or estrogen-containing therapies may be at increased risk of venous thromboembolism. To avoid embryo-fetal exposure, lenalidomide is available only through a restricted distribution program, the Revlimid REMSTM program, formerly known as the “RevAssist®” program (information available at www.celgeneriskmanagement.com or 1-888423-5436).

Safety Profile The median duration of lenalidomide therapy in the mantle cell lymphoma trial was 95 days (range, 1–1,002), and 58% of patients received three or more cycles. The most common nonhematologic adverse events of any grade were fatigue (34%), diarrhea (31%), nausea (30%), and cough (28%); the most common grade 3 or 4 adverse events were pneumonia (9%),

OF NOTE Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells, mantle cell lymphoma, multiple myeloma, and del(5q) myelodysplastic syndromes in vitro. fatigue (7%), diarrhea (6%), and dyspnea (6%). Hematologic toxicities of any grade included neutropenia in 49%, thrombocytopenia in 36%, anemia in 31%, and leukopenia in 15%, with toxicity being grade 3 or 4 in 43%, 28%, 11%, and 7%, respectively. Grade 3 or 4 febrile neutropenia occurred in 6%. Adverse events caused dose interruption in 57% of patients, dose reduction in 38%, and treatment discontinuation in 19%. Lenalidomide carries boxed warnings for embryo-fetal toxicity, hematologic toxicity, and venous thromboembolism. It also carries warnings/ precautions for allergic reactions (hypersensitivity, angioedema, StevensJohnson syndrome, toxic epidermal necrolysis), including fatalities; tumor lysis syndrome, including fatalities; tumor flare reaction (observed during investigational use in chronic lymphocytic leukemia and lymphoma); hepatotoxicity (eg, hepatic failure, including fatalities); and second primary malignancies (observed in trials in multiple myeloma). Liver function must be monitored regularly during lenalidomide treatment, and patients with high tumor burden must be monitored for potential tumor lysis syndrome. Lenalidomide is contraindicated in pregnancy and in patients with demonstrated hypersensitivity to the agent. n References 1. U.S. Food and Drug Administration: Lenalidomide. Avalable at http://www. fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm355438.htm. Accessed July 1, 2013. 2. REVLIMID® (lenalidomide) capsules prescribing information, Celgene Corporation, June 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021880s034lbl.pdf. Accessed July 1, 2013.


Because Endocrine Monotherapy Can Only Take You So Far


In postmenopausal women with advanced HR+, HER2-negative breast cancer after failure of treatment with letrozole or anastrozole

Change the Treatment Paradigm With AFINITOR Plus Exemestane AFINITOR plus exemestane more than doubles median progression-free survival (PFS) over exemestane monotherapy1

Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

HR=0.45 [95% CI, 0.38-0.54] Log-rank P value: <0.0001

7.8 months Placebo plus exemestane: 3.2 months

AFINITOR plus exemestane:

PFS Probability (%)

80

60

Median PFS: 3.2 months

55%

Median PFS: 7.8 months

reduction in risk of progression or death2

40

20 AFINITOR plus exemestane (n/N=310/485) Placebo plus exemestane (n/N=200/239)

0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

Time (months)

• Median PFS was 7.8 months with AFINITOR® (everolimus) Tablets plus exemestane [95% CI, 6.9-8.5] vs 3.2 months with placebo plus exemestane

[95% CI, 2.8-4.1] (P<0.0001)1

PFS curves for the 2 treatment arms began to diverge at 6 weeks (the first tumor assessment)1,2 An independent central review confirmed a significant PFS improvement with AFINITOR plus exemestane treatment vs placebo plus exemestane1,2 • Median PFS was 11.0 months with AFINITOR plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6]

(HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

BOLERO-2=Breast Cancer Trials of Oral Everolimus; HR=hazard ratio.


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AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Important Safety Information.

• AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients • There have been reports of noninfectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR, some with

fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared with patients <65 years of age

• Oral ulceration is the most frequently occurring adverse event and occurred in 44% to 86% of AFINITOR-treated patients across the clinical trial

experience. Most of these events were grade 1/2. Grade 3/4 stomatitis was reported in 4% to 9% of patients

• Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have

also been reported; monitoring of laboratory tests is recommended

• The use of live vaccines and close contact with those who have received live vaccines should be avoided • AFINITOR can cause fetal harm when administered to a pregnant woman

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

References: 1. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2012. 2. Data on file. Study CRAD001Y2301. Novartis Pharmaceuticals Corp; 2012.


• Careful monitoring and appropriate dose adjustments for adverse

Important Safety Information. AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, patients should be managed with dose interruption until symptoms improve • The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 • AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred • Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR • Treatment of preexisting invasive fungal infections should be completed prior to starting treatment • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients • In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared to 2% in patients <65 years of age • Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2012 Novartis

reactions are recommended Laboratory Tests and Monitoring: • Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported • Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter • When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) • Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments Hepatic Impairment: • Exposure of everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), 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 Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%) • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%)

Please see Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

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AFB-1043056


AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009

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Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations]. Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), 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) and Clinical Pharmacology (12.3) in the full prescribing information]. For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. 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 this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.


The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 e Median duration of treatment 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration

Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo c

Key observed laboratory abnormalities are presented in Table 3. Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory Parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or 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]. Agents That May Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, 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 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]. 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 non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.


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B:14.25”

S:13”

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 two 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 Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, 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, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. 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. 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 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. Pediatric Use Pediatric use of AFINITOR Tablets is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in diseaserelated symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown. Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least one serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information].The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information]. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. 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 subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 and over. 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]. 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]. 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 (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, 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]. For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (ChildPugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) 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: Distributed by: Novartis Pharma Stein AG Novartis Pharmaceuticals Corporation Stein, Switzerland East Hanover, New Jersey 07936 © Novartis T2012-153 August 2012


The ASCO Post | JULY 25, 2013

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Direct from ASCO

ASCO Completes Electronic Data Sharing Standard for Breast Cancer Treatment

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SCO has completed the first phase in developing several sets of interoperability standards for cancer care data and overcoming the widespread inconsistencies that currently limit secure sharing of information between providers, patients, and researchers. The first standard, the Breast Cancer Treatment Plan and Summary Standard and Implementation Guide, was announced at the 2013 ASCO Annual Meeting and will be published later this summer. “This data standard will allow oncologists to share data dur-

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

ing care, but also provide a summary for primary care physicians and patients after treatment ends. ASCO and other oncology organizations can and will use it as a foundation for creating additional standards,” said ASCO Immediate Past President Sandra M. Swain, MD, FACP.

Improving Electronic Health Records The Society’s work in data standards is in conjunction with the development of CancerLinQ, a learning computer network that

5 most-accessed Top 10Top most-accessed articles recently published articles published in 2011 in in Journal of Clinical Oncology Journal of Clinical Oncology

What’s Hot in

JCO

JCO.org Treatment of Metastatic Colon Cancer: “The Times They Are A-Changing” by Nancy E. Kemeny

Randomized Controlled Trial of Cetuximab Plus Chemotherapy for Patients With KRAS Wild-Type Unresectable Colorectal Liver-Limited Metastases by Le-Chi Ye, et al

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update by Gary H. Lyman, et al

Magnitude of Trastuzumab Benefit in Patients With HER2Positive, Invasive Lobular Breast Carcinoma: Results From the HERA Trial by Otto Metzger-Filho, et al

Multicenter Phase II Study of Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma by Ken Ohmachi, et al

will collect and analyze cancer care data from millions of patient visits, together with expert guidelines and other evidence, to generate real-time, personalized guidance and quality feedback for physicians. All of ASCO’s health information technology efforts are based on the fact that future cancer care will depend on the ability to electronically share clinical information between practitioners.  However, electronic health records often contain data that cannot easily be shared among physicians or contributed to quality improvement, public health reporting or analytics.  In addition, the current exchange standards do not include disease-specific templates needed for continuity of cancer care.

Data Interoperability Standards Summit ASCO hosted a Data Interoperability Standards Summit in February of 2013 to encourage collaboration in developing standards that will overcome these barriers. The Society selected adjuvant treatment for breast cancer as the focus for the first oncology standard. The draft standard was approved by open ballot through

Health Level Seven International (HL7®), an accredited Standards Developing Organization (SDO) and the leading global SDO focused solely on health care, in May and the standard is expected to be published by HL7 and ready for implementation in summer of 2013. Major elements covered with the standard include: • Diagnosis (site, histology, and stage) • Pertinent patient health and comorbidity information • Surgical history and pathology • Goals of therapy • Chemotherapy regimen and dosage • Duration of treatment and number of cycles • Major chemotherapy side effects Future areas of focus for ASCO’s data standards initiative will include developing standards for other specific cancers, for additional types of data such as patient-entered information, or for additional cancer care priorities, such as survivorship.  n © 2013. American Society of Clinical Oncology. All rights reserved.

Cancer.Net Mobile App: Now in Spanish

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ancer.Net’s award-winning app for patients is now available in Spanish. If your patients are using a Spanish-language enabled iPhone, iPod touch, or iPad, they can use the app to access Cancer.Net’s Spanish content, as well as use interactive tools in Spanish to help track side effects

and manage medications. Look for the app in Android soon. Direct your patients to www.cancer.net/ app to download the Cancer.Net mobile app. n © 2013. American Society of Clinical Oncology. All rights reserved.


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Direct from ASCO

Young Investigator Awards and Career Development Awards Build a Pipeline of Cancer Researchers

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ehind the scenes, researchers are working to unlock the secrets of cancer in its many forms— researchers who are well acquainted with the human cost of this disease and who see the vast scientific and clinical opportunities for conquering it. Some are well established in their careers and have been conducting studies for years, while others are just starting out, full of passion and commitment to start their first project. When you are a young researcher, however, competing for grants to fund a potentially groundbreaking study can be incredibly challenging. This is where the Conquer Cancer Foundation comes in. Through its Young Investigator Awards (YIAs) and Career Development Awards (CDAs), the Foundation funds researchers early in their careers, at a time when energy and capacity for innovation outpace the years of experience needed to compete for funding.

Over $4 Million in Funding This year the Foundation was able to support the innovative work of more than 50 promising young researchers with YIAs and CDAs totaling over $4 million. The YIA provides $50,000 in research funding to promising physicians to support the transition from final years of training to fac-

ulty appointment and to encourage and promote quality research in clinical oncology. With this year’s 30th class of YIA grantees, more than $31 million has been awarded to over 750 researchers since the first YIA was given to Judith Kaur, MD, in 1984. Of equal importance, the CDA provides $200,000 in research

funding over 3 years to clinical investigators who have already received their initial faculty appointment, to establish an independent clinical cancer research program. Established in 1992, the CDA program has provided more than $37 million to over 200 recipients, helping to launch the careers of young cancer researchers around the world. As the application cycle for the 2014 grants opened July 1, the Foundation is not only looking for applicants who are seeking to answer the most compelling clinical questions, but also for people to join in its mission to build a pipeline of talent that will enrich cancer care and research for years to come. Visit www.conquercancerfoundation.org for more information or to make a gift in support of ambitious young researchers. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO Targets Health Disparities, Need for Research in Achieving Health Equity

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he American Society of Clinical Oncology (ASCO), the Association of Black Cardiologists (ABC), and the Heart Failure Society of America (HSFA) recently held a Capitol Hill Briefing to draw attention to health disparities among minority and underserved patients and opportunities to achieve health equity for all Americans. The briefing, sponsored by Representative Bobby Rush (D-Illinois), highlighted criti-

cal federal investments in research to help close the health disparities gap.

Removing Barriers to Cancer Care “In cancer, we can move toward health equity for all patients by strengthening research on health disparities and enrolling more underserved patients in clinical trials,” said Sandra M. Swain, MD, FACP, ASCO Immediate Past President.

In cancer, we can move toward health equity for all patients by strengthening research on health disparities and enrolling more underserved patients in clinical trials. —Sandra M. Swain, MD, FACP

“Research offers real hope to improving care for underserved groups and removing barriers that impede access to cancer care.” Briefing keynote speaker Gary H. Gibbons, MD, Director of the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health, highlighted the NHLBI’s Systems Science Approach to Addressing Health Inequities: Enabling Diverse Networks of Community Partners. “Minorities are disproportionately affected by a number of cardiovascular disorders,” said Joseph Hill, MD, PhD, Advocacy Chair of the Heart Failure Society of America. “Among those disorders, heart failure, a highly morbid and lethal diagnosis, is rampant. There is an urgent need to identify novel means of preventing, diagnosing, and treating this syndrome, which is already the

Joseph Hill, MD, PhD

number one discharge diagnosis in Medicare.” “Each year this briefing offers us an opportunity to communicate with Members of Congress and key staff regarding the ongoing need to address health-care disparities,” said Boisey Barnes, MD, founding member of the Association of Black Cardiologists. “We hope that attendees will spread the word to their colleagues about the continued on page 54


The ASCO Post | JULY 25, 2013

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Health Disparities continued from page 53

need for federal investments to help achieve health equity.”

Role of Research, States in Addressing Disparities The Institute of Medicine land-

mark report Unequal Treatment provides compelling evidence that racial, ethnic and socioeconomic disparities persist in medical care for a number of health conditions and services. The report calls for a more robust research agenda to reduce or eliminate racial and ethnic health-

care disparities, and to address some of the social factors that affect health-care outcomes.1 ASCO also highlighted the role of states in addressing health disparities. A recent Journal of Clinical Oncology analysis showed Delaware’s cancer control program was able to

reduce colorectal cancer mortality rates for blacks by 41%.2 The study provides analysis on a novel design and approach used to eliminate colorectal cancer disparities for the first time by a state cancer control program. The findings indicate that eliminating disparities in cancer screening, diagnosis, treatment, and mortality is an essential step toward improved health outcomes for all Americans with cancer. n © 2013. American Society of Clinical Oncology. All rights reserved. References 1. Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care; Smedley BD, Stith AY, Nelson AR (eds): Unequal treatment: Confronting racial and ethnic disparities in health care. Washington, DC, The National Academies Press, 2003. 2. Grubbs SS, Polite BN, Carney J, et al: Eliminating racial disparities in colorectal cancer in the real world: It took a village. J Clin Oncol. April 15, 2013 (early release online).

Save the Date Best of ASCO 2013 Best of ASCO® Chicago August 9-10, 2013 Best of ASCO® Los Angeles August 16-17, 2013 Best of ASCO® Boston August 23-24, 2013 For more information, visit boa.asco.org


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News Health-care Policy

ASCO Urges Administration to Provide Clear Affordable Care Act Guidance on Protecting Patient Access to Clinical Trials

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SCO has joined more than 50 other organizations in urging the Administration to issue regulations or guidance before January 2014 to ensure health plans implement an important provision of the Affordable Care Act that would remove a critical obstacle to patients interested in participating in research. In a jointly signed letter to the Department of Health and Human Services and the Department of Labor, ASCO and the other organizations called for clear federal guidance on coverage of routine medical costs for individuals participating in approved clinical trials, as required under section 2709 of the Public Health Service Act—a provision of the Patient Protection and Affordable Care Act that goes into effect on January 1, 2014.

Need for Uniform Coverage Nationwide A recent HHS and DOL announcement effectively leaves the implementation details of this provision up to the individual states, which is likely to produce a patchwork of uneven and unpredictable coverage that will confuse patients and their health-care providers and impact timely access to potentially life-extending research. According to the co-signed letter, “Implementation of this provision will be very uneven across the country and many consumers may be denied a new protection they should be guaranteed under the law.” “While the Administration has made it clear that insurance companies must proceed with compliance, it has left important details unaddressed,” said ASCO President Clifford A. Hudis, MD, FACP. “We know that insured patients with coverage for clinical trial participation have faced denials and delays even in those states that require such coverage, a situation that is unacceptable to patients for whom clinical trials of new therapies may represent their best hope for extension of life or a better quality of life. This also unnecessarily delays the development of better treatments for everyone.”  The letter builds on ASCO’s earlier advocacy efforts with 18 cancer organizations that resulted in submission of recommendations to federal agencies on how to implement the coverage requirement. ASCO is also developing

We know that insured patients with coverage for clinical trial participation have faced denials and delays, ... a situation that is unacceptable when clinical trials of new therapies may represent their best hope for extension of life or a better quality of life.

—Clifford A. Hudis, MD, FACP

detailed information on the new law for cancer patients, investigators, and research staff and will be closely tracking implementation of the law.

Four Key Issues ASCO and the other organizations signing the letter identified four key issues that should be addressed through federal rulemaking to ensure that the

clinical trials provision of the Affordable Care Act is fully implemented: • Prevention, Detection, and Treatment of Complications: Explicit safeguards should ensure that the prevention, detection, and treatment of complications arising from clinical trials are covered under the definition of “routine costs.”

Meaningful Access to Clinical Trials: Regulations should prevent group health plans and insurance issuers from requiring patients to travel unreasonable distances to enroll in a clinical trial with an innetwork provider. Prevention of Delays and Administrative Barriers: Safeguards should protect patients from delays and administrative barriers that undermine access to clinical trials, including preventing financial incentives arising from new delivery models from inadvertently creating barriers for patients to participate in clinical trials. Determining a Life-Threatening Condition: Determination about whether an individual is an appropriate candidate for participation in a trial that qualifies for coverage should be made by the patient’s health care professional. n

Societies Call for Protection of Patient Access to Clinical Trials American Academy of Neurology American Association for Cancer Research American Cancer Society Cancer Action Network American Childhood Cancer Foundation American Diabetes Association American Epilepsy Society American Heart Association/ American Stroke Association American Lung Association American Society for Gastrointestinal Endoscopy American Society of Clinical Oncology American Society of Hematology Association of American Cancer Institutes Association of Community Cancer Centers Autism Speaks Bladder Cancer Advocacy Network (BCAN) Children’s Cause for Cancer Advocacy Coalition of Cancer Cooperative Groups Debbie’s Dream Foundation: Curing Stomach Cancer Dravet Syndrome Foundation Epilepsy Foundation Families USA Fight Colorectal Cancer Friends of Cancer Research Hematology/Oncology Pharmacy Association Hydrocephalus Association International Cancer Advocacy Network (ICAN) International Myeloma Foundation Kidney Cancer Association Leukemia & Lymphoma Society

LIVESTRONG Foundation Lupus Foundation of America Melanoma Research Alliance (MRA) NAMI (National Alliance on Mental Illness) National Coalition for Cancer Research (NCCR) National Comprehensive Cancer Network National Health Council National Hemophilia Foundation National Lung Cancer Partnership National Multiple Sclerosis Society National Stroke Association North American Commission of the International League Against Epilepsy North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Oncology Nursing Society Ovarian Cancer National Alliance Pancreatic Cancer Action Network Parkinson’s Action Network Phelan-McDermid Syndrome Foundation Prevent Cancer Foundation Research Advocacy Network Sarcoma Foundation of America Society for Women’s Health Research (SWHR) Society of Gynecologic Oncology Susan G. Komen Advocacy Alliance Tuberous Sclerosis Alliance V Foundation for Cancer Research WomenHeart: The National Coalition for Women with Heart Disease


Amgen is researching ways to help T cells target cancer.

Find it T cell

Reference: 1. Melcher A, Parato K, Rooney CM, Bell JC. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol Ther. 2011;19:1008-1016. Š2013 Amgen Inc. All rights reserved. 5/13 74386-R1-V2


Fight it ONCOLYTIC IMMUNOTHERAPY Cancer cell

is an innovative area of research that uses a modified virus to help T cells find and fight cancer cells as part of a systemic, tumor-specific immune response.1 Learn more at: www.oncolyticimmunotherapy.com

Amgen. Leading the way in the study of Oncolytic Immunotherapy.


The ASCO Post | JULY 25, 2013

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ASCO Annual Meeting New Research Presented in Breast, Gastric, Esophageal Cancers, Melanoma, and Multiple Myeloma, plus Supportive Care By Caroline Helwick and Alice Goodman

BOLERO-3, which included 569 patients who received everolimus daily plus vinorelbine and trastuzumab weekly, or vinorelbine/trastuzumab alone. All had received prior taxane

© ASCO/Todd Buchanan 2013

A

ttendees at the ASCO Annual Meeting are faced with a major challenge of trying to attend as many important sessions as they can over a 4-day period. Our challenge is to feature the major news in The ASCO Post. In addition to our regular comprehensive coverage of key presentations, the following selected highlights describe other noteworthy studies of interest.

BOLERO-3: mTOR Inhibition in Breast Cancer The addition of everolimus (Afinitor) to therapy improved progressionfree survival in patients with HER2-positive, trastuzumab (Herceptin)-resistant, taxane-pretreated advanced breast cancer in the BOLERO-3 trial.1 However, clinical benefit rates were not improved, suggesting that the overall benefit of this treatment approach may be less than striking. Ruth O’Regan, MD, of Emo-

Ruth O’Regan, MD

ry University School of Medicine, Atlanta, presented the results of

Kimberly L. Blackwell, MD

therapy, and 27% had received prior lapatinib (Tykerb). The study met its primary endpoint. Everolimus improved median progression-free survival to 7.0 months, a small increase from 5.78 months with placebo (hazard ratio [HR] = .78; P = .0067). Subgroup analyses suggested the benefits were greatest among patients younger than age 65, those with hormone receptor–negative tumors, and those who had received prior adjuvant or neoadjuvant trastuzumab. Response rates and stable disease rates were not significantly different between the groups, and overall survival data were not mature. Discussant Kimberly L. Blackwell, MD, of the Duke Cancer Institute, Durham, North Carolina, said the role for mTOR inhibition in this patient population remains unclear after the study. The lack of effect on overall survival (to date) or clinically meaningful

Brief Reports from ASCO 2013 ■ Everolimus improved median progression-free survival in patients with

HER2-positive, trastuzumab-resistant, taxane-pretreated advanced breast cancer in the BOLERO-3 trial, but clinical benefit rates were not improved.

■ In patients with HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma, adding lapatinib to CapeOx (capecitabine plus oxaliplatin) failed to improve overall survival in the TRIO-013/LOGiC trial.

■ Among patients with newly diagnosed multiple myeloma, treatment

with high-dose melphalan and autologous transplantation, followed by lenalidomide maintenance therapy produced the best progression-free survival in a four-arm comparison.

■ Half of advanced melanoma patients receiving lambrolizumab at its

optimal dose responded to the anti-PD-1 monoclonal antibody in an openlabel trial.

outcomes makes it difficult to call for a change to the standard of care, despite the improvement in progression-free survival, she maintained. “There are other HER2-targeted agents that do provide a documented overall survival benefit,” including the combination of docetaxel, trastuzumab, and pertuzumab (Perjeta), Dr. Blackwell noted.

Lapatinib plus CapeOx in Gastric, Esophageal Cancer In patients with HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma, the addition of lapatinib to CapeOx (capecitabine [Xeloda] plus oxaliplatin) failed to improve overall survival, the primary endpoint of the TRIO-013/LOGiC trial, presented by J. Randolph Hecht, MD, of the David Geffen School of Medicine at the University of California, Los Angeles.2 In the study of 545 patients, median overall survival was 12.2 months with lapatinib plus CapeOx, vs 10.5 months

J. Randolph Hecht, MD

with CapeOx alone (HR .91; P = .35). Median progression-free survival was 6.0 vs 5.4 months, respectively (HR = .86; P = .10), though in an analysis that censored patients from the start of second-line therapy, a benefit was observed with the lapatinib-containing regimen (HR = .82; P = .04). “In subgroup analyses, patients from Asia and those younger than age 60 experienced an increased effect from lapatinib,” Dr. Hecht added. The median overall survival in Asian patients improved from 10.9 months with CapeOx alone to 16.5 months with lapatinib added (HR = .68). In younger patients, median overall survival improved from 9.0 to 12.9 months (HR = .69). Serious adverse events were more common in the lapatinib-containing arm (27%

vs 19%) as were fatal adverse events (6% vs 3%).

Early Transplant plus Maintenance in Multiple Myeloma In patients with newly diagnosed multiple myeloma, treating with highdose melphalan and autologous transplantation (MEL200), followed by maintenance therapy with lenalidomide (Revlimid), resulted in the best progression-free survival in a four-

Antonio Palumbo, MD

arm comparison reported by Antonio Palumbo, MD, of the University of Torino, Italy.3 In fact, each of the two components of this strategy was independently associated with improvement. The trial randomly assigned 402 patients aged 65 or younger to the combination of melphalan, prednisone, and lenalidomide (MPR) or MEL200, and subsequently to maintenance with lenalidomide or no maintenance. Median progression-free survival was 38 months with MEL200 vs 24 months with MPR, with MEL200 providing an additional 14 months of remission (HR  = 1.69; P < .0001). Overall survival was not different, but longer follow-up may be required, Dr. Palumbo suggested. For the secondary randomization, response rates were similar whether patients received lenalidomide maintenance or not. However, patients receiving maintenance therapy had a significantly longer progression-free survival (37 vs 26 months: HR = .52; P < .0001) and, at 5 years, a difference in overall survival as well (75% vs 58%; HR = .62; P = .02). Sagar Lonial, MD, of Emory University, who discussed the paper, commented, “It appears pretty clear from these data that the benefit of


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ASCO Annual Meeting Two Supportive Care Interventions Ineffective

Sagar Lonial, MD

high-dose therapy and autologous transplant is clear and, in my mind, the benefit of maintenance post–autologous transplant is also very clear. We now have two trials demonstrating a significant improvement in overall survival.”

For patients being treated with FOLFOX (leucovorin, 5-FU, oxaliplatin) for colorectal cancer, intravenous calcium and magnesium did not reduce the risk of neuropathy associated with oxaliplatin. This study supports that this practice should be discontinued, said Charles Loprinzi, MD, of the Mayo Clinic, Rochester, Minnesota.5 The multicenter N08CB trial randomly assigned 350 patients receiving FOLFOX into three groups: one re-

Charles Loprinzi, MD

ceiving the calcium/magnesium infusion before and after chemotherapy, a second receiving placebo, and a third receiving calcium/magnesium before chemotherapy and a placebo afterward. Symptoms of neuropathy, which were measured in multiple ways, were no different among the groups, nor were there differences in the average

at a dose of 100 mg for 14 days followed by 200 mg for 14 days, did ameliorate fatigue, as determined by the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue subscale.6 At 28 days, patients receiving modafinil had a change of 5.38 points compared to 5.11 points among patients receiving placebo, and no doseresponse relationship was observed, reported Kate Fife, MD, of the NIHR Cambridge Biomedical Research Centre in the United Kingdom. “Thus, the improvement in fatigue score was the same in both arms of the study, showing that the placebo effect was at work and that placebo was equally effective as modafinil,” explained Dr. Fife.

Brief Reports from ASCO 2013 ■ For patients being treated with FOLFOX for colorectal cancer, intravenous calcium and magnesium did not reduce the risk of neuropathy associated with oxaliplatin.

■ In a phase II study, modafinil therapy failed to ameliorate fatigue in patients with lung cancer.

■ Middle-aged men who are cardiovascularly fit have a reduced risk of

■ In the first comprehensive screen of all known breast cancer susceptibility

genes among black women using next-generation sequencing, damaging abnormalities were more prevalent in women with triple-negative breast cancer, early-onset breast cancer, and a family history of breast and ovarian cancer.

zumab is ongoing in melanoma, non– small cell lung cancer, breast cancer, head and neck cancer, and bladder cancer. A global phase II study of the drug vs chemotherapy for ipilimumabrefractory advanced melanoma patients will enroll 510 patients.

Middle-aged Fitness Level Predicts Cancer Risk Men with a high level of cardiovascular fitness in middle-age have a

developing and dying from lung and colorectal cancer, as well as dying from prostate cancer, compared with less fit counterparts according to a large prospective study.

Antonio Ribas, MD, PhD

re-evaluate guidelines, and until there are more data to support psychostimulants, their use in clinical practice needs to be scrutinized,” Dr. Barton said.

Kate Fife, MD

Lambrolizumab in Melanoma Half of advanced melanoma patients receiving lambrolizumab at its optimal dose responded to the antiPD-1 monoclonal antibody in an open-label trial reported by Antonio Ribas, MD, PhD, of the University of California, Los Angeles.4 The study of lambrolizumab, which recently was granted “breakthrough therapy” status by the FDA, involved 135 patients, of whom 38% responded overall and 52% responded to the dose of 10 mg/kg every 2 weeks. Median progression-free survival exceeded 7 months, and responses were durable in the majority of patients. At a median follow-up of 11 months, 81% of the responding patients were still on treatment. “Importantly, we found that efficacy and safety were similar in ipilimumab (Yervoy)-naive patients and those who had received prior treatment with ipilimumab,” Dr. Ribas noted. Clinical development of lambroli-

ate cessation of this intervention. Another study called into question the clinical benefit of a common intervention in lung cancer. In a phase  III study of 208 patients, modafinil given

number of days until symptoms became significant, or in the number of patients who discontinued chemotherapy. The study was called “practice changing,” by Richard H. Wilson, MD, of Queen’s University Belfast in Northern Ireland, who commented on the findings at a “Highlights of the Day” ASCO session, and supported immedi-

The study discussant, Debra L. Barton, RN, PhD, of the Mayo Clinic, said the results call into question the clinical guidelines for treating fatigue in patients with cancer, which recommend that providers consider using psychostimulants to control fatigue, regardless of stage of disease or expectations for survival. “I think it is time to

Debra L. Barton, PhD

reduced risk of developing and dying from lung and colorectal cancer, as well as dying from prostate cancer, compared with their less fit counterparts according to a large prospective population-based study.7 As is well known, men with good cardiovascular fitness are also at lower risk of death due to cardiovascular causes. Lead author Susan Lakoski, MD, of the University of Vermont, Burlington, explained that fitness level—as measured in this study—is an independent predictive marker distinct from body weight and/or exercise level. “This is the first study to explore fitness as a marker of future cancer risk prognosis. This finding makes clear that patients should be advised that they need to achieve a certain level of fitness, and not just be told that they need to exercise. Unlike exercise behavior, fitness level can be measured objectively in a clinical setting. Previous studies have shown that poor fitness level is associated with increased risk of cardiovascular disease,” Dr. Lakowski stated. The findings were based on the large, prospective Cooper Center Longitudinal Study, conducted at the Cooper Clinic in Dallas. The men (n = 17,049) had a single cardiovascular fitness assessment as part of a preventive health checkup at a mean age of 50 years. The fitness test involved treadmill-walking under conditions of changing speed and elevation, and performance was measured by units of fitness called metabolic equivalents (METs). continued on page 60


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ASCO Annual Meeting Brief Reports continued from page 59

At a median follow-up of 20 to 25 years, 2,332 men were diagnosed with prostate cancer, 276 with colorectal cancer, and 277 with lung cancer, according to Medicare claims. Cancer deaths numbered 347, and 159 men died of cardiovascular disease. In an adjusted analysis for smoking, body mass index, age, and other factors, men with the highest levels of fitness had a 68% lower risk of a diagnosis of lung cancer compared with men in the lowest fitness quintile; the risk of colorectal cancer was reduced by 38% in the highest vs the lowest quintile for fitness. No impact of fitness was found for development of prostate cancer. Among those who developed cancer, men at the higher levels of fitness had a lower risk of cancer-related death from all three cancers, as well as a lower risk of death due to cardiovascular disease. Dr. Lakowski said that even a 1-MET different reduced the risk of dying from cancer and cardiovascular disease by 23% and 14%, respectively. Low fitness levels were associated with increased risk of cancer and cardiovascular disease independently of body weight.

Black Women, Breast Cancer, and Genetic Mutations About 1 in 5 African American women with breast cancer who were referred for genetic counseling were found to carry a mutation in at least 1 of 6 genes associated with increased risk of developing breast cancer.8 These damaging mutations were more prevalent in women with triple-negative breast cancer, early-onset breast cancer, and a family history of breast and ovarian cancer. The majority of mutations found were in BRCA1 and BRCA2, but 21% of the mutations identified with next-generation sequencing of 18 genes involved in breast cancer susceptibilty were in other genes that had clear associations with breast cancer susceptibility. This was the first comprehensive screen of all known breast cancer susceptibility genes in black women, said lead author Jane E. Churpek, MD, of The University of Chicago. She said that the findings suggest that testing for BRCA1 and BRCA2 mutations alone may not be sufficient for black women. The study population included 249 unrelated black women with breast

cancer referred for genetic counseling at The University of Chicago. A single genomic test called the BROCA assay was used to screen for mutations in 42 genes, including 18 known breast cancer susceptibility genes. Of these women, 27 had a known BRCA1 or BRCA2 mutation. Screening identified 58 clearly damaging inherited mutations in six different genes in 56 of the 249 women (22%). The breakdown of mutations identified is as follows: 79% in BRCA1 or BRCA2, and 21% in other genes that included ATM, CHEK2, PALB2, and PTEN. Most of the women who had a mutation had only one, but three women—all with early-onset breast cancer—had more than one inher-

Gypsyamber D’Souza, PhD, MPH, MSA

potential for a more cost-effective and efficient approach to genetic testing.

HPV-related Oropharyngeal Cancer in Patients’ Spouses In a study that should be reassuring to those married or partnered with a patient with human papillomavirus

Brief Reports from ASCO 2013 ■ The HOTSPOT study identified no increased risk of HPV-related cancer in

spouses or partners of patients with HPV-positive oropharyngeal cancer.

■ Patients, physicians, and caregivers have negative attitudes toward lung

cancer, in contrast with attitudes about breast cancer, according to a study that quantitated and characterized attitudes toward both types of cancer.

■ Novel agents being studied in adults with acute lymphocytic leukemia

include the monoclonal antibodies epratuzumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, moxetumomab pasudotox, and blinatumomab, as well as chimeric antigen receptor–modified (CAR) T cells.

ited mutation, and two of them had no family history of breast or ovarian cancer. Factors associated with an increasing number of mutations included younger age at diagnosis, a second diagnosis of breast or ovarian cancer, triple-negative breast cancer, a family history of breast, ovarian, or pancreatic cancer, and grade 3 breast cancer. Dr. Churpek said that the majority of mutations found in these women were unique to an individual patient. By contrast, other populations such as Ashkenazi Jews carry one of three specific mutations in the BRCA1 and BRCA2 genes, thus allowing genetic testing to begin with these 3 specific genetic sites, rather than by sequencing the whole genes which is more expensive. Dr. Churpek pointed out that this study shows that such site-specific genetic testing is not adequate for black women, because they have such diverse inherited mutations. A test like BROCA allows assessment of several types of genetic abnormalities including single nucleotide changes, small insertions and deletions, and large genomic rearrangements in multiple genes at the same time; previously, multiple tests were needed for this type of assessment, showing the

(HPV)-positive oropharyngeal cancer, no increased risk of oral HPV infection was identified in spouses/partners of patients with HPV-positive oropharyngeal cancer.9 Most often HPV-positive oropharyngeal cancer occurs in males, and some spouses worry about their own HPV exposure and cancer risk, explained lead author Gypsyamber D’Souza, PhD, MPH, MSA, of Johns Hopkins University, Baltimore. The Human Oral Papillomavirus Transmission in Partners over Time [HOTSPOT] is the first study to examine oral HPV prevalence among spouses of patients with HPV-positive oropharyngeal cancer. “The study suggests that long-term couples have already shared whatever infections they have, and no changes in their physical intimacy are required,” Dr. D’Souza said. HOTSPOT enrolled 166 patients with HPV-positive oropharyngeal cancer and 94 spouses/long-term partners. Of the 166 patients, 147 were male and 19 were female. Median age was 56 years. An oral rinse/gargle sample was used to measure HPV DNA in spouses and partners. Among the cancer cases, 65% of cases had HPV detected at diagnosis,

and most cases no longer had HPV detectable after therapy. The overall prevalence of HPV infection among partners was 7.2%. The prevalence among the female partners was 5%, which is similar to women in the general population, she noted. HPV16, the subtype responsible for most cases of HPVpositive oropharyngeal cancer, was detected in 54% of patients but only 2.7% of the 88 female partners and none of the 6 male partners. Five (3.4%) of the male cases reported having a partner who developed cervical cancer or precancer. A history of cervical cancer was reported in one current partner and two previous partners, and a history of cervical dysplasia was reported in two current partners of HPV-positive oropharyngeal cancer cases. “It is not known how HPV is transmitted. The presumption is that oral sex is a route of transmission from the female genitals to the oropharynx, but there is no evidence that saliva transmits it to the genitals,” she said.

New Drugs for Acute Lymphocytic Leukemia “We’ve reached the limits of what we can do for older adults with acute lymphocytic leukemia [ALL] using standard therapies. Progress will come from monoclonal antibodies and other novel therapies, and we have some encouraging data,” stated Mark Litzow, MD, of Mayo Clinic College of Medicine, Rochester, Minnesota, during an Education Session at the ASCO Annual Meeting.10 Novel monoclonal antibodies being studied in adults with ALL include epratuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, and blinatumomab. Also, preliminary studies using a patient’s own genetically engineered T cells are encouraging thus far. Epratuzumab is a humanized antibody that binds to the CD22 antigen expressed on B-lineage ALL cells. Small studies show that this drug in combination with chemotherapy has good activity in ALL. Gemtuzumab ozogamicin is a monoclonal antibody directed against the CD33 antigen expressed on leukemic cells and was primarily used in acute myeloid leukemia. This drug is no longer on the U.S. market, but the mechanism of action is attractive, which led to the development of inotuzumab ozogamicin, Dr. Litzow said. Preliminary study of inotuzumab showed impressive results in relapsed/ continued on page 62


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ASCO Annual Meeting Brief Reports continued from page 60

refractory ALL, allowing approximately one-third of 89 patients to go on to stem cell transplantation, but like gemtuzumab, the drug can be associated with hepatic toxicity. A novel anti-CD22 murine monoclonal antibody called moxetumomab pasudotox is being studied in ALL, but these studies are still accruing patients, and, although it improves response, results are preliminary, Dr. Litzow said. Blinatumomab, a bi-specific T-cell engaging (BiTE) antibody directed against CD19, shows good activity in patients with B-precursor ALL with minimal residual disease. Of 20 evaluable patients receiving blinatumomab, 16 achieved minimal residual disease negativity. The drug is now being tested in a clinical trial in relapsed/refractory patients. Safety concerns include cytokine release syndrome and central nervous system adverse events. This drug could be considered as a bridge to transplantation and can also be used in patients with prior transplant. There are plans to study blinatumomab in a randomized trial of patients with newly diagnosed Philadelphia-negative B-cell ALL starting later this year. Chimeric antigen receptor–modified (CAR) T cells offer an intriguing immunologic therapy under study in ALL as well as in other leukemias, Dr. Litzow continued. Reports have been published in small groups of patients treated with CAR-T, including five pediatric patients with ALL and five adults with refractory ALL or minimal residual disease. A few end-stage patients have had life-saving results with this therapy, which have been reported in The New York Times and other newspapers. “This therapy may enable patients

to avoid transplantation, but the jury is still out,” he said. “We are going to hear much more about this form of therapy as time goes on.”

Lung Cancer Stigmatized Compared with Breast Cancer Patients with cancer, physicians, other health-care specialists, and caregivers have negative attitudes toward lung cancer, whereas this is not true for breast cancer, according to a study that quantitated and characterized attitudes toward both types of cancer.11

Joan Schiller, MD

In this online study, 1,778 participants responded to a set of exercises specifically designed to elicit explicit and implicit attitudes toward lung and breast cancer. A 6-point scale to measure explicit attitudes revealed significantly more negativity toward lung cancer than breast cancer (P < .001). Implicit attitudes were also significantly more negative toward lung cancer than breast cancer (P < .0001). For both explicit and implicit attitudes, females had much stronger negative attitudes than males. More research is needed to determine whether these attitudes affect care, said lead author Joan Schiller, MD, of the University of Texas Southwestern, Dallas. Dr. Schiller noted that lung cancer is perceived as self-induced due to its strong association with smoking cigarettes, but that addiction to tobacco is

powerful and very difficult to break. The stigmatization of lung cancer leaves these patients without powerful advocacy groups for support, and this extends to patients with lung cancer who never smoked cigarettes. By contrast, many advocacy groups and support groups are available for patients with breast cancer. n Disclosure: Dr. O’Regan has served as a consultant or advisor for Novartis and has received research funding from Genentech and Novartis. Dr. Hecht has received research funding from GlaxoSmithKline. Dr. Palumbo has served as a consultant or advisor for and has received honoraria from Celgene. Dr. Lonial has been a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, and Onyx. Dr. Ribas has served as a consultant or advisor for Amgen, Genentech, GlaxoSmithKline, Merck, and Novartis, and owns stock in Kite Pharma. Dr. Wilson has served as a consultant or advisor for Merck Serono, Pfizer, Roche/Genentech, and Sanofi, and has received honoraria from Hospira. Dr. D’Souza has received research funding from Merck. Dr. Schiller has served as a consultant or advisor for Genentech. Dr. Litzow has served as a consultant or advisor for Talon Therapeutics, has received honoraria from Amgen and Sigma-Tau, and has received research funding from Amgen. Drs. Loprinzi, Fife, Barton, Lakoski, and Churpek reported no potential conflicts of interest.

References 1. O’Regan R, Ozguroglu M, Andre F, et al: Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3). 2013 ASCO Annual Meeting. Abstract 505. Presented June 2, 2013. 2. Hecht JR, Bang Y-J, Qin S, et al: Lapatinib in combination with capecitabine plus oxaliplatin in HER2-positive advanced or metastatic gastric, esophageal or gastroesophageal adenocarcinoma: The TRIO-013/LOGiC trial. 2013 ASCO Annual Meeting. Abstract LBA4001. Presented June 3, 2013. 3. Boccadoro M, Cavallo F, Gay FM, et al: Melphalan/prednisone/lenalidomide versus high-dose melphalan and autolo-

gous transplantation plus lenalidomide maintenance or not maintenance in newly diagnosed multiple myeloma patients. 2013 ASCO Annual Meeting. Abstract 8509. Presented June 3, 2013. 4. Ribas A, Robert C, Daud A, et al: Clinical efficacy and safety of lambrolizumab (MK-3475, anti-PD-1 monoclonal antibody) in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9009. Presented June 1, 2013. 5. Loprinzi CL, Qin R, Dakhil SR, et al: Phase III randomized, placebo-controlled, double-blind study of intravenous calcium/magnesium to prevent oxaliplatin-induced sensory neurotoxicity, N08CB: An alliance for clinical trials in oncology. 2013 ASCO Annual Meeting. Abstract 3501. Presented June 1, 2013. 6. Fife K, Spathis A, Dutton SJ, et al: A multicenter, randomized, double-blinded, placebo-controlled trial of modafinil for lung cancer-related fatigue. 2013 ASCO Annual Meeting. Abstract 9503. Presented June 2, 2013. 7. Lakoski SG, Barlow C, Gao A,, et al: Cardiorespiratory fitness and risk of cancer incidence and cause-specific mortality following a cancer diagnosis in men: The Cooper Center longitudinal study. 2013 ASCO Annual Meeting. Abstract 1520. Presented June 2, 2013. 8. Churpek JE, Walsh T, Zheng Y, et al: Inherited mutations in breast cancer genes in African American breast cancer patients revealed by targeted genomic capture and next generation sequencing. 2013 ASCO Annual Meeting. Abstract CRA1501. Presented June 3, 2013. 9. D’Souza G, Gross ND, Pai SI, et al: Oral HPV infection in HPV-positive oropharyngeal cancer cases and their spouses. 2013 ASCO Annual Meeting. Abstract CRA6031. Presented June 1, 2013. 10. Litzow MR: Monoclonal antibodybased therapies in the treatment of acute lymphoblastic leukemia (ALL). 2013 ASCO Annual Meeting. Education Session. Presented May 31, 2013. 11. Schiller JH, Bowden CJ, Mills J, et al: Explicit and implicit attitudes toward lung cancer, relative to breast cancer. 2013 ASCO Annual Meeting. Abstract 8017. Presented June 3, 2013.

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Journal Spotlight Gastrointestinal Oncology

Addition of Brivanib to Cetuximab in Chemotherapy-refractory Metastatic Wild-type KRAS Colorectal Cancer: Key Results By Matthew Stenger

T

he addition of a combination of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors to chemotherapy has not improved outcome in first-line treatment of advanced colorectal cancer. However, in early-phase evaluation, the addition of the investigational VEGF and fibroblast growth factor tyrosine kinase inhibitor brivanib to the EGFR inhibitor cetuximab (Erbitux) produced encouraging antitumor activity in wild-type KRAS metastatic colorectal cancer. As reported in the Journal of

Clinical Oncology by Lillian L. Siu, FRCPC, MD, Senior Staff Physician in the Division of Medical Oncology and Hematology at Princess Margaret Hospital, and Professor of Medicine at the University of Toronto, Canada, and colleagues, the phase  III NCIC Clinical Trials Group and AGITG CO.20 trial has shown that the addition of brivanib to cetuximab resulted in no overall survival benefit and increased toxicity in patients with chemotherapy-refractory metastatic wild-type KRAS colorectal cancer, despite prolonged progression-free survival and improved response rate.1 Both brivanib and cetuximab dose intensities were limited by toxicity in the combination group.

CO.20 Trial In this trial, 750 patients were randomly assigned to receive cetuximab (400 mg/m2 loading dose followed by weekly maintenance of 250 mg/m2) plus either oral brivanib at 800 mg/d (n = 376) or placebo (n = 374). The primary endpoint of the trial was overall survival. The combination group and the cetuximab-alone group were well matched for baseline characteristics, including age (median, 64 and 63 years), sex (66% and 63% male), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 in 89% and 90%), site of primary cancer, sites of metastatic disease (liver in 77% and 76%, lung in 65% and 60%), number of disease sites (three or more in 50% and

48%), prior radiotherapy (32% and 35%), prior adjuvant chemotherapy (38% and 39%), number of prior chemotherapy regimens (>3 in 92% and 91%), prior VEGF inhibitor therapy (40% and 42%), and proportion of patients with normal lactate dehydrogenase (LDH; 29% and 30%). Mutant KRAS was found in 2.4% of patients in the combination group and in 3.2% of the cetuximab-alone group.

Survival Data Median follow-up was 18.7 months, and 17% of combination patients and 20% of cetuximab-alone patients received other anticancer treatment after disease progression. There continued on page 64

Looking for Drivers in the Rearview Mirror By John L. Marshall, MD

T

he latest clinical trial looking at combining vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibition in metastatic colorectal cancer adds little to our overall understanding of the mechanisms for optimizing selection of patients to receive such therapies. While we continue to see small gains in outcomes when targeted agents are combined, we have failed to demonstrate a clear, clinically useful benefit for our patients.

Search for Biomarkers Our current model for developing anticancer agents involves conducting very large randomized clinical trials of treatment A vs treatment B. These trials are large because we know that we will get very small differences in the primary and secondary endpoints. To date, we have valued these small changes, and as a result, medicines have been approved and their high price is being covered, but for only small gains. However, we are increasingly intolerant of this approach, mostly due to toxicity and cost for patients and society, and Dr. Marshall is Chief, Division of Hematology/Oncology, and Director, Otto J Ruesch Center for the Cure of GI Cancers, Georgetown University, Washington, DC.

we have come to conclude that while findings can be statistically significant, often they are clinically irrelevant. To try and compensate for this, we are increasingly looking for biomarkers. So now, we still do large clinical trials and find small differences but look

Frankly, in gastrointestinal cancers, we have yet to identify a significant driving mutation. Even KRAS, for all the hype, has failed to deliver the same types of dramatic improvements that we have observed with HER2 targeting in breast cancer, for example.

Only by working together and on a global scale will we define the intricacies of metastatic gastrointestinal cancers. We will no longer tolerate the statistically significant but clinically irrelevant results of large randomized clinical trials that are unenriched for the proper patients. â&#x20AC;&#x201D;John L. Marshall, MD

backwards through the rearview mirror in the hopes of finding the drivers. In a few cancers, this has been successful; where luck has prevailed, driver mutations have been discovered due to clever observations by those evaluating clinical trial results. In gastrointestinal cancers, we have not been nearly so successful or lucky.

I believe part of our problem relates to the fact that we continue to look at old banked tumors and not fresh tissue biopsies in order to measure our biomarkers. It is possible that gastrointestinal tract cancers are much more complicated, with no clear patterns of driver mutations. Of course, if this is true, we have a very steep uphill battle ahead.

Novel Trial Designs The trial reported by Siu and colleagues as well as other trials clearly point to the need for novel clinical trial designs. Small prospectively enriched studies with fresh tumor samples, using biomarkers as the entry criteria, will be critical for us moving forward. The Otto J. Ruesch Center at Georgetown, which I am proud to direct, is focused on linking centers around the world interested in performing such clinical trials. Our model will be to obtain tissue and do biomarker analysis on all patients prospectively and assign them to treatments, both standard and experimental, based on their biomarker and oncogene expression. Only by working together and on a global scale will we define the intricacies of metastatic gastrointestinal cancers. We will no longer tolerate the statistically significant but clinically irrelevant results of large randomized clinical trials that are unenriched for the proper patients. There is hope going forward, but it will require a global collaboration and partnership among our patients, our clinical research partners, and our academic institutions. n

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


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Journal Spotlight Sarcoma

Nearly Half of Sarcoma Surgeries Performed by Non-oncology Surgeons By Caroline Helwick

N

agement of these challenging lesions, said lead author of the study Robert J. Canter, MD, MAS, Associate Pro-

early half the surgical procedures for sarcoma done at 85 academic medical centers were performed by surgeons untrained in oncology, according to national data analyzed by researchers from the University of California Davis Medical Center, Sacramento. Orthopedic oncologists and surgical oncologists, who have been trained in the complex procedures required to remove sarcomas located deep in the muscles and soft tissues of the limbs, conducted only 52% of these operations during a 3-year period, according to the study published in the Journal of Surgical Oncology.1 The remaining 48% of these ex-

tremity soft tissue tumor resections were conducted by general surgeons, plastic surgeons, and orthopedic

surgeons, whose fellowship training does not emphasize the multidisciplinary evaluation and surgical man-

fessor of Surgery at University of California Davis. The study is the first to examine

Brivanib/Cetuximab in CRC

1 and across all subgroups according to age, sex, prior VEGF inhibitor therapy, and LDH levels. Objective response rates (all partial responses) were 13.6% in the combination group and 7.2% in the cetuximab-alone group (P = .004), and median durations of response were 5.8 and 5.4 months.

group and in 53% of patents in the cetuximab-alone group (P < .001), with rates being significantly higher in the combination group for fatigue (25% vs 11%), hypertension (11% vs 1%), rash (10% vs 5%), abdominal pain (10% vs 5%), dyspnea (8% vs 5%), dehydration (7% vs 2%), and anorexia (5% vs 1%). Hematologic adverse events were uncommon in both groups. Rates of grade 3 or higher AST increase (17% vs 6%), ALT increase (21% vs 4%),

continued from page 63

was no significant difference between the combination and cetuximab-alone groups in overall survival (median, 8.8 vs 8.1 months, hazard ratio [HR]  = 0.88, P =  .12). One-year overall survival rates were 35.8% vs 30.9%. Results were similar after adjustment for potential prognostic factors in a multivariate analysis and in a sensitivity analysis among the 725 patients with confirmed wild-type KRAS status. Planned subgroup analyses showed a borderline significant benefit of combination therapy in patients with ECOG performance status of 0 or 1 (P = .052), .052), but no significant significant differences according to age or sex. Post hoc analyses according to prior VEGF inhibitor therapy and baseline LDH level showed a trend toward significant benefit of the combination in patients with normal LDH levels. Progression-free survival was significantly prolonged in the combination group (median 5.0 vs 3.4 months, HR = 0.72, P < .001). A similar degree of benefit was observed among patients with ECOG performance status of 0 or

Our findings may have significant implications for the quality of care provided to patients who undergo surgery to resect sarcomas in the deep soft tissue of the limbs. —Robert J. Canter, MD, MAS

Toxicity Findings The spectrum of adverse events with combination therapy was consis-

Despite not meeting its primary end point, CO.20, with its large sample size as well as annotated tissue repository, will provide an invaluable clinical and correlative scientific data resource to enhance the biologic understanding of metastatic [colorectal cancer]. —Lillian L. Siu, FRCPC, MD, and colleagues

tent with the toxicity profiles of either agent given alone. Grade 3 or higher adverse events occurred in 78% of patients in the brivanib-plus-cetuximab

Brivanib/Cetuximab in Colorectal Cancer ■ The addition of the VEGF and fibroblast growth factor inhibitor brivanib to

the EGFR inhibitor cetuximab did not produce an overall survival benefit in chemotherapy-refractory metastatic wild-type KRAS colorectal cancer.

■ Progression-free survival and response rate were improved in the combination group, but toxicity was also increased.

hyponatremia (13% vs 7%), and increased thyroid-stimulating hormone (24% vs 4%) were significantly higher with combination treatment. Brivanib/placebo treatment was discontinued due to adverse events in 22% of combination group patients and in 3% of the cetuximab-alone group, with fatigue, increased aminotransferases, and dyspnea being the most common reasons. Cetuximab dose intensity of at least 90% was received by 57% of patients in the combination group com-

the overall frequency and distribution nationwide of the different surgical specialists who remove sarcomas and similar tumors.

Study Details The researchers queried the University Health System Consortium and the Association of American Medical Colleges database on 85 institutions for the years 2007 to 2009. They identified 2,195 general surgeons, 792 plastic surgeons, 533 surgical oncologists, 1,079 general orthopedic surgeons, and 83 orthocontinued on page 66

pared with 83% of cetuximab-alone patients, and dose intensity of brivanib/ placebo was at least 90% in only 48% of patients in the combination group and in 87% of the cetuximab-alone group. As noted by the investigators, reduced dose intensity of cetuximab in the combination arm may have been due to brivanib-related toxicity, which may have contributed to reduced efficacy of the combination. The investigators concluded, “Despite positive effects on [progressionfree survival] and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve [overall survival] in patients with metastatic, chemotherapy-refractory, wild-type KRAS [colorectal cancer].” They noted, “Despite not meeting its primary end point, CO.20, with its large sample size as well as annotated tissue repository, will provide an invaluable clinical and correlative scientific data resource to enhance the biologic understanding of metastatic [colorectal cancer].” n

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Siu LL, Shapiro JD, Jonker DJ, et al: Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 trial. J Clin Oncol 31:2477–2484, 2013.


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Š2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. FIL-40083 June 2013. Printed in USA.


The ASCO Post | JULY 25, 2013

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Journal Spotlight

Sarcoma Surgeries continued from page 64

pedic oncologists. Non–oncology-trained surgeons performed approximately 50% of deep and malignant soft tissue tumor resections. Adjusting for the number of physicians in the database, the investigators determined that of the

total deep and malignant extremity soft tissue tumor resections, 9.4% were performed by general surgeons, 7.7% by plastic surgeons, 26.0% by surgical oncologists, 30.8% by general orthopedic surgeons, and 26.0% by orthopedic oncologists. In contrast, the mean number of operations to remove nonmalignant

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR tbo-filgrastim Injection for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Tbo-filgrastim is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving tbo-filgrastim, discontinue tbo-filgrastim and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving tbo-filgrastim, for ARDS. Discontinue tbo-filgrastim in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue tbo-filgrastim in patients with serious allergic reactions. Do not administer tbo-filgrastim to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue tbo-filgrastim in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which tbo-filgrastim acts has been found on tumor cell lines. The possibility that tbo-filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which tbo-filgrastim is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with tbo-filgrastim at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 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 clinical practice. Tbo-filgrastim clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both tbo-filgrastim and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with tbo-filgrastim at the recommended dose and was numerically two times more frequent

subcutaneous soft tissue tumors did not differ significantly among the specialists. The analysis also revealed that 17% of the cancer operations were by surgeons who performed an average of only one or two of these procedures each year. Previous studies have linked better clinical outcomes

than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% tbo-filgrastim, 1.4% placebo, 7.5% non-USapproved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving tbo-filgrastim. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving tbo-filgrastim has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between tbo-filgrastim and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of tbo-filgrastim in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. Tbo-filgrastim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tbo-filgrastim is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of tbo-filgrastim in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of tbo-filgrastim, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of tbo-filgrastim have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of tbo-filgrastim have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported.

Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA North Wales, PA 19454 Product of Israel FIL-40085

August 2012

This brief summary is based on the tbo-filgrastim full Prescribing Information.

with higher volume. The database does not include information about clinical outcomes.

Implications for Quality of Care “Our findings may have significant implications for the quality of care provided to patients who undergo surgery to resect sarcomas in the deep soft tissue of the limbs,” Dr. Canter said. He suggested that orthopedic or surgical oncologists are probably more likely to achieve negative surgi-

Surgery in Patients with Sarcoma ■ Data from 85 academic medical centers suggest that nearly half the resections for sarcoma are performed by surgeons not trained in oncology.

■ Almost 20% of operations were

performed by surgeons who complete an average of only one or two of these procedures per year.

cal margins, thus helping patients to avoid additional surgeries and death from recurrence. About 50% of soft tissue sarcomas occur in the limbs, and about 50% metastasize. Part of the problem is that, since sarcomas are rare, some tumors may remain undiagnosed at the time of surgery and the need for an oncologist may not be recognized. The National Comprehensive Cancer Network and the European Society of Medical Oncology recommend that only surgeons with expertise and training in the management of soft tissue sarcomas should operate on patients with tumors that may be sarcomas. n

Disclosure: The study was funded by the Department of Surgery at the University of California Davis Health System.

Reference 1. Canter RJ, Smith CA, Martinez SR: Extremity soft tissue tumor surgery by surgical specialty: A comparison of case volume among oncology and non-oncologydesignated surgeons. J Surg Oncol. July 3, 2013 (early release online).


ASCOPost.com | JULY 25, 2013

PAGE 67

Journal Spotlight Hematology

Critically Ill Hematology Patients Admitted to ICU Have Good Survival, Disease Control, and Quality of Life By Matthew Stenger

A

large prospective multicenter cohort study in France and Belgium, reported by Elie Azoulay, MD, of Saint-Louis Hospital, Paris, and colleagues from the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique,1 has shown that critically ill patients with hematologic malignancies admitted to the intensive care unit (ICU) have good survival, disease control, and post-ICU health-related quality of life. Earlier admission to the ICU, a potentially modifiable risk factor, was associated with better survival. The study involved 1,011 patients with life-threatening events hospitalized at 17 centers. Of these patients, 38.2% had newly diagnosed malignancies, 23.1% were in remission, and 24.9% had received bone marrow transplantation or hematopoietic stem-cell transplantation, including allogeneic transplantation in 14.3%. Patients with non-Hodgkin lymphoma (31.6%), acute myeloid leukemia (27.2%), and myeloma (12.5%) accounted for the majority of the cohort. On day 1, 72.5% of patients received life-supporting interventions. The primary reasons for ICU admission were acute respiratory failure (62.5%) or shock (42.3%). Neutropenia was present in 28.6% of patients at ICU admission and developed in the ICU in an additional 9%. The median time from hospital admission to ICU admission was 4 days, with ICU admission occurring within 1 day in 44.6% of patients and 26% being admitted directly to the ICU.

Patient Characteristics Patients admitted to the ICU within 1 day after hospital admission had similar Sepsis-Related Organ Failure Assessment (SOFA) scores on day 1 compared with those admitted later, but were less likely to have life supporting intervention (67.7% vs 74.2%). These patients also had shorter

times since malignancy diagnosis (median, 153 vs 173.5 days), were more likely to have good performance status (86.6% vs 75.5%), and were less likely to have their primary hematologist in the same hospital as the ICU (57.6%

ICU admission led to prolonged survival with good quality of life [and disease control in a significant number of patients.] ICU admission within 24 hours of hospital admission was significantly associated with better survival. —Elie Azoulay, MD, and colleagues

vs 96.7%), history of allogeneic bone marrow transplantation or hematopoietic stem-cell transplantation (11% vs 17%), neutropenia (19.6% vs 35.8%), and treatment with antifungal (27% vs 47%) or antiviral agents (36% vs 48%) during the first 3 days in the ICU. These patients were also significantly less likely to require more than one call to the ICU physician for admission than those admitted after 1 day (5.9% vs 18%).

Predictors of Mortality Overall hospital, 90-day, and 1-year survival rates were 60.7%, 52.5%, and 43.3%, respectively. On multivariate analysis (using a model without imputation of missing data from the SOFA score), 10 variables were independently associated with hospital mortality. Time from hospital to ICU admission of < 24 hours (odds ratio = 0.7) and complete or partial remission status (odds ratio = 0.63) were associated with significantly reduced risk of mortality. Poor performance status (odds ratio  = 1.58), higher Charlson comorbidity index (odds ratio  = 1.13/ point), receipt of allogeneic bone marrow transplantation or hematopoietic stem cell transplantation (odds

Hematologic Disorders and the ICU ■ ICU admission led to prolonged survival with good quality of life and disease control in critically ill hematology patients.

■ Earlier ICU admission is a potentially modifiable variable associated with better survival.

ratio  = 2.18), higher SOFA score on admission (odds ratio  = 1.21/point), admission after cardiac arrest (odds ratio  = 2.63), admission with acute respiratory failure (odds ratio = 1.34), organ infiltration by malignancy (odds

ratio = 1.89), and invasive pulmonary aspergillosis (odds ratio  = 1.97) were associated with significantly increased risk of mortality. Overall, mechanical ventilation was used in 47.9% of patients, vasoactive drugs in 51.2%, and dialysis in 25.9%. Mortality rates in these patients were 60.5%, 57.5%, and 59.2%, respectively.

Survivors’ Status Assessment of health-related quality of life with the short form-36 questionnaire on day  90 indicated no dif-

ference between survivors on physical and mental health measures compared with age- and gender-matched patients with cancer not admitted to the ICU. At 6 months, hematologists reported that all but seven of the ICU survivors were continuing their cancer treatment, that ICU admission did not alter therapeutic intensity in 80% of patients, and that 80% were in complete or partial remission. The investigators concluded, “ICU admission led to prolonged survival with good quality of life [and disease control in a significant number of patients.] ICU admission within 24 hours of hospital admission was identified as a variable significantly associated with better survival and possibly amenable to modification.” n Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Azoulay E, Mokart D, Pène F, et al: Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium— a Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique study. J Clin Oncol. June 10, 2013 (early release online).

Just Say ‘Know’ By Jeffrey S. Groeger, MD, and Kathleen N. Cathcart, MD

I

n 1989, Denardo and associates reported the results of intensive care unit (ICU) therapy in a series of patients who developed acute respiratory failure and required mechanical ventilation after bone marrow transplantation. Of those on mechanical ventilatory support longer than 4 days, not one survived.1 The editorial that accompanied the study publication was titled, “Just Say No.”2 Over the ensuing decades, our understanding of the cellular etiology of hematologic malignancies has deepened, targeted therapies have been developed, and we have seen Dr. Groeger is Chief, Urgent Care Service, Attending Critical Care Physician, and Dr. Cathcart, is Associate Attending Hematologist-Oncologist, Memorial Sloan-Kettering Cancer Center, New York.

great advances in the management of therapy-related toxicities. This has culminated in the ability to more safely widen therapeutic options offered to patients with hematologic malignancies. As demonstrated in the publication of a report by Azoulay et al,3 ICU management should now be seen as a reasonable intervention in an extraordinarily ill population, leading not only to a greater probability of survival than in the past, but also to a survival associated with a reasonable quality of life. Appropriate initiation of ICU management in patients with hematologic cancers offers a good chance of leaving the patient with physiology that permits ongoing attempts at disease management and possible cure. continued on page 68


The ASCO Post | JULY 25, 2013

PAGE 68

Journal Spotlight

Drs. Groeger and Cathcart continued from page 67

While the combination of respiratory failure, circulatory compromise requiring vasopressors, and renal replacement therapy is extremely ominous, the presence of a single–organ system failure is not. The earlier patients enter the ICU, the less likely their chance of dying.

Advances in Critical Care Management Independent of the remarkable inroads in the treatment of liquid tumors, advances in critical care management likely contribute to this beneficial trend. Salient examples include the implementation of low–tidal volume mechanical ventilation in patients with respiratory failure,4 fluid restriction in acute lung injury,5 the understanding that there is no advantage of use of pulmonary artery catheters,6 the use of protocols to prevent catheter-related bacteremia and ventilator-associated pneumonia, as well as management of hypotension with norepinephrine rather than dopamine.7 What is of striking importance in the study of Azoulay et al is the collaboration between oncologist and inten-

sivist. Management of the complexity of ICU care in the setting of coagulopathy, neutropenia, and immunosuppression can be daunting and requires

soned end-of-life discussions when appropriate. Thus, the observations of Azoulay and colleagues strongly suggest that this contemporary editorial

What is of striking importance in the study of Azoulay et al is the collaboration between oncologist and intensivist. Management of the complexity of ICU care in the setting of coagulopathy, neutropenia, and immunosuppression can be daunting and requires multidisciplinary interaction. —Jeffrey S. Groeger, MD, and Kathleen N. Cathcart, MD

multidisciplinary interaction. Understanding the disease status, comorbid conditions, and organ function status should improve the ability of health-care providers to present probability-of-survival data to patients and family members and allow for rea-

should be titled “Just Say ‘Know.’”n

Disclosure: Drs. Groeger and Cathcart reported no potential conflicts of interest.

References 1. Denardo SJ, Oye RK, Bellamy PE: Efficacy of intensive care for bone marrow

transplant patients with respiratory failure. Crit Care Med 14:4-6, 1989. 2. Carlon GC: Just say no. Crit Care Med 7:106-107, 1989. 3. Azoulay E, Mokart D, Pène F, et al: Outcomes of critically ill patients with hematologic malignancies: Prospective multicenter data from France and Belgium— a Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique study. J Clin Oncol. June 10, 2013 (early release online). 4. The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301-1308, 2000. 5. National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354:2564-2575, 2006. 6. Shah MR, Hasselblad V, Stevenson LW, et al: Impact of the pulmonary artery catheter in critically ill patients: Meta-analysis of randomized clinical trials. JAMA 294:1664-1670, 2005. 7. De Backer D, Biston P, Devriendt J, et al, for the SOAP II Investigators: Comparison of dopamine and norepinephrine in the treatment of septic shock. N Engl J Med 362:779-789, 2010.

News and Views from the World of Clinical Oncology and Hematology

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POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm 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 a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages. To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.


POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm 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 a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide 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 POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST 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 POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.


WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST 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 if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN. Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation 04/13 US-POM120044a(1)


The ASCO Post | JULY 25, 2013

PAGE 72

FDA Update

FDA Grants Priority Review to Obinutuzumab in CLL and Pertuzumab in Neoadjuvant Therapy for HER2-positive Early-stage Breast Cancer

T

wo drugs were recently given Priority Review designation by FDA. Obinutuzumab (GA101) was granted Priority Review for the

treatment of chronic lymphocytic leukemia, based on final stage 1 data from the pivotal CLL11 trial. The FDA confirmed the action date is

December 20, 2013. FDA also granted Priority Review to a pertuzumab (Perjeta) regimen in the neoadjuvant setting for patients with HER2-

positive early-stage breast cancer. The FDA will make a decision on approval of pertuzumab by October 31, 2013.

T:7”

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST 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 POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST 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 POMALYST 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 Pomalidomide 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 POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST 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 POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber 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 POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

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1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities

Toxicity


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FDA Update

Obinutuzumab Review The FDA is evaluating data on obinutuzumab, also known as GA101, from the pivotal phase III CLL11 trial that found obinutuzumab demonstrated a statistically significant 86% reduction in the risk of disease worsening or death (HR = 0.14, 95% CI 0.09-0.21, P < .0001) when combined with chlo-

rambucil chemotherapy compared to chlorambucil alone in previously untreated people with CLL and coexisting medical conditions. In the CLL11 trial, no new safety signals were detected for obinutuzumab. The most common grade 3/4 adverse events for obinutuzumab were infusion-related reactions and neu-

tropenia, which did not result in an increased risk of infection. The inci-

dence and severity of infusion-related reactions decreased after the first infu-

sion and no grade 3/4 infusion-related reactions have been reported beyond the first infusion. Obinutuzumab is currently being investigated in multiple phase III studies vs rituximab in indolent non-Hodgkin lymphoma and diffuse large B-cell lymphoma. continued on page 74

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(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112). Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST 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. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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 of POMALYST in patients below the age of 18 have not been established.

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• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma 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. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia


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FDA Update

FDA Announces Decisions on New Tobacco Products

F

or the first time since the Family Smoking Prevention and Tobacco Control Act of 2009 gave the FDA the authority to regulate tobacco products, the agency has authorized the marketing of two new tobacco products and

denied the marketing of four others through the substantial equivalence pathway. Under the law, one way manufacturers can legally sell a new tobacco product is to establish that their prod-

uct is substantially equivalent to a valid predicate product already on the market. The FDA works to ensure that any new tobacco product authorized through the substantial equivalence pathway will not present more harm

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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide). Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may 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 POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST 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 POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. 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 POMALYST 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 POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST 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 POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. 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)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, 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 POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved. POMBSv.001a 02/13

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public health by not allowing new tobacco products under FDA’s authority to come to market without FDA review.” Once a company receives an SE Marketing Order for a product, it means only that the FDA has found that the new tobacco product is substantially equivalent to a predicate product and in compliance with the requirements of the Federal Food, Drug & Cosmetic Act (FD&C Act). An SE Marketing Order is not a finding that the product it is safe or safer than its predicate product, or less harmful in general. In addition the law makes clear that companies cannot say their products are FDA approved. n

Obinutuzumab and Pertuzumab

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8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST 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 POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST 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 POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. 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. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

to public health than the product with which it was compared. “[This] historic announcement marks an important step toward the FDA’s goal of reducing preventable disease and death caused by tobacco,” said FDA Commissioner Margaret A. Hamburg, MD. “The FDA has unprecedented responsibility to protect

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Pertuzumab

Recently FDA also accepted a supplemental Biologics License Application from Genentech for the use of a pertuzumab (Perjeta) regimen in the neoadjuvant setting for patients with HER2-positive earlystage breast cancer. The FDA will make a decision on approval of pertuzumab by October 31, 2013. The application is based primarily on results from two phase II studies of pertuzumab in HER2-positive early stage breast cancer (NEOSPHERE and TRYPHAENA), as well as on longer-term safety data from the phase III CLEOPATRA study of pertuzumab in HER2-positive metastatic breast cancer. n


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ACCC Annual National Meeting Rare Cancers

ACCC Institutes Network to Provide Assistance in Treating Uncommon Cancers By Margot J. Fromer

A

mong the more than 200 types of cancer are those called “forgotten” or “orphan” cancers, with fewer than 40,000 new cases each year. They present treatment challenges in community cancer centers. Because of the low incidence of these diseases, such as chronic myeloid leukemia, acute promyelocytic leukemia, and multiple myeloma, many community oncologists have trouble keeping up with clinical data and would benefit from colleagues’ experience. Moreover, because nurses, social workers, and other providers see these diseases infrequently, more information would help provide better supportive care. Whereas some patients with smallpopulation cancers are referred to major academic centers, most are treated and followed in community-based care. “Patients want to be at home,” said Wendy Mitsuyama, RN, MSN, MBA, Program Manager, Hematology/Hematologic Malignancies, Seattle Cancer Care Alliance. Last year, her organization received 341 requests for help from community oncologists.

ACCC Seeks to Expand Expertise In 2010, the Association of Community Cancers Centers (ACCC) began its Improving Quality Care in Small-Population Cancers program, specifically in chronic myeloid leukemia, acute promyelocytic leukemia, and multiple myeloma. It is designed to take advantage of the expertise of ACCC member specialists who can disseminate effective clinical practices. An advisory board was composed of a multidisciplinary team that provided guidance for the project, which has three components: • Provider portal, an interactive website that provides clinical and practical information. It is the first step for ACCC member oncologists looking for information about how best to treat a patient with one of the three cancers. • Effective practices, standards-

based examples that focus on clinical, patient support, and program management. • Community resource centers, providing access for ACCC members to virtual “experts in residence.” Community resource centers allow providers who may see only a few pa-

and have a number of community programs. We also have a large mailing list for our newsletters and other informational material directed toward community oncologists.” She explained that the center sends physicians to satellite clinics as far away as Wyoming, Alaska, Oregon, Montana, and Idaho. “We have particularly respon-

There are good treatment guidelines available, but some patients don’t fit the guidelines, so we discuss options on a case-by-case basis. —Julie M. Vose, MD, MBA

tients with small-population cancers to keep up with necessary expertise— for instance, treatment guidelines, expected adverse events, supportive care, transplant eligibility, insurance reimbursement, and other financial matters. “Information, experience, and best practices do exist for these less common cancers,” said ACCC President Virginia T. Vaitones, MSW, OSW-C. “The [community resource center] aspect of this project aims to make this knowledge accessible on demand to cancer care providers around the country so that patients with these diseases can have quality care and cutting-edge treatments, regardless of where they choose to be treated.” In establishing the quality care program, ACCC surveyed cancer centers to determine the adequacy and effectiveness of their overall resources, specific clinical processes, and support services. Five programs were chosen to be community resource centers: John Theurer Cancer Center, Hackensack NJ; The Nebraska Medical Center, Omaha; Seattle Cancer Care Alliance; St. Vincent Hospitals and Health Care Center, Indianapolis; and Winship Cancer Institute, Atlanta. Ms. Mitsuyama said that the Seattle center has always had a policy of community outreach. “We do a great deal of clinical and translational research

sive doctors,” she said. “There’s a central phone number for referrals, and we’ve set up a phone tree so that people out in the community can get expert help quickly. Our physicians really care that patients in the community have what they need.”

How Community Resource Centers Help There are fewer than 6,000 new cases of chronic myeloid leukemia each year. Slightly more men than women get it, and more than half the cases are diagnosed in people over age 65. There has been significant improvement in treatment; therefore most patients survive at least 5 years after diagnosis. Acute promyelocytic leukemia is a subtype of acute myeloid leukemia and accounts for only 5% to 10% of all cases of the latter disease. It is commonly diagnosed around 40 years of age. Multiple myeloma has about 8,000 new cases every year. Its treatment also is improving, so prevalence is increasing. Julie M. Vose, MD, MBA, Professor of Internal Medicine and Chief of Hematology and Oncology at University of Nebraska Medical Center, said, “These patients are on treatment for the rest of their lives, so for many of them the problems of having a relatively rare type of cancer are compounded by living far from a treatment center, perhaps one that has little or

no experience with their disease.” The community resource center in Nebraska also provides resources for a wide geographic area: Iowa, Kansas, Missouri, and South Dakota in addition to its home state. Dr. Vose said that she and her colleagues can provide information about treatment, as well as educational resources, especially for all health-care professionals who offer oncology services. “There are good treatment guidelines available, but some patients don’t fit the guidelines, so we discuss options on a case-by-case basis.” She added that there’s not much call for help with supportive care. “That’s mostly done locally.” She believes that the community resource center program is much needed and will be valuable if community oncologists use it. ACCC’s research found that the most effective treatment of patients with small-population cancers is teambased, coordinated by case managers (navigators). Because people with these diseases are not cured but rather stabilized, they must be continuously monitored and their need for support services assessed throughout the course of the disease. Some community cancer programs do this well, but many don’t. Community resource centers can help uninsured and underinsured patients obtain expensive treatment, check on clinic visit compliance, follow-up between visits to see if prescriptions have been filled, and establish policies or guidelines to ensure drug compliance. Ms. Mitsuyama believes that the community resource center program in Seattle is successful for three major reasons: • A high degree of experience and expertise in blood and marrow transplantation • A world-class faculty • A large portfolio of clinical trials ACCC members can access information from any of the community resource centers by going to http:// mynetwork.accc-cancer.org. n Disclosure: Ms. Mitsuyama, Ms. Vaitones, and Dr. Vose reported no potential conflicts of interest.


The ASCO Post | JULY 25, 2013

PAGE 76

In the Clinic

Denosumab in Adults and Skeletally Mature Adolescents with Giant Cell Tumor of Bone 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.

patients. Median time to response was 3 months. The median duration of follow-up was 20 months (range 2–44  months) in responders, with 51% (n = 24) having responses lasting at least 8 months, and three patients experiencing disease progression following response. 

Indication

How It Works

On June 13, 2013, denosumab (Xgeva) was approved for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.1,2 Denosumab is already indicated for prevention of skeletal-related events in patients with bone metastases from solid tumors. Denosumab is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. Approval was based on demonstration of durable objective responses in two multicenter open-label trials in a total of 304 adults and skeletally mature adolescents (n = 10) = 10) 10) with histologically confirmed, measurable giant cell tumor of bone. The tumors were recurrent, unresectable, or located where planned surgery was likely to result in severe morbidity. Patients in these trials received subcutaneous denosumab at 120 mg every 4 weeks with additional doses on days 8 and 15 of the first month. Patients receiving concurrent bisphosphonate therapy were excluded from both trials and patients with history of osteonecrosis of the jaw or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, unhealed dental/oral surgery, or any planned invasive dental procedure were excluded from the larger (N = 282) of the two trials. During the trials, serum chemistries including calcium and phosphorus were monitored every 4 weeks, and calcium and vitamin D supplementation was recommended but not required. Radiographic assessments at baseline and following denosumab treatment were available for 187 (61%) patients. A retrospective assessment by an independent review committee found objective response (all partial responses) in 47 (25%) of the 187

The human monoclonal antibody denosumab binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, which are the cells responsible for bone resorption. Increased osteoclast activity stimulated by RANKL is a mediator of bone pathology in solid tumors with osseous metastases. Giant cell tumors of bone consist of stromal cells expressing

15 of the first month of therapy. Calcium and vitamin D should be taken as necessary to treat or prevent hypocalcemia. There is no evidence that anticancer treatments affect denosumab exposure or pharmacodynamics. Serum denosumab concentrations at 1 and 3 months and reductions in bone turnover markers at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy and were not altered by concomitant chemotherapy or hormone therapy.

Safety Profile Safety was evaluated in 304 patients, of whom 145 were treated for at least 1 year.  The median number of doses given was 14. Patients had a median age of 33 years, 58% were

Expanded Indications for Denosumab in Giant Cell Bone Tumor ■ Denosumab (Xgeva) has been approved in adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection would cause severe morbidity.

■ The recommended dose of denosumab in patients with giant cell tumor

of bone is 120 mg every 4 weeks given subcutaneously in the upper arm, upper thigh, or abdomen, with additional 120 mg doses on days 8 and 15 of the first month of therapy.

RANKL and osteoclast-like giant cells expressing RANK receptors; signaling through the RANK receptor contributes to osteolysis and tumor growth. Denosumab prevents RANKL from activating RANK receptors on the surface of osteoclasts, osteoclast precursors, and osteoclast-like giant cells.

How It Is Given The recommended dose of denosumab in patients with giant cell tumor of bone is 120 mg every 4 weeks

OF NOTE Denosumab carries warnings/precautions for hypocalcemia, osteonecrosis of the jaw, and embryofetal toxicity. given subcutaneously in the upper arm, upper thigh, or abdomen, with additional 120 mg doses on days 8 and

women, and 80% were white. The adverse event profile was similar to that in patients with bone metastases from solid tumors. The most common adverse events (≥ 10% incidence) were arthralgia, headache, nausea, back pain, fatigue, and extremity pain. Moderate hypocalcemia occurred in 2.6% of patients and severe hypophosphatemia in 9.5%. Osteonecrosis of the jaw was confirmed in four patients (1.3%), with a median time to onset of 16 months (range, 13–20 months). The most common adverse events resulting in discontinuation of treatment were osteonecrosis of the jaw (0.7%) and tooth abscess or tooth infection (0.7%). The adverse event profile appeared similar in skeletally mature adolescents and adults. Denosumab carries warnings/precautions for hypocalcemia (including fatalities), osteonecrosis of the jaw, and embryo-fetal toxicity. Patients

should have hypocalcemia corrected before starting denosumab treatment, and calcium levels should be monitored regularly, with all patients

OF NOTE Denosumab binds to and blocks the activity of RANKL, a protein essential for the survival of osteoclasts, which contribute to osteolysis and tumor growth. receiving adequate calcium and vitamin D supplementation. Patients with creatinine clearance less than 30 mL/ min or on dialysis are at increased risk for hypocalcemia. Patients should receive an oral exam prior to starting treatment and should be monitored for symptoms of osteonecrosis of the jaw. Dental procedures should be avoided during treatment. Women of reproductive potential should be advised of risk to the fetus and to use effective contraception. Nursing mothers should discontinue nursing or denosumab based on consideration of importance of denosumab treatment to the mother. n References 1. U.S. Food and Drug Administration: Denosumab. Available at http://www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm356667.htm. Accessed July 3, 2013. 2. XGEVA® (denosumab) injection prescribing information, Amgen Inc, June 2013. Available at http://www. accessdata.fda.gov/drugsatfda_docs/ label/2013/125320s094lbl.pdf. Accessed July 3, 2013.

REPORT ADVERSE EVENTS Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


When hemoglobin falls...


Catch hemoglobin levels before they fall too far Reduce RBC transfusions and achieve a gradual and steady Hb rise with Aranesp

®1-4

• In untreated patients whose Hb fell below 10 g/dL, 1 in 3 required an RBC transfusion within 6 weeks.5* • Aranesp® significantly reduced the need for RBC transfusions by 48% compared to placebo.2,3† • Aranesp® can be synchronized with the majority of chemotherapy regimens, including Q3W.6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa ACC trials. Patients had baseline Hb ≥ 10 g/dL and decline to Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of patients with transfusions by Weeks 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Seventy-two percent of patients had lung cancer.5 †Data from a randomized, double-blind, placebo-controlled trial of 314 anemic (Hb ≤ 11 g/dL) patients with lung cancer receiving platinum-containing chemotherapy. Patients received once-weekly treatment with either Aranesp® (2.25 mcg/kg) or placebo, administered by subcutaneous injection, for up to 12 weeks. Per the pivotal trial protocol, doses were withheld if Hb exceeded 14 g/dL for women or 15 g/dL for men.2,3

Aranesp® (darbepoetin alfa) Indication Aranesp® is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

Limitations of Use: Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp® is not for use: • In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. • In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • As a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia.

References: 1. Vansteenkiste J, Hedenus M, Gascon P, et al. BMC Cancer. 2009;9:311. doi:10.1186/1471-2407-9-311. 2. Aranesp® (darbepoetin alfa) Prescribing Information, Amgen. 3. Vansteenkiste J, Pirker R, Massuti B, et al. J Natl Cancer Inst. 2002;94:1211-1220. 4. Canon JL, Vansteenkiste J, Bodoky G, et al. J Natl Cancer Inst. 2006;98:273-284. 5. Pirker R, Collins H, Legg J, et al. J Clin Oncol. 2011;29(suppl). Abstract e19637. 6. Data on file, Amgen; [Tandem Anti-cancer and Tumor Audit].

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799 www.amgen.com

© 2013 Amgen Inc. All rights reserved. Not for Reproduction. G69514-R2-V2 68701-R2-V2

RBC = red blood cell.

Hb = hemoglobin.

Q3W = once every three weeks.


Important Safety Information including Boxed WARNINGS for Aranesp® (darbepoetin alfa) WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, Aranesp® dose, or dosing strategy that does not increase these risks. • Use the lowest Aranesp® dose sufficient to reduce the need for red blood cell (RBC) transfusions. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. • Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/ or dispense Aranesp® to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions. • Use ESAs only for anemia from myelosuppressive chemotherapy. • ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • Discontinue following the completion of a chemotherapy course. • Aranesp® is contraindicated in patients with: − Uncontrolled hypertension − Pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs − Serious allergic reactions to Aranesp®

• In controlled clinical trials of patients with cancer, Aranesp® and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures. • Control hypertension prior to initiating and during treatment with Aranesp®. • For lack or loss of hemoglobin response to Aranesp®, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. • Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp®. − This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. − PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp® is not approved). − If severe anemia and low reticulocyte count develop during treatment with Aranesp®, withhold Aranesp® and evaluate patients for neutralizing antibodies to erythropoietin. − Permanently discontinue Aranesp® in patients who develop PRCA following treatment with Aranesp® or other erythropoietin protein drugs. Do not switch patients to other ESAs. • Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp®. Immediately and permanently discontinue Aranesp® if a serious allergic reaction occurs. • Adverse reactions (≥ 1%) in clinical studies in cancer patients receiving chemotherapy were abdominal pain, edema, and thrombovascular events. Please see Aranesp® brief summary of prescribing information, including Boxed WARNINGS, on the adjacent page. Visit Aranesp.com for more information.


BRIEF SUMMARY: Consult package insert for complete prescribing information. Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *ODPOUSPMMFEUSJBMT QBUJFOUTFYQFSJFODFEHSFBUFSSJTLTGPSEFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT  BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJTTUJNVMBUJOHBHFOUT &4"T UPUBSHFUBIFNPHMPCJOMFWFM PGHSFBUFSUIBOHE- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM  "SBOFTQ EPTF  PS EPTJOHTUSBUFHZUIBUEPFTOPUJODSFBTFUIFTFSJTLT t 6TFUIFMPXFTU"SBOFTQEPTFTVGmDJFOUUPSFEVDFUIFOFFEGPSSFECMPPE cell (RBC) transfusions. Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOEPS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU  OPOTNBMMDFMMMVOH IFBEBOEOFDL MZNQIPJE BOEDFSWJDBMDBODFST t #FDBVTF PG UIFTF SJTLT  QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZXJUIUIF&4""113*4&0ODPMPHZ1SPHSBNUPQSFTDSJCFBOEPS EJTQFOTF"SBOFTQUPQBUJFOUTXJUIDBODFS5PFOSPMMJOUIF&4""113*4& 0ODPMPHZ1SPHSBN WJTJUXXXFTBBQQSJTFDPNPSDBMMGPS GVSUIFSBTTJTUBODF t 5PEFDSFBTFUIFTFSJTLT BTXFMMBTUIFSJTLPGTFSJPVTDBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT  VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF&4"TPOMZGPSBOFNJBGSPNNZFMPTVQQSFTTJWFDIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZXIFOUIFBOUJDJQBUFEPVUDPNFJTDVSF t %JTDPOUJOVFGPMMPXJOHUIFDPNQMFUJPOPGBDIFNPUIFSBQZDPVSTF

INDICATION AND USAGE "OFNJB%VFUP$IFNPUIFSBQZJO1BUJFOUT8JUI$BODFS Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp is not indicated for use: t *OQBUJFOUTXJUIDBODFSSFDFJWJOHIPSNPOBMBHFOUT CJPMPHJDQSPEVDUT  or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *OQBUJFOUTXJUIDBODFSSFDFJWJOHNZFMPTVQQSFTTJWFDIFNPUIFSBQZXIFOUIF anticipated outcome is cure. t "T B TVCTUJUVUF GPS 3#$ USBOTGVTJPOT JO QBUJFOUT XIP SFRVJSF JNNFEJBUF correction of anemia.

CONTRAINDICATIONS

Aranesp is contraindicated in patients with: t 6ODPOUSPMMFEIZQFSUFOTJPO t 1VSFSFEDFMMBQMBTJB 13$" UIBUCFHJOTBGUFSUSFBUNFOUXJUI"SBOFTQPSPUIFS erythropoietin protein drugs. t 4FSJPVTBMMFSHJDSFBDUJPOTUP"SBOFTQ

WARNINGS AND PRECAUTIONS *ODSFBTFE.PSUBMJUZ .ZPDBSEJBM*OGBSDUJPO 4USPLF BOE5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT HE-  UPMPXFSUBSHFUT  HE-  "SBOFTQBOE PUIFS&4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. 6TJOH"SBOFTQUPUBSHFUBIFNPHMPCJOMFWFMPGHSFBUFSUIBOHE-JODSFBTFTUIFSJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBMCFOFmU6TFDBVUJPOJOQBUJFOUTXJUIDPFYJTUFOUDBSEJPWBTDVMBSEJTFBTFBOE TUSPLF1BUJFOUTXJUI$,%BOEBOJOTVGmDJFOUIFNPHMPCJOSFTQPOTFUP&4"UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT"SBUFPGIFNPHMPCJOSJTFPGHSFBUFSUIBOHE-PWFSXFFLTNBZDPOUSJCVUF to these risks. *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI DBODFS  "SBOFTQ BOE PUIFS &4"T increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. *ODPOUSPMMFEDMJOJDBMUSJBMT &4"TJODSFBTFEUIFSJTLPGEFBUIJOQBUJFOUTVOEFSHPJOH DPSPOBSZBSUFSZCZQBTTHSBGUTVSHFSZ $"#( BOEUIFSJTLPGEFFQWFOPVTUISPNCPTJT %75 JOQBUJFOUTVOEFSHPJOHPSUIPQFEJDQSPDFEVSFT 1BUJFOUTXJUI$BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFEJOQBUJFOUTXJUIDBODFSUSFBUFEXJUI&4"T *O B SBOEPNJ[FE  QMBDFCPDPOUSPMMFE TUVEZ TFF 4UVEZ  JO 5BCMF  JO 1SFTDSJCJOH *OGPSNBUJPO PGXPNFOXJUINFUBTUBUJDCSFBTUDBODFSSFDFJWJOHDIFNPUIFSBQZ  patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered UPQSFWFOUBOFNJB NBJOUBJOIFNPHMPCJOMFWFMTCFUXFFOBOEHE-PSIFNBUPDSJU CFUXFFOBOE 5IJTTUVEZXBTUFSNJOBUFEQSFNBUVSFMZXIFOJOUFSJNSFTVMUT EFNPOTUSBUFEBIJHIFSNPSUBMJUZBUNPOUIT WT BOEBIJHIFSSBUFPG GBUBMUISPNCPUJDSFBDUJPOT WT JOUIFmSTUNPOUITPGUIFTUVEZBNPOH QBUJFOUTUSFBUFEXJUIFQPFUJOBMGB#BTFEPO,BQMBO.FJFSFTUJNBUFT BUUIFUJNFPG TUVEZUFSNJOBUJPO UIFNPOUITVSWJWBMXBTMPXFSJOUIFFQPFUJOBMGBHSPVQUIBOJO UIFQMBDFCPHSPVQ WT)3 $* Q  1SFTDSJCJOHBOE%JTUSJCVUJPO1SPHSBNGPS"SBOFTQJO1BUJFOUT8JUI$BODFS *OPSEFSUPQSFTDSJCFBOEPSEJTQFOTF"SBOFTQUPQBUJFOUTXJUIDBODFSBOEBOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZXJUIUIF&4""113*4&0ODPMPHZ1SPHSBNSFRVJSFNFOUT5PFOSPMM WJTJUXXX FTBBQQSJTFDPNPSDBMMGPSGVSUIFSBTTJTUBODF"EEJUJPOBMMZ QSJPSUP each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.

*ODSFBTFE.PSUBMJUZBOEPS*ODSFBTFE3JTLPG5VNPS1SPHSFTTJPOPS3FDVSSFODF JO1BUJFOUT8JUI$BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPMQSPHSFTTJPOGSFF TVSWJWBM BOE PS PWFSBMM TVSWJWBM 4FF 5BCMF  JO 1SFTDSJCJOH *OGPSNBUJPO  5IFTF mOEJOHT XFSF observed in studies of patients with advanced head and neck cancer receiving SBEJBUJPOUIFSBQZ 4UVEJFTBOE JOQBUJFOUTSFDFJWJOHDIFNPUIFSBQZGPSNFUBTUBUJD CSFBTUDBODFS 4UVEZ PSMZNQIPJENBMJHOBODZ 4UVEZ BOEJOQBUJFOUTXJUIOPO small cell lung cancer or various malignancies who were not receiving chemotherapy PSSBEJPUIFSBQZ 4UVEJFTBOE  Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT  BQQSPYJNBUFMZ  PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWFFODFQIBMPQBUIZBOETFJ[VSFTIBWFCFFOSFQPSUFEJOQBUJFOUTXJUI$,% receiving Aranesp. Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ3FEVDFPSXJUIIPME"SBOFTQJGCMPPEQSFTTVSFCFDPNFTEJGmDVMUUPDPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Seizures "SBOFTQJODSFBTFTUIFSJTLPGTFJ[VSFTJOQBUJFOUTXJUI$,%%VSJOHUIFmSTUTFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFXPOTFUTFJ[VSFT QSFNPOJUPSZTZNQUPNT PSDIBOHFJOTFJ[VSFGSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST FH JSPOEFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *GUZQJDBMDBVTFTPG MBDLPSMPTTPGIFNPHMPCJOSFTQPOTFBSFFYDMVEFE FWBMVBUFGPS13$"*OUIFBCTFODF PG 13$"  GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy. Pure Red Cell Aplasia $BTFTPG13$"BOEPGTFWFSFBOFNJB XJUIPSXJUIPVUPUIFSDZUPQFOJBTUIBUBSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in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erious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT  JODMVEJOH BOBQIZMBDUJD SFBDUJPOT  BOHJPFEFNB  CSPODIPTQBTN TLJOSBTI BOEVSUJDBSJBNBZPDDVSXJUI"SBOFTQ*NNFEJBUFMZBOE permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs. Dialysis Management 1BUJFOUT NBZ SFRVJSF BEKVTUNFOUT JO UIFJS EJBMZTJT QSFTDSJQUJPOT BGUFS JOJUJBUJPO PG "SBOFTQ 1BUJFOUT SFDFJWJOH "SBOFTQ NBZ SFRVJSF JODSFBTFE BOUJDPBHVMBUJPO XJUI IFQBSJOUPQSFWFOUDMPUUJOHPGUIFFYUSBDPSQPSFBMDJSDVJUEVSJOHIFNPEJBMZTJT Laboratory Monitoring &WBMVBUF USBOTGFSSJO TBUVSBUJPO BOE TFSVN GFSSJUJO QSJPS UP BOE EVSJOH "SBOFTQ treatment. Administer supplemental iron therapy when serum ferritin is less than NDH-PSXIFOTFSVNUSBOTGFSSJOTBUVSBUJPOJTMFTTUIBO5IFNBKPSJUZPG QBUJFOUTXJUI$,%XJMMSFRVJSFTVQQMFNFOUBMJSPOEVSJOHUIFDPVSTFPG&4"UIFSBQZ 'PMMPXJOHJOJUJBUJPOPGUIFSBQZBOEBGUFSFBDIEPTFBEKVTUNFOU NPOJUPSIFNPHMPCJO XFFLMZVOUJMUIFIFNPHMPCJOJTTUBCMFBOETVGmDJFOUUPNJOJNJ[FUIFOFFEGPS3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM5SJBM&YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT  BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UPSBUFTJOUIFDMJOJDBMUSJBMTPGPUIFSESVHTBOENBZOPUSFnFDUUIFSBUFTPCTFSWFE in practice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tudy Adverse Reaction 5ISPNCPFNCPMJD"EWFSTF3FBDUJPOT  O 

Arterial .ZPDBSEJBMJOGBSDUJPO 7FOPVT 1VMNPOBSZFNCPMJTN $FSFCSPWBTDVMBSEJTPSEFST

"MM1MBDFCP controlled Studies

*O BEEJUJPO UP UIF UISPNCPWBTDVMBS BEWFSTF SFBDUJPOT  BCEPNJOBM QBJO BOE FEFNB occurred at a higher incidence in patients taking Aranesp compared to patients on QMBDFCP"NPOHBMMQMBDFCPDPOUSPMMFETUVEJFT BCEPNJOBMQBJO WT BOE FEFNB WT XFSFSFQPSUFENPSFGSFRVFOUMZJOQBUJFOUTSFDFJWJOH"SBOFTQ DPNQBSFE UP UIF QMBDFCP HSPVQ *O UIF 4$-$ TUVEZ UIF JODJEFODF PG BCEPNJOBM QBJO WT BOEFEFNB WT JOUIF"SBOFTQUSFBUFEQBUJFOUT compared to those receiving placebo. 1PTUNBSLFUJOH&YQFSJFODF #FDBVTF QPTUNBSLFUJOH SFQPSUJOH PG BEWFSTF SFBDUJPOT JT WPMVOUBSZ BOE GSPN B QPQVMBUJPO PG VODFSUBJO TJ[F  JU JT OPU BMXBZT QPTTJCMF UP SFMJBCMZ FTUJNBUF UIFJS GSFRVFODZPSFTUBCMJTIBDBVTBMSFMBUJPOTIJQUPESVHFYQPTVSF The following adverse reactions have been identiямБed during postmarketing use of Aranesp: t 4FJ[VSFT t 13$" t 4FSJPVTBMMFSHJDSFBDUJPOT Immunogenicity "TXJUIBMMUIFSBQFVUJDQSPUFJOT UIFSFJTBQPUFOUJBMGPSJNNVOPHFOJDJUZ/FVUSBMJ[JOH antibodies to darbepoetin alfa that cross-react with endogenous erythropoietin and PUIFS&4"TDBOSFTVMUJO13$"PSTFWFSFBOFNJB XJUIPSXJUIPVUPUIFSDZUPQFOJBT  *O DMJOJDBM TUVEJFT  UIF QFSDFOUBHF PG QBUJFOUT XJUI BOUJCPEJFT UP "SBOFTQ XBT FYBNJOFEVTJOHUIF#JBDPSF┬оBTTBZ4FSBGSPNQBUJFOUTXJUI$,%BOE cancer patients were tested. At baseline, prior to Aranesp treatment, binding BOUJCPEJFT XFSF EFUFDUFE JO  QBUJFOUT   XJUI $,% BOE  DBODFS QBUJFOUT   %VSJOH "SBOFTQ UIFSBQZ SBOHF  UP  XFFLT  B GPMMPXVQ TBNQMF XBT UBLFO0OFBEEJUJPOBMQBUJFOUXJUI$,%BOEBEEJUJPOBMDBODFSQBUJFOUTEFWFMPQFE BOUJCPEJFTDBQBCMFPGCJOEJOH"SBOFTQ/POFPGUIFQBUJFOUTIBEBOUJCPEJFTDBQBCMF PGOFVUSBMJ[JOHUIFBDUJWJUZPG"SBOFTQPSFOEPHFOPVTFSZUISPQPJFUJOBUCBTFMJOFPSBU FOEPGTUVEZ/PDMJOJDBMTFRVFMBFDPOTJTUFOUXJUI13$"XFSFBTTPDJBUFEXJUIUIF presence of these antibodies. The incidence of antibody formation is highly dependent on the sensitivity and TQFDJmDJUZPGUIFBTTBZ"EEJUJPOBMMZ UIFPCTFSWFEJODJEFODFPGBOUJCPEZ JODMVEJOH OFVUSBMJ[JOH BOUJCPEZ  QPTJUJWJUZ JO BO BTTBZ NBZ CF JOnVFODFE CZ TFWFSBM GBDUPST  including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aranesp with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS

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USE IN SPECIFIC POPULATIONS Pregnancy 1SFHOBODZ$BUFHPSZ$ There are no adequate and well-controlled studies of Aranesp use in pregnant women. *O BOJNBM SFQSPEVDUJPO BOE EFWFMPQNFOUBM UPYJDJUZ TUVEJFT  "SBOFTQ JODSFBTFE FBSMZ QPTUJNQMBOUBUJPO MPTT 6TF "SBOFTQ EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFmU KVTUJmFTUIFQPUFOUJBMSJTLUPUIFGFUVT8IFO"SBOFTQXBTBENJOJTUFSFEJOUSBWFOPVTMZ to healthy pregnant rats and rabbits, there was no evidence of embryofetal UPYJDJUZ PS PUIFS BEWFSTF PVUDPNFT BU UIF JOUSBWFOPVT EPTFT UFTUFE  VQ UP  NDHLHEBZ 5IJT BOJNBM EPTF MFWFM PG  NDHLHEBZ JT BQQSPYJNBUFMZ GPME IJHIFS UIBO UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF  EFQFOEJOH PO UIF QBUJFOUTUSFBUNFOUJOEJDBUJPO4MJHIUMZSFEVDFEGFUBMXFJHIUTXFSFPCTFSWFEXIFO IFBMUIZSBUBOESBCCJUNPUIFSTSFDFJWFEEPTFTPGNDHLHPSNPSF5IJTEPTFPG NDHLHJTOFBSUIFDMJOJDBMSFDPNNFOEFETUBSUJOHEPTF8IJMFOPBEWFSTFFGGFDUT on uterine implantation occurred in animals, there was an increase in early postJNQMBOUBUJPO MPTT JO BOJNBM GFSUJMJUZ TUVEJFT *U JT OPU DMFBS XIFUIFS UIF JODSFBTFE QPTUJNQMBOUBUJPOMPTTSFnFDUTBESVHFGGFDUPOUIFVUFSJOFFOWJSPONFOUPSPOUIF DPODFQUVT/PTJHOJmDBOUQMBDFOUBMUSBOTGFSPG"SBOFTQXBTEFUFDUFE *O B QFSJQPTUOBUBM EFWFMPQNFOU TUVEZ  QSFHOBOU GFNBMF SBUT SFDFJWFE "SBOFTQ intravenously every other day from implantation throughout pregnancy and MBDUBUJPO 5IF MPXFTU EPTF UFTUFE   NDHLH  EJE OPU DBVTF GFUBM UPYJDJUZ UIJT EPTF JT BQQSPYJNBUFMZ FRVJWBMFOU UP UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF "U NBUFSOBMEPTFTPGNDHLHBOEIJHIFS QVQTIBEEFDSFBTFEGFUBMCPEZXFJHIUT  which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. 8PNFOXIPCFDPNFQSFHOBOUEVSJOH"SBOFTQUSFBUNFOUBSFFODPVSBHFEUPFOSPMM JO"NHFOT1SFHOBODZ4VSWFJMMBODF1SPHSBN1BUJFOUTPSUIFJSQIZTJDJBOTTIPVME DBMM ".(&/ UPFOSPMM /VSTJOH.PUIFST *UJTOPULOPXOXIFUIFS"SBOFTQJTFYDSFUFEJOIVNBONJML#FDBVTFNBOZESVHTBSF FYDSFUFEJOIVNBONJML DBVUJPOTIPVMECFFYFSDJTFEXIFO"SBOFTQJTBENJOJTUFSFE to a nursing woman. Pediatric Use The safety and efямБcacy of Aranesp in pediatric cancer patients have not been established. Geriatric Use 0GUIFQBUJFOUTXJUI$,%JODMJOJDBMTUVEJFTPG"SBOFTQ XFSFBHFBOE PWFS XIJMFXFSFBHFBOEPWFS0GUIFQBUJFOUTJODMJOJDBMTUVEJFTSFDFJWJOH "SBOFTQBOEDPODPNJUBOUDBODFSDIFNPUIFSBQZ XFSFBHFBOEPWFS XIJMF  XFSF BHF  BOE PWFS /P EJGGFSFODFT JO TBGFUZ PS FGmDBDZ XFSF PCTFSWFE between older and younger patients.

OVERDOSAGE

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Manufactured by: "NHFO.BOVGBDUVSJOH-JNJUFE BTVCTJEJBSZPG"NHFO*OD 0OF"NHFO$FOUFS%SJWF 5IPVTBOE0BLT $" This product, the process of its manufacture, or its use, may be covered by one or NPSF641BUFOUT JODMVEJOH641BUFOU/P   ┬к"NHFO*OD"MMSJHIUTSFTFSWFE 37


ASCOPost.com | JULY 25, 2013

PAGE 81

Expert’s Corner Hematology

Barriers to Successful Hematopoietic Stem Cell Transplantation A Conversation with Mary M. Horowitz, MD, MS By Susan London

Mary M. Horowitz, MD, MS

T

he Center for International Blood and Marrow Transplant Research is a combined research program of the National Marrow Donor Program and the Medical College of Wisconsin, Milwaukee. At the forefront of research to increase access to hematopoietic stem cell transplantation and improve outcomes, the Center has amassed a clinical database containing information on nearly 350,000 transplant recipients. The Scientific Director of the Center is Mary M. Horowitz, MD, MS, Chief of the Division of Hematology/ Oncology, Professor of Medicine, and Robert A. Uihlein, Jr. Chair in Hematologic Research at the Medical College of Wisconsin. She is also Principal Investigator for the Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network. The ASCO Post recently spoke with Dr. Horowitz about advances and challenges in the use of hematopoietic stem cell transplantation.

State of the Art How would you characterize the current status of hematopoietic stem cell transplant? It’s really a very exciting time. Over the past decade in particular, there have been significant improvements in how we do transplants so that they can be used successfully in a broader population. This is particularly true in the area of allogeneic transplantation, where the major barriers to widespread use were the toxicity associated with high-dose chemotherapy and radiation given beforehand, and the high risk of graft-vs-host disease, especially when using donors

other than human leukocyte antigen (HLA)-identical siblings. New reduced-intensity preparative regimens cause considerably less morbidity and mortality, but are still sufficiently immunosuppressive to allow donor cells to engraft. These regimens make it possible for much older—and sicker—patients to undergo allogeneic transplantation. This is important because hematologic malignancies, where allografting has its greatest efficacy, largely affect an older population. Much of the recent increase in the numbers of transplants being performed is in patients older than 60. We are also able to use these regimens in patients with comorbidities, like cardiac and pulmonary dysfunction, who previously were considered to be too sick to receive a transplant. Another important development is the increased availability of donors. We can find fully matched unrelated

effective therapy and a therapy we are able to apply to many more people.

Major Barriers What are the main barriers to successful hematopoietic stem cell transplant today, and what will it take to overcome them? Disease recurrence is the major cause of treatment failure after transplantation. A lot of effort really needs to be devoted to addressing why some patients are cured and others are not after autologous transplant and allogeneic transplant—the answer might differ for those two approaches—and what can we do about it. In the autologous setting, additional dose intensification of treatment may be possible with targeted therapies like radiolabeled antibodies that deliver higher doses to the tumor. Another approach is maintenance after transplant, which has been shown to prolong not

I suspect that in 10 years, there will be a combination of advances in the chemotherapeutic approach, particularly with targeted therapies, improvements in supportive care, and advances in immunotherapy, which will enable us to treat hematologic malignancies with a lot less toxicity and much greater success. —Mary M. Horowitz, MD, MS

donors for about 70% of Caucasian patients, and acceptable donors or cord blood units for most patients. And we are able to do alternativedonor transplants with an acceptable rate of graft-vs-host disease and transplant-related mortality. Previously, allogeneic transplantation was limited to patients who had an HLA-identical matched sibling, or only about 30% of people who might benefit. These advances make transplantation a viable treatment for many more patients with hematologic malignancies. They also allow us to consider transplantation in other disorders where high transplant-related mortality rates were previously considered prohibitive—for example, in people with severe sickle cell disease or autoimmune disease. The bottom line is that transplantation today is a much more

only remission but also survival in the multiple myeloma setting. Furthermore, we may be able to use immune therapy in the autologous setting, perhaps with vaccination strategies or with genetically altered immune cells (ie, chimeric antigen receptors) that target residual cancer. In the allogeneic setting, we need to understand why some patients are not susceptible to graft-vs-tumor effects. Here, as well, we need to evaluate things like maintenance therapy in the minimal residual disease state, and augmentation of antitumor effects using tumor-specific T cells or natural killer cells. Also, we still don’t find an optimal donor for everybody, meaning one who will give you the same outcome as a fully HLA-matched adult donor. Additional donor recruitment is

probably not going to help much because the diversity of the HLA system in humans is so great that you would essentially have to type everyone on the planet to find a full match for every patient. We need to find ways to do HLA-mismatched transplants with the same degree of success we see with HLA-matched transplantation. That requires us to explore new ways of promoting engraftment with low rates of graft-vs-host disease and good recovery of immune function.

Other Issues Are there any big-picture issues that stand in the way of progress? I am greatly concerned that the current very tight research-funding budget at the National Institutes of Health (NIH) will prevent us from continuing the pace of success established in the past few decades. It’s not just that there are some very good ideas that now lack the funding to be explored. I fear we may lose an entire generation of people who could be generating the next big ideas, the things that will keep us moving forward. Young physicians and doctoral graduates coming out of training now are looking at how hard it is to continue funding throughout an academic career in the current climate and are thinking twice. If they are going to work hard, they want to have some reasonable assurance that they will have a chance at success, and it’s pretty difficult to say that when only 5% to 10% of applications for funding succeed. So we need a continued commitment on the part of the government to fund basic, translational, and clinical research.

Promising Approaches What emerging therapeutic approaches in the field appear most promising? Approaches like genetically modifying cells to target the immune response against cancer cells and/or infectious organisms have a lot of potential. One might say that hematopoietic stem cell transplantation is the oldest proven successful adoptive immunotherapy approach. But it’s not specific enough; you could characterize it as bombing a continued on page 82


The ASCO Post | JULY 25, 2013

PAGE 82

News Hematology

New Guidelines Issued in the Treatment of Multiple Myeloma-Related Bone Disease By Jo Cavallo

T

he International Myeloma Working Group  (IMWG) has developed clinical practice recommendations for the management of multiple myeloma-related bone disease based on published study data through August 2012. Consensus of the interdisciplinary panel of clinical experts on the plasma-cell cancer was used to propose additional guidelines in situations in which there were insufficient published data. The recommendations were recently published in the Journal of Clinical Oncology (JCO).1

IMWG Recommendations Included in the recommendations is the use of bisphosphonates for all multiple myeloma patients receiving front-line therapy, regardless of the presence of osteolytic bones lesions on conventional radiography. The IMWG made the recommendation even though it is unknown whether bisphosphonates offer any advantage to patients with no bone disease as determined by magnetic resonance imaging or positron emission tomography/ computed tomography. The panel also recommended the use of intravenous zoledronic acid (Zometa) and pamidronate  (Aredia) in the prevention of skeletal-related

International Myeloma Working Group Recommendations ■ The use of intravenous bisphosphonates should be considered for all

multiple myeloma patients receiving frontline antimyeloma therapy, regardless of the presence of osteolytic bone lesions on conventional radiography.

■ Intravenous bisphosphonates provide greater protection against skeletalrelated events and greater survival benefits than oral bisphosphonates.

■ Between 70% and 80% of newly diagnosed multiple myeloma patients

have osteolytic lesions, putting them at increased risk for skeletal-related events, such as spinal cord compression, and diminishing their quality of life.

Mary M. Horowitz, MD, MS continued from page 81

city to take out a building. We need to enhance our ability to refine the immune effects to be against the cells we want to target while sparing the cells we don’t want to target, thereby increasing efficacy and decreasing toxicity. Combining these immune approaches with targeted therapies—molecules that target specific molecular pathways—is likely to be more effective than the use of targeted molecules alone.

Looking Ahead Where do you think the field will be in 10 years? Prediction is prone to error, so it’s

hard to say. But I suspect that in 10 years, there will be a combination of advances in the chemotherapeutic approach, particularly with targeted therapies, improvements in supportive care, and advances in immunotherapy, which will enable us to treat hematologic malignancies with a lot less toxicity and much greater success. Our ability to better characterize malignancies at the molecular level will allow us to personalize our therapies. Those developments will increase the safety and efficacy of transplantation and make it a more acceptable therapy for a wider range of diseases, including some common noncancer diseases. We will likely see more multi-

events over oral bisphosphonates, such as clodronate (Bonefos), in newly diagnosed myeloma patients because of their antimyeloma effects and survival benefits. Other recommendations include: • Intravenous bisphosphonates should be administered every 3 to 4 weeks during initial therapy. Discontinuation of bisphosphonate therapy may be considered after 1 to 2 years in patients who have achieved complete remission or very good partial response. • Patients with active disease should continue to receive zoldronic acid or pamidronate. and the treatment should resume after disease relapse if it was discontinued in patients achieving complete or very good partial response. • Although bisphosphonates are well tolerated, patients should be made aware of any symptoms suggesting adverse events, including osteonecrosis of the jaw, and physicians should monitor patients for renal toxicity. All myeloma patients treated with bisphosphonates should have creatinine clearance (CrC1), serum electrolytes, center trials in blood and marrow transplantation. The investment by the NIH in the Blood and Marrow Transplant Clinical Trials Network has led to an effective infrastructure for doing multicenter trials that allow us to make definitive decisions about which approaches work—or don’t—much more quickly than was possible in the past. Finally, we will increasingly use observational data to assess and improve patient outcomes. The Center for International Blood and Marrow Transplant Research maintains an outcomes registry on 350,000 transplant recipients—it had its beginnings in the 1970s, when the term outcomes registry didn’t even exist.

and urinary albumin monitored. • Balloon kyphoplasty should be considered in patients with symptomatic vertebral compression fractures. • The use of low-dose radiation (up to 30 Gy) can be used as palliative treatment for uncontrolled pain, impending pathologic fracture, or spinal cord compression, and vertebral column instability. According to the report, osteolytic lesions are found in 70% to 80% of newly diagnosed multiple myeloma patients, putting them at increased risk for skeletal-related events, such as spinal cord compression, requiring surgery or palliative radiotherapy to the bone. “Skeletal-related events impair survival, undermine quality of life, and increase treatment costs,” said panel members. n

Disclosure: For full disclosure of the study authors, visit www.jco.ascopubs.org.

Reference 1. Terpos E, Morgan G, Dimopoulos MA, et al: International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma-related Bone Disease. J Clin Oncol 31(18):2347-2357, 2013.

Appreciation of the value of analyzing very large sets of data to determine what’s going on in the population is so much greater now, and I predict it will be even more so in the future. There will still be a place for clinical trials. But we will more and more expect to have access to data on our patients—and to use those data to inform clinical decisions and to conduct research. Large databases and an increasing array of computational tools available to analyze them will allow us to make faster progress on many fronts, not just in blood and marrow transplantation. n Disclosure: Dr. Horowitz reported no potential conflicts of interest.


ASCOPost.com | JULY 25, 2013

PAGE 83

FDA Update

FDA Approves Afatinib for Late-stage Lung Cancer

O

n July 12, 2013, the FDA approved the tyrosine kinase inhibitor afatinib (Gilotrif) for the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors express epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Concurrent with this action, the FDA approved the therascreen EGFR RGQ PCR Kit for detection of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

tions from afatinib were diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, and pruritus. Serious side effects included diarrhea that can result in kidney failure and severe dehydration,

severe rash, lung inflammation and liver toxicity. 

Companion Diagnostic Test The FDA’s approval of the therascreen EGFR RGQ PCR Kit is based

on data from the clinical study used to support afatinib’s approval. Tumor samples from NSCLC participants in the clinical trial helped to validate the test’s use for detecting EGFR mutations in this patient population. n

Study Details The approval of afatinib was based on the demonstration of improved progression-free survival in a multi-

center, international phase III trial (LUX-Lung 3). The trial enrolled 345 patients with metastatic NSCLC whose tumors tested positive for EGFR mutations. Patients were randomly assigned (2:1) to receive oral afatinib 40 mg once daily (n = 230) or pemetrexed (Alimta) plus cisplatin (n = 115). Randomization was stratified according to EGFR mutation status and race (Asian vs non-Asian). The major efficacy outcome was progression-free survival as assessed by an independent review committee.

Results A statistically significant improvement in progression-free survival was demonstrated for patients in the afatinib arm (P < .001). The median progression-free survival was 11.1 months in the afatinib arm and 6.9 months in the pemetrexed arm. In patients whose tumors had exon 19 deletions or exon 21 (L858R) substitution mutations, the median progression-free survival was 13.6 months in the afatinib arm and 6.9 months in the chemotherapy arm. Objective response rates were 50.4% and 19.1% in the afatinib and chemotherapy arms, respectively. No statistically significant difference in overall survival between the two arms was demonstrated. The most frequent adverse reac-

Our world centers around theirs ACTION PurPOse IMPACT

As cancer researchers, we dare to advocate uncharted paths in science and research. We engage and execute with a vision, collaborating with the oncology community to deliver personalized and measurable outcomes that improve and extend lives. We strive to advance the fight against cancer, continuously applying research to clinical practice and targeting the individual needs of people living with cancer.

This is our pledge. This is GSK Oncology. Learn more at GSKoncology.com

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The ASCO Post | JULY 25, 2013

PAGE 84

Pearls in Neuro-oncology

Management of Anaplastic Oligodendroglial Tumors By Andrew S. Chi, MD, PhD

A

naplastic oligodendroglial tumors (oligodendrogliomas and mixed oligoastrocytomas) account for approximately 7% of all intracranial gliomas in adults and generally have a better prognosis than other types of high-grade gliomas. Several uncontrolled studies in the early 1990s suggested that these tumors were chemosensitive; therefore two large, prospective, randomized trials were initiated to investigate the role of adjuvant chemotherapy in addition to radiotherapy in newly diagnosed anaplastic oligodendroglial tumors. Recently, the long-term results from these trials were reported.1,2 In addition to updating the progressionfree and overall survival data since the

mustine [CeeNu], vincristine).3 In the Radiation Therapy Oncology Group phase III trial (RTOG 9402) patients were randomized to receive either radiotherapy alone or up to four cycles of dose-intensified PCV prior to radiotherapy.4 In both studies, patients were treated with focal radiotherapy to a total dose of 59.4 Gy in 1.8-Gy fractions. Retrospectively, the status of chromosomes 1p and 19q were determined in 91% of patients in the RTOG study and 86% of patients in the EORTC study, and IDH status was evaluated in a subset of patients in both trials. In the initial study results published in 2006, the addition of chemotherapy to radiotherapy improved progressionfree survival but not overall survival in

Treatment of anaplastic oligodendroglial tumors should be individualized, taking into account molecular prognostic markers, functional status, and comorbidities. Enrollment onto one of the ongoing randomized trials should be strongly considered. —Andrew S. Chi, MD, PhD

initial publications,3,4 the follow-up reports retrospectively analyzed the prognostic and predictive impact of genetic markers frequently observed in oligodendroglial tumors. Both studies assessed for codeletion of chromosomes 1p and 19q, an alteration found in 60% to 90% of anaplastic oligodendrogliomas,5 and for isocitrate dehydrogenase (IDH) mutation, which occurs in 70% to 90% of anaplastic oligodendroglial tumors.6

Two Key Trials In the European Organisation for Research and Treatment of Cancer phase�� III trial (EORTC 26951), patients were randomly assigned to receive either radiotherapy alone or radiotherapy followed by up to six cycles of PCV (procarbazine [Matulane], loDr. Chi is Assistant Professor of Neurology at Harvard Medical School and in the Division of Neuro-Oncology at Massachusetts General Hospital Cancer Center, Boston.

both trials.3,4 In addition, in both studies 1p/19q codeletion was a strong prognostic factor regardless of treatment assignment. However, in neither study was 1p/19q codeletion predictive for improved overall survival with the addition of chemotherapy, although the median overall survival had not been achieved in the codeleted subgroups, suggesting longer followup was needed.

Long-term Data In the long-term follow-up results, the two trials differed in their findings with regard to overall survival in the overall study populations.1,2 In the RTOG trial, median overall survival was not different based on treatment group (4.6 years for PCV plus radiotherapy vs 4.7 years for radiotherapy alone, P = .1). However, in the EORTC study longer overall survival was observed for patients who received adjuvant PCV in the intent-to-treat analysis (42.3 vs 30.6 months in the

radiotherapy arm, hazard ratio [HR] = 0.75; P = .018).

1p/19q Codeletion Moreover, there was a significant impact of 1p/19q codeletion on overall survival in these trials. Regardless of treatment assignment, in both trials patients with 1p/19q codeletion survived longer than non-codeleted patients (eg, overall survival of 123 vs 23 months in the EORTC study), confirming the strong prognostic effect of 1p/19q codeletion.1,2 In subset analyses, both studies suggested 1p/19q codeletion predicts sensitivity to PCV. In the RTOG study, patients with 1p/19q codeletion treated with radiotherapy plus PCV lived longer than those treated with radiotherapy alone (median overall survival = 14.7 vs 7.3 years, P = .03).2 Conversely, there was no difference in survival of non-codeleted patients between treatment assignments. In the EORTC study, the median survival of 1p/19q codeleted patients who received PCV was not yet reached compared to 112 months for those treated with radiotherapy alone, which trended to significance (P = .059). In the non-codeleted subset, there was no difference in survival between treatment groups.1 These results are summarized in Table 1.

IDH Mutation The prognostic impact of IDH mutation was also confirmed in both studies. (The vast majority of these mutations were in IDH1; only one case of IDH2 mutation was reported, in the EORTC trial.) The EORTC trial retrospectively evaluated IDH status in 179 of 368 enrolled patients, and IDH mutation was an independent prognostic factor (median overall survival = 8.4 years for IDH-mutant vs 1.4 years for IDH wild-type patients).1 IDH mutation was also an important prognostic factor for overall survival in the RTOG study.2 Whether IDH mutation predicts sensitivity to chemotherapy, however, remains unresolved. In the EORTC study, IDH-mutant tumors seemed to derive more benefit from PCV, but the difference did not reach statistical significance.1 The RTOG

Pearls in Neuro-oncology is guest edited by Tracy Batchelor, MD, Director, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, and Professor of Neurology, Harvard Medical School, Boston. The series is intended to provide the practicing oncologist with guidance in managing neuro-oncology issues that may present in their patients with cancer. investigators did not report on the predictive utility of IDH mutation.

Unresolved Questions Taken together, these results suggest that the standard of care for 1p/19q codeleted anaplastic oligodendroglial tumors should include both radiotherapy and chemotherapy. However, many questions remain regarding the treatment of both 1p/19q codeleted and non-codeleted subsets. One question is whether temozolomide, which is well tolerated and has activity in oligodendrogliomas,7,8 is equivalent to PCV. Limited data suggest that the relative efficacy may be similar: In the NOA-04 randomized phase III trial in anaplastic gliomas, there was no difference between the temozolomide and PCV arms in time to treatment failure, although the study was not powered for this comparison and the follow-up time was limited.9 In addition, a large retrospective study of anaplastic oligodendroglial tumors showed no statistically significant difference in progression-free or overall survival between PCV and temozolomide in 1p/19q codeleted patients who also received radiotherapy.10 However, prospective comparisons of PCV vs temozolomide are lacking.


ASCOPost.com | JULY 25, 2013

PAGE 85

Pearls in Neuro-oncology

Another question concerns the relative efficacy of concurrent chemoradiation vs sequential radiotherapy and chemotherapy with either PCV or temozolomide. Finally, the apparent chemosensitivity and prolonged natural history of 1p/19q codeleted tumors raises the question of whether chemotherapy can be used alone in these patients, with deferral of radiotherapy to mitigate the risk of cognitive dysfunction. Some of these questions may be answered by the ongoing phase�III �III III intergroup RTOG/North Central Cancer Treatment Group (NCCTG) CODEL trial (NCT00887146) for 1p/19q codeleted anaplastic gliomas. The study arms include (1) radiotherapy followed by PCV, (2) concurrent radiotherapy plus temozolomide followed by temozolomide, and (3) temozolomide. The optimal treatment for 1p/19q non-codeleted anaplastic oligodendroglial tumors also remains unresolved. No statistically significant overall survival benefit was observed in this subset treated with adjuvant PCV1,2 in either the EORTC or RTOG trials. Also, whether concurrent radiotherapy plus temozolomide is effective for these patients is unknown. The ongoing phase III intergroup EORTC/RTOG CATNON trial (NCT00626990) for newly diagnosed anaplastic gliomas without 1p/19q codeletion will address these questions. Patients are randomly assigned to (1) radiotherapy, (2) concurrent radiotherpay plus temozolomide, (3) radiotherapy followed by temozolomide, or (4) concurrent radiotherapy plus temozolomide followed by temozolomide.

In Summary The long-term, follow-up results of EORTC 26951 and RTOG 9402 for anaplastic oligodendroglial tumors provide strong evidence for the predictive value of 1p/19q codeletion and confirm the prognostic effect of both 1p/19q codeletion and IDH mutation. Patients with these types of tumors should have testing for chromosome 1p and 19q status as part of routine clinical practice. However, many questions remain unanswered regarding the optimal treatment for both 1p/19q codeleted and non-codeleted patients. Evidence supports the use of both radiotherapy and PCV for newly diagnosed 1p/19q codeleted anaplastic oligodendroglial tumors. It remains to be determined whether temozolomide is equivalent to PCV, whether PCV or temozolo-

Table 1: Overview of EORTC 26951 and RTOG 9402 Trials in Anaplastic Oligodendroglial Tumors n

HR

RT

183

1

RT+PCV

185

0.75

RT

122

1

RT+PCV

114

0.83

RT

37

1

RT+PCV

43

0.56

RT

143

1

RT+PCV

148

0.79

RT

61

1

RT+PCV

76

0.85

RT

67

1

RT+PCV

59

0.59

95% CI

P

Median OS

95% CI

30.6 mo

21.5–44.5

42.3 mo

28.7–62.0

21.1 mo

17.6–28.7

25.0 mo

18.0–36.8

111.8 mo

75.7–134.3

EORTC 269511 Overall population 0.60–0.95

.018

1p/19q Nondeleted 0.62–1.10

.185

Codeleted

0.31–1.03

.059

NR

RTOG 94022 Overall population 4.7 yr 0.60–1.04

.1

4.6 yr

1p/19q Nondeleted 2.6 yr 0.58–1.23

.39

2.7 yr

Codeleted 7.3 yr 0.37–0.95

.03

14.7 yr

CI = confidence interval; HR = hazard ratio; NR = not reached; OS = overall survival; PCV = procarbazine, lomustine, vincristine; RT = radiotherapy.

mide can be used alone with deferral of radiotherapy until the time of progression, and whether concurrent radiotherapy plus temozolomide has a role among these options. For non-codeleted tumors, adjuvant PCV does not confer a survival benefit. Although the poorer prognosis of these patients could justify a more aggressive treatment approach, the added toxicity, the impact on quality of life, and the uncertain efficacy of chemotherapy should be considered. Ultimately, treatment of anaplastic oligodendroglial tumors should be individualized, taking into account molecular prognostic markers (1p/19q and IDH status), functional status, and comorbidities. Enrollment onto one of the ongoing randomized trials—either CODEL or CATNON—should be strongly considered. n Disclosure: Dr. Chi reported no potential conflicts of interest.

References 1. van den Bent MJ, Brandes AA, Taphoorn MJ, et al: Adjuvant procarbazine,

lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 31:344-50, 2013. 2. Cairncross G, Wang M, Shaw E, et al: Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: longterm results of RTOG 9402. J Clin Oncol 31:337-43, 2013. 3. van den Bent M, Carpentier A, Brandes A, et al: Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 24:2715-22, 2006. 4. Cairncross G, Berkey B, Shaw E, et al: Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 24:2707-14, 2006. 5. Reifenberger J, Reifenberger G, Liu L, et al: Molecular genetic analysis of oligodendroglial tumors shows preferen-

tial allelic deletions on 19q and 1p. Am J Pathol 145:1175-1190, 1994. 6. Yan H, Parsons D, Jin G, et al: IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765-73, 2009. 7. Chinot OL, Honore S, Dufour H, et al: Safety and efficacy of temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy. J Clin Oncol 19:244955, 2001. 8. van den Bent MJ, Taphoorn MJ, Brandes AA, et al: Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol 21:2525-8, 2003. 9. Wick W, Hartmann C, Engel C, et al: NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27:5874-80, 2009. 10. Lassman AB, Iwamoto FM, Cloughesy TF, et al: International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro Oncol 13:649-59, 2011.


The ASCO Post | JULY 25, 2013

PAGE 86

Announcements

University of Michigan Cancer Center Names New Medical Director

T

he University of Michigan Comprehensive Cancer Center has named Alon Weizer, MD, MS, as Medical Director. In this new role Dr. Weizer will be responsible for managing the day-to-day clinical outpatient

operations at the Cancer Center. Dr. Weizer is Associate Professor of Urology at the University of Michigan Medical School. His clinical and research interests focus on prevention and early detection of bladder can-

cer, novel treatments for early bladder cancer, and the use of minimally invasive approaches to treat bladder, prostate, kidney, testicular, and other genitourinary malignancies. He is also interested in the development of

Breast Cancer Symposium 2013

Alon Weizer, MD, MS

quality indicators for cancer care. Dr. Weizer earned his medical degree from Baylor College of Medicine in Houston and completed a 6-year training program in general surgery and urology at Duke University, where he was Chief Resident in urology. He then completed a urologic oncology and minimally invasive surgery fel-

MULTIDISCIPLINARY PERSPECTIVES ON CLINICAL MANAGEMENT

SATURDAY, SEPTEMBER 7 – MONDAY, SEPTEMBER 9, 2013 SAN FRANCISCO MARRIOTT MARQUIS | SAN FRANCISCO, CALIFORNIA

HOUSING AND EARLY REGISTRATION DEADLINE APPROACHING Bringing together medical oncologists, radiation oncologists, and surgeons to strengthen collaborative treatment approaches

Point-counterpoint discussions on challenges and controversies, featuring a multidisciplinary panel of experts

Keynote Lectures by Monica Morrow, MD and George Sledge, MD: “How Will We Be Treating Breast Cancer in 5 to 10 Years?”

An expanded selection of interactive Meet the Professor Sessions

ASCO Gianni Bonadonna Breast Cancer Award and Lecture by Larry Norton, MD

Fellows, residents, and junior faculty ticketed sessions, including a: • Best of Journals Literature Review • Networking Reception • Special Session: “How to Give a Talk and Write a Paper”

REGISTER AND RESERVE HOUSING BY JULY 31, 2013, AT 11:59 PM (EDT) FOR BEST RATES

breastcasym.org

This live activity has been approved for AMA PRA Category 1 Credit.™

Douglas Blayney, MD

Kathleen Cooney, MD

lowship at University of Michigan before joining the faculty in 2007. He has also completed the master’s program in clinical research design and statistical analysis at the University of Michigan School of Public Health. The medical director position was formerly held by Douglas Blayney, MD. Dr. Weizer will work closely with Kathleen Cooney, MD, who in January was appointed Deputy Director for Clinical Services for the Cancer Center. n


ASCOPost.com | JULY 25, 2013

PAGE 87

Dermatologic Events in Oncology Diagnosing and Treating Acute Graft-vs-Host Disease By Jonathan A. Cotliar, MD

A

cute graft-vs-host disease is the major cause of nonrelapse mortality following hematopoietic stem cell transplantation for patients with hematologic malignancies. Acute graft-vs-host disease results from epithelial tissue damage following conditioning chemotherapy with subsequent infusion of competent donor lymphocytes within the allograft that result in damage to the skin, gut, and liver. The incidence of acute graft-vs-host disease is estimated to be 40% to 60% for those undergoing allogeneic stem cell transplantation, and cutaneous involvement is frequently the earliest manifes-

recipient, total-body irradiation as a component of conditioning chemotherapy, gender mismatch between donor and recipient, and prior host exposure to blood products. Acute graft-vs-host disease usually presents within the first 100 days following hematopoietic stem cell transplantation. However, in this era of reducedintensity stem cell transplantation and the dynamic nature of immunosuppressive medications used in the prophylaxis against and treatment of graft-vs-host disease, other forms of acute graft-vshost disease are now recognized; these

The cornerstone of treatment for acute graft-vs-host disease is the prophylactic regimen, but once cutaneous lesions develop, treatment is based on the stage of disease. —Jonathan Cotliar, MD

tation. Acute graft-vs-host disease may occur either in isolation or in combination with intestinal or hepatic disease. Skin biopsy may demonstrate interface dermatitis with necrotic keratinocytes, but its utility in diagnosing acute graftvs-host disease is controversial. Risk factors for acute graft-vs-host disease include histocompatibility antigen mismatch, older age of transplant Dr. Cotliar is in the Departments of Dermatology & Medicine at Northwestern University Feinberg School of Medicine in Chicago.

include late-onset acute, recurrent acute, and persistent acute graft-vs-host disease. Clinical grading of acute cutaneous graft-vs-host disease is based on stage I (rash on < 25% of body surface area), stage II (rash on 25%–50% of body surface area), stage III (rash on > 50% of body surface area) and stage IV (erythroderma with bullae or desquamation). Notable omissions from these criteria include the morphology of skin lesions, anatomic distribution of lesions, and the symptoms produced by the eruption. Erythema of the ears or palms may

Fig. 1: Morbilliform rash, the most common skin manifestation of acute graft-vs-host disease.

herald the onset of acute graft-vs-host disease. While a morbilliform appearance (Fig. 1) is the most common skin manifestation of acute graft-vs-host disease, other morphologies are well recognized and include violaceous lesions, reticulated variants, and severe forms that produce widespread desquamation that may mimic toxic epidermal necrolysis. Follicular accentuation (Fig. 2) of skin lesions may be an early but important clinical clue during the development of acute graft-vs-host disease.

Treatment Recommendations The cornerstone of treatment for acute graft-vs-host disease is the prophylactic regimen, but once cutaneous lesions develop, treatment is based on the stage of disease. Stage I disease can be treated with mid- to high-potency topical steroids alone (eg, alclometasone cream to the face, or fluocinonide or clobetasol creams or ointments to the body) or calcineurin inhibitors (pimecrolimus [Elidel] cream or tacrolimus [Protopic] ointment). Stages II to IV require both topical and systemic steroids, with systemic doses ranging from 1 to 2 mg/kg daily given over the course of several weeks and slowly tapered depending on patient response. Ensuring that the calcineurin inhibitor used for graft-vs-host disease prophylaxis is within the serum therapeutic range, or restarting a systemic calcineurin inhibitor along with high-dose systemic steroids at the onset of stage II to IV acute graft-vshost disease is preferred. The application of topical steroids twice daily to moist skin and covered with warm wet towels as an occlusive

Mario E. Lacouture, MD

Dermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, an Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan-Kettering Cancer Center, New York. He is a boardcertified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. measure (“wet wrap”) is particularly effective for patients with diffuse skin graft-vs-host disease. The use of systemic antihistamines (eg, hydroxyzine) and nonprescription antipruritic topical agents containing camphor or menthol are also efficacious for symptom control. Narrow-band UVB phototherapy is an additional adjunct that may help expedite the tapering of systemic steroids. Extracorporeal photopheresis, an effective treatment for patients with chronic graft-vs-host disease, has recently been shown to benefit patients with steroid-refractory graft-vshost disease. n Disclosure: Dr. Cotliar reported no potential conflicts of interest.

Fig. 2: Follicular accentuation of skin lesions may be an early but important clinical clue during the development of acute graft-vs-host disease.


VOTRIENT® (pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1

VOTRIENT – Move Forward in Advanced RCC VOTRIENT: Significant PFS improvement in patients with advanced RCC1 Median PFS in patients with advanced RCC receiving VOTRIENT vs placebo1,2

11.1

12 10

MONTHS

9.2

MONTHS

7.4

8 Months

VOTRIENT Placebo

MONTHS

6

4.2

MONTHS

4

4.2

MONTHS

2.8

MONTHS

2 0 HR 0.46; 95% CI 0.34-0.62 (P<0.001)

HR 0.40; 95% CI 0.27-0.60 (P<0.001)

HR 0.54; 95% CI 0.35-0.84 (P<0.001)

All patients

Treatment-naïve patients

Cytokine-pretreated patients

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC of clear cell or predominantly clear cell histology were randomized (2:1) to receive either VOTRIENT 800 mg (n=290) once daily or placebo (n=145). The study included treatment-naïve patients receiving VOTRIENT (n=155) or placebo (n=78) as well as cytokine-pretreated patients receiving VOTRIENT (n=135) or placebo (n=67).1

Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

• Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thrombotic Events: Arterial thrombotic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, venous thromboembolic

events were reported in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended.

Please see additional Important Safety Information and Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.


Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In advanced RCC, initial dose reduction should be 400 mg and additional dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced RCC trial, 42% of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose reduced • The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications based on drug interactions, please see Section 2.2 in accompanying Brief Summary

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial thrombotic and venous thromboembolic events, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting Please see additional Important Safety Information and Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

NCCN Guidelines Category 1 recommendation as a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than pazopanib (VOTRIENT) as first-line treatment options.3

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• Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. • Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT.

• Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. • Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

The most common adverse reactions (≥20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.1.2013. ©National Comprehensive Cancer Network, Inc. 2013. All rights reserved. Accessed February 1, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced.

VOTRIENT.com/HCP GSKSource.com


BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had postbaseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/ intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy

and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.16 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. 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. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 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. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290) All All Gradesa Gradesa Grade 3 Grade 4 % % % % Adverse Reactions Diarrhea 52 3 <1 9 Hypertension 40 4 0 10 Hair color changes 38 <1 0 3 Nausea 26 <1 0 9 Anorexia 22 2 0 10 Vomiting 21 2 <1 8 Fatigue 19 2 0 8 Asthenia 14 3 0 8 Abdominal pain 11 2 0 1 Headache 10 0 0 5 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

(N=145) Grade 3 % <1 <1 0 0 <1 2 1 0 0 0

Grade 4 % 0 0 0 0 0 0 1 0 0 0

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290) All Gradesa %

Grade 3 %

Placebo (N=145) Grade 4 %

All Gradesa %

Parameters Hematologic Leukopenia 37 0 0 6 Neutropenia 34 1 <1 6 Thrombocytopenia 32 <1 <1 5 Lymphocytopenia 31 4 <1 24 Chemistry ALT increased 53 10 2 22 AST increased 53 7 <1 19 Glucose increased 41 <1 0 33 Total bilirubin increased 36 3 <1 10 Phosphorus decreased 34 4 0 11 Sodium decreased 31 4 1 24 Magnesium decreased 26 <1 1 14 Glucose decreased 17 0 <1 3 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Grade 3 %

Grade 4 %

0 0 0 1

0 0 <1 0

1 <1 1 1 0 4 0 0

0 0 0 <1 0 0 0 0


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Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)]. 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drugdrug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.16)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). 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. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 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 serious adverse reactions in nursing infants from VOTRIENT, 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: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.15)]. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility

in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

©2013, GlaxoSmithKline. All rights reserved. Revised 02/2013 VTR:9BRS ©2013 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. VOT419R0 April 2013


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2013

2013 Oncology Meetings July 14th International Lung Cancer Congress July 25-27 • Huntington Beach, California For more information: www.gotoper.com/conferences Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org

ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna

2013 Interscience Conference on Antimicrobial Agents and Chemotherapy September 10-13 • Denver, Colorado For more informaton: www.icaac.org

Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org

Rocky Mountain Oncology Society Fall Membership Conference September 12 • Denver, Colorado For more information: www.rmos-colorado.com

North Carolina Oncology Association Fall Membership Conference August 24 • Greensboro, North Carolina For more information: www.ncoa-northcarolina.com 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences Second Annual 2013 World Cutaneous Malignancies Congress July 26-28 • San Diego, California For more information: www.cutaneousmalignancies.com

August Best of ASCO® Chicago August 9-10 • Chicago, Illinois For more information: boa.asco.org South Carolina Oncology Society Fall 2013 Membership Conference August 9-10 • Charleston, South Carolina For more information: www.scosonline.com Hematology and Medical Oncology Best Practices August 15-22 • Arlington, Virginia For more information: www.gwumc.edu/cehp/ hemoncbestpractices/ Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org

September Georgia Society of Clinical Oncology 2013 GASCO Annual Meeting September 6 • Atlanta, Georgia For more information: www.gasco.us SGI Summit Turkey 2013: Innovations in Obstetrics and Gynecology September 6-8 • Istanbul, Turkey For more information: www.sgiturkey2013.org/ Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org

Minnesota Society of Clinical Oncology - MSCO Fall Membership Conference September 10 • Minneapolis, Minnesota For more information: www.msco-minnesota.com

9th Scientific Meeting of the Australasian Society for Breast Disease September 12-14 • Cairns, Queensland, Australia For more information: www.asbd.org.au International Liver Cancer Association Seventh Annual Conference September 13-15 • Washington, DC For more information: www.ilca2013.org/ Inflammation, Microbiota, and Cancer September 19-20 • Bethesda, Maryland For more information: ncifrederick.cancer.gov/events/ microbiota/agenda.asp Continuum Cancer Centers of New York Conference on Quality of Care in Oncology September 20 • New York, New York For more information: www.chpnet. org/cme Tennessee Oncology Practice Society 2013 Membership Conference September 20 • Nashville, Tennessee For more information www.tops-tennessee.com Michigan Society of Hematology and Oncology Annual Meeting September 20-21 • Traverse City, Michigan For more information: www.msho.org NCCN 8th Annual Congress: Hematologic Malignancies September 20-21, 2013 New York, New York For more information: www.nccn.org

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13 Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences ASH Consultative Hematology Course September 27 • Chicago, Illinois For more information: www.hematology.org Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences 2013 ASH State-of-the-Art Symposium September 27-28 • Chicago, Illinois For more information: www.hematology.org ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu 28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston, Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

October The 2nd International Multidisciplinary Forum on Palliative Care (IMFPC 2013) October 3-6 • Sofia, Bulgaria For more information: www.imfpc.org


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2013

2013 Oncology Meetings Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences Second Annual Conference Global Biomarkers Consortium October 4-6 • Boston, Massachusetts For more information: www.globalbiomarkersconsortium. com Virginia Association of Hematologists and Oncologists Fall Membership Conference October 11 • Virginia Beach, Virginia For more information: www.vah-o.org 17th Annual Interdisciplinary Conference on Supportive Care, Hospice, and Palliative Medicine October 11-12 • Houston, Texas For more information: www. mdanderson.org/conferences 4th International Breast Cancer Prevention Symposium: Genes, the Environment, and Breast Cancer Risks October 11-13 • Beirut, Lebanon For more information: www.purdue.edu/breastcancer/

4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in 18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 19-23, 2013 • Boston, Massachusetts For more information: www.aacr.org 10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org

15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

November Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org Multidisciplinary Symposium on Head and Neck Cancer November 2 • Chicago, Illinois For more information: www.gotoper.com/conferences EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de

Merrill J. Egorin Workshop in Cancer Therapeutics and Drug Development October 11-14 • Leesburg, Virginia For more information: www.cancereducationconsortium. org/programs_paaw.html 9th International Symposium on Hodgkin Lymphoma October 12-15, 2013 • Cologne, Germany For more information: www.hodgkinsymposium.org/

Illinois Medical Oncology Society 2013 Membership Conference October 25 • Itasca, Illinois For more information: www.imos-illinois.com

Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas For more information: www.mdanderson.org/conferences

9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/ Diagnostic Development Tutorial November 5-7 • Brussels, Belgium For more information: www.markersincancer.eu

International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/About+ASCO/ International+Affairs/International+Cli nical+Trials+Workshops

2013 International Society of Geriatric Oncology Congress October 24-26 • Copenhagen, Denmark For more information: www.siog.org

SITC Workshop on Personalized Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013

International Stereotactic Radiotherapy Conference October 19-20 • Houston, Texas For more information: www. mdanderson.org/conferences

51st Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www2.convention.co.jp/jsco2013/

SITC Primer on Tumor Immunology and Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013

Advanced Breast Cancer Second International Consensus Conference November 7-9 • Lisbon, Portugal For more information: www.abc-lisbon.org/ International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw 11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro New York Lung Cancer Symposium November 9 • New York, New York For more information: www.gotoper.com/conferences Academy of Oncology Nurse Navigators 4th Annual Navigation and Survivorship Conference November 14-17 • Memphis, Tennessee For more information: aonnonline.org/conference African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

December 55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org 36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org


The ASCO Post | JULY 25, 2013

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Announcements

Rocky Mountain Cancer Centers and St. Anthony Hospital Complete Affiliation for a Comprehensive Oncology Center

C

olorado’s Rocky Mountain Cancer Centers, with 20 centers throughout the state, and St. Anthony Hospital have completed an agreement to provide comprehensive inpa-

tient and outpatient cancer services to patients on the St. Anthony Hospital campus in Lakewood, Colorado. Expanded radiation therapy services are expected to begin on August 5, 2013,

and the medical oncology office is anticipated to open in the winter of 2013.

Shared Strengths and Services The new collaboration will enable St.

InsIght

New iN every issue Of

JnCCn

NEW

Read the July Issue of JNCCN: • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Myelodysplastic Syndromes NCCN Guidelines® insights: Breast Cancer In this new section, Panel members shed light on the process behind the creation of the NCCN Guidelines, clarifying why and how these important decisions are made.

• Optimizing systemic Therapy for Bladder Cancer • Next-Generation Cancer vaccine Approaches: integrating Lessons Learned from Current successes with Promising Biotechnologic Advances • The Case for including Bowel urgency in Toxicity reporting After Pelvic Cancer Treatment • systemic Therapy for small Cell Lung Cancer

register for your free subscription at JNCCN.org

DowNloaD the JNCCN app Visit the iTunes store or use your QR code reader to download the JNCCN mobile application.

Anthony Hospital and Rocky Mountain Cancer Centers (RMCC) to utilize their shared strengths to provide patients with coordinated multidisciplinary care, high-quality clinical outcomes, access to leading-edge technology, and a nationwide network of clinical research trials through RMCC’s affiliation with US Oncology Research. It also provides the framework for cost-efficient care, a positive patient experience, research and innovation, and access to holistic, complementary medicine. Under the new affiliation, Rocky Mountain Cancer Centers will be the oncology care provider for both medical oncology and radiation oncology in Lakewood. RMCC will open a medical oncology office on campus and will close its existing medical oncology office in Lakewood. St. Anthony Hospital will continue to provide all inpatient oncology services. Intensity modulated radiation therapy (IMRT), image guided radiation therapy (IGRT), 3-D conformal therapy, 4-D treatment planning, and stereotactic body radiation therapy (SBRT) are all performed at St. Anthony Hospital. In addition, the specialized Brain Lab stereotactic radiosurgery system treats brain tumors as well as benign neurological disorders. “This new venture will assist us in growing our regional offering of services by accelerating our development of a comprehensive cancer center to better serve our Mountains and North Denver Operating Group and the communities we serve,” said Jeff Brickman, President and CEO, St. Anthony Hospital. John Fleagle, MD, President of Rocky Mountain Cancer Centers, said “This is a tremendous opportunity to showcase our expertise in both radiation and medical oncology. This collaboration allows us to work hand-in-hand with a premier hospital in the Denver metro area. Cancer patients in the Lakewood, Colorado area and beyond will benefit from this truly integrated approach to care.” n

Send Us Your NEWS We invite readers to share their news with The ASCO Post. Write to editor@ASCOPost.com.


ASCOPost.com  |   JULY 25, 2013

PAGE 95

Pioneers in Oncology Co-discoverer of DNA Double Helix, James Watson, PhD, Offers a New Theory on Cancer Progression By Jo Cavallo

James Dewey Watson, PhD

D

espite his fame as co-discoverer—along with Francis Crick, PhD—of the double-helix structure of deoxyribonucleic acid (DNA) in 1953, that accomplishment is not what James Dewey Watson, PhD, came to talk about during a recent presentation he gave at the World Science Festival in New York. Instead, Dr. Watson wanted to expand on his theory of curing cancer and why the search for a cure is taking so long, which he details in a recent paper in the online journal, Open Biology.1 “Even though we will soon have comprehensive views of how most cancers arise and function at the genetic and biochemical level, their ‘curing’ seems now to many seasoned scientists an even more daunting objective than when the ‘War on Cancer’ was started by President Nixon in December 1971,” wrote Dr. Watson. “We now have no general of influence, much less power … leading our country’s War on Cancer.”

Key Role of Antioxidants Dr. Watson’s hypothesis links cancer progression to the presence of antioxidants and contends that antioxidant levels within cancer cells correspond with treatment resistance. His theory focuses on reactive oxygen species, a group of oxidizing molecules that are naturally occurring in cells at low levels, but which are directly or indirectly generated in abundance by most types of cancer therapy, including radiation and chemotherapy, and block key steps in the cell cycle. As malignant cells go through a transformation from epithelial to mesenchymal, “they almost

inevitably possess much-heightened amounts of antioxidants that effectively block otherwise highly effective oxidative therapies,” wrote Dr. Watson. The reason cancer cells largely driven by mutant RAS and Myc proteins are so difficult to cure, explained Dr. Watson, may be due to their high levels of antioxidants, keeping in check otherwise potentially celllethal reactive oxygen species. What we most need now are drugs that inhibit the antioxidative molecules that likely make late-stage malignancies so incurable, he said.

A Meeting of Minds Dr. Watson’s interest in cancer and tumor viruses dates back nearly 6 decades to his tenure as Professor in the Biology Department at Harvard

genes. He enrolled in a graduate program at Indiana University and wrote his thesis on x-ray inactivation of bacteriophage, which piqued his interest in DNA. In 1951, Dr. Watson went to work at the Cavendish Physics Laboratory of Cambridge University in England, where he met Francis Crick. “We were made for each other,” said Dr. Watson. Their collaboration on building hypothetical three-dimensional models of DNA led to their discovery of the double helix in 1953, when Dr. Watson was just 24. Soon thereafter, Dr. Watson left England to become a Senior Research Fellow in Biology at the California Institute of Technology, where he studied x-ray diffraction of RNA, and 3 years later he joined the staff at Harvard University, where he stayed until

The biggest obstacle to moving forward effectively toward a true war against cancer may, in fact, come from the inherently conservative nature of today’s cancer research establishments. —James Dewey Watson, PhD

University, where he lectured on how cancer might be induced by DNA tumor viruses. Born in Chicago in 1928, a year before the start of the Great Depression, books and learning were central parts of his early childhood. Although his father, businessman James D. Watson, managed to find work during those years, a reduced salary plunged the family into poverty. Still, whatever spare money there was, said Dr. Watson, went to pay for books. Dr. Watson’s early scientific interest was in natural history and the study of ornithology, a result of his father’s—and later his—fascination with bird-watching. At 15, Dr. Watson’s mother, Jean, helped her son apply for a scholarship in an advanced placement program at the University of Chicago’s Hutchins College. He then completed the University’s 4-year program, receiving a Bachelor of Science degree in zoology in 1947. By then, Dr. Watson wanted to study

1976. It was during his time at Harvard that Dr. Watson wrote the textbook Molecular Biology of the Gene,2 which raised the question of how a virus might have the capacity to turn on the cell cycle, and has become one of the most widely used textbooks on biology.

Pursuing the Origins of Cancer In 1962, Drs. Crick and Watson received the Nobel Prize in Physiology or Medicine for their discovery of the structure of DNA and later shared several other awards, including the Lasker Award and the Research Corporation Prize. Six years later, Dr. Watson was named Director of Cold Spring Harbor Laboratory of Quantitative Biology (which later became simply Cold Spring Harbor Laboratory) in New York. Having first spent time at the Laboratory while a graduate student in 1948, and returning again in 1953

to give the first public presentation of the DNA double helix, the move was a sort of a homecoming for him. When he cut ties with Harvard in 1976, Dr. Watson had already been director of Cold Spring Harbor Laboratory for 8 years. Dr. Watson changed the focus of the Laboratory’s research from microbial genetics to the study of cancer, with the hiring of molecular biologist Joseph Sambrook, PhD, from the Salk Institute. Dr. Sambrook launched a Tumor Virus Group, which is still in place today. Under Dr. Watson’s leadership, Cold Spring Harbor Laboratory has been transformed into one of the world’s premier research facilities in cancer, neurobiology, and basic molecular genetics. From 1988 to 1992, while still Director of Cold Spring Harbor Laboratory, Dr. Watson was named the first Director of the Human Genome Project at the National Institutes of Health. He later became President and then Chancellor of Cold Spring Harbor Laboratory and is currently Chancellor Emeritus.

Obstacle to Curing Cancer Dr. Watson credits his accomplishments with an insatiable curiosity and the ability to surround himself with intelligent people. “I knew I wasn’t a genius,” he insisted. “I like meeting bright people and I don’t do anything that is not important.” At 85, Dr. Watson remains actively engaged in his two passions, playing tennis and finding a cure for cancer, although he admits, the latter goal remains elusive. “The biggest obstacle to moving forward effectively toward a true war against cancer may, in fact, come from the inherently conservative nature of today’s cancer research establishments,” wrote Dr. Watson. n References 1. Watson J: Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biology. January 9, 2013. Available at http://rsob.royalsocietypublishing.org. Accessed July 5, 2013. 2. Watson JD: Molecular Biology of the Gene. New York, W.A. Benjamin, Inc, 1965.


Š 2013 Genentech USA, Inc. All rights reserved. BIO0001813200 Printed in USA. June 2013


At first glAnCe, we sAw AChievement. with foCus, we see even more potentiAl. A closer look at targeting CD20 may bring new possibilities into view

CD20: A signifiCAnt tArget The advent of monoclonal antibody therapies has helped transform the treatment of hematologic malignancies.1 CD20 is an important target due to its unique features and presence on a majority of B cells.2 The success of targeting CD20 is due, in part, to the ability to activate cell death through a variety of potential mechanisms.2 In addition, CD20 is a stable antigen that is not typically down-regulated or shed upon antibody binding.2 Targeting CD20 is an important strategy for hematologic malignancies, including chronic lymphocytic leukemia (CLL).3 Despite clinical developments, certain patients with hematologic malignancies, including CLL, lack clear or effective treatment options and trade-offs between efficacy and tolerability are often made.3 To meet these needs, we continue to research anti-CD20 antibodies that optimize the potential of this target. ADvAnCements in tArgeting CD20 There is an opportunity to make additional clinical gains with new treatment options for a broader range of patients.3 As a leader in targeted treatments for B-cell malignancies, we remain committed to advancing the science of targeting CD20 in an effort to improve clinical outcomes for patients with hematologic malignancies, including CLL.

To find out more about advancing the science of targeting CD20, visit ResearchBcell.com References: 1. Castillo J, Winer E, Quesenberry P. Newer monoclonal antibodies for hematological malignancies. Exp Hematol. 2008;36(7):755-768. 2. Golay J, Zaffaroni L, Vaccari T, et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood. 2000;95(12):3900-3908. 3. Alduaij W, Illidge TM. The future of anti-CD20 monoclonal antibodies: are we making progress? Blood. 2011;117(11):2993-3001.


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Letters to the Editor

Conversations with Breast Cancer Patients

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am a retired oncologist, previously an attending physician at Memorial Sloan-Kettering Cancer Center, with a professional lifetime experience in caring for patients with all stages of breast cancer, and now I am a regular reader of The ASCO Post. In recent months there have been several articles published in The ASCO Post on the subject of the care of the whole patients when faced with the advanced stages of cancer. Reports have also been published from patients on their experiences with the problems they have faced, physical as well as emotional, in dealing with their illness (breast cancer in particular), as well as with its treatment.

Many if not most of these issues were addressed in a book I published in 2002 titled Conversations with Breast Cancer Patients. I hope this book could be of interest to readers both in the field of patient care as well as to patients and their families. The treatment modalities that are mentioned incidentally in the text are outdated to a large extent. However, the main feature of this book relates to the problems faced by the patient and to the communication between patient and physician along the entire course of the illness, and it remains, I believe, very much up to date. I hope you may find it of interest and

worth mentioning its main features in The ASCO Post. n —Ernest Greenberg, MD Forest Hills, New York Dr. Greenberg is a retired oncologist who practiced as an attending physician at Memorial Sloan-Kettering Cancer Center in New York. For more information about the book Conversations with Breast Cancer Patients, contact Dr. Greenberg at egreen5402@aol.com.

Editor’s note: Adaptations from Dr. Greenberg’s book will be published on an occasional basis in future issues of The ASCO Post.

Public’s Need for Better Understanding of the Science of Cancer

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am a cancer researcher involved in studying chemotherapy for smallcell lung carcinoma at The City of Hope Medical Center in Duarte, California. Previously I was a college professor who mentored many students at the undergraduate level. After developing one of the first high-level university courses in the science of cancer 25 years ago and also having given many public lectures, I saw a need for better public

understanding of the science behind cancer and its treatment. I have used my experiences as a teacher and researcher to develop a new video course, “What Science Knows About Cancer.” The course is written at the college level but it assumes no prior knowledge of biology, chemistry, or allied health subjects on the part of the viewer. My only aim here is public education. I believe that ASCO members

should become aware of the course, as it may be valuable to patients. To find more information about the video course, please visit http://www.thegreatcourses.com/tgc/ courses/course_detail.aspx?cid=1956 or contact me at dsadava@coh.org. n —David Sadava, PhD Dr. Sadava is Adjunct Professor in Cancer Cell Biology at City of Hope Cancer Center in Duarte, California.

Clinical Trials for Patients in Africa

T

hank you very much for The ASCO Post Evening News,* which ensures I don’t miss anything that happened at the ASCO 2013 meeting. Due to financial constraints I could not attend the ASCO Annual Meeting in Chicago. My comment is that pharmaceutical companies should extend their oncology drug trials to Africa so our patients can benefit from the new drugs and also to assess their pharmacogenomics. It is not fair to conduct all trials in Europe and North America and sell expensive drugs in Africa. n —Ogidiagba Louis Efe, MBBS Dr. Ogidiagba Louis Efe is a member of ASCO and Senior Registrar in General Surgery, Department of Surgery, Olabisi Onabanjo University Teaching Hospital, Sagamu, Ogun State, Nigeria.

*The ASCO Post Evening News is delivered via email Monday through Friday evenings. It is circulated to all members of ASCO worldwide. Visit ASCOPost.com to learn more.

‘Medicalizing’ Physician-assisted Suicide

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t was with regret that I read the article and commentary on physician-assisted suicide in the June 10 issue of The ASCO Post (“Death with Dignity Program at Seattle Cancer Care Alliance,” by Matthew Stenger, and “One Cancer Center’s Approach to Death with Dignity,” by Frederick R. Appelbaum, MD). The ethics of assisting a hopeless

person with suicide is debatable. I see these articles as an effort to legitimize physician-assisted suicide by “medicalizing” the act—that is, by describing the activity in a scientific format. This is a tactic often used to legitimize activity previously recognized as negative or harmful. Moreover, the article uses euphemism— for example “assistance with dying”

instead of “assisted suicide.” Regardless of how physicianassisted suicide is described or analyzed, it does not change the fact that it may be unethical. Many physicians and oncologists in Washington State continue to care for patients with terminal illness and do not believe the legalization of this physician practice is necessary to

provide compassionate care. I think it is unfortunate that The ASCO Post chose to assist in the effort to legitimize this ethically controversial practice by presenting the information in a scientific format. n —Mitchell Garrison, MD Hematology/Oncology Wenatchee Valley Medical Center Wenatchee, Washington

Share Your Opinion

Write to The ASCO Post at editor@ASCOPost.com We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.


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Patient’s Corner

I Have No Fear

Living with pancreatic cancer has brought me peace. By Margaret O’Donnell, as told to Jo Cavallo

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found out that I had stage III pancreatic cancer on Valentine’s Day in 2011, but I think the disease had been brewing for a long time. For 19 years, I had experienced intermittent right upper quadrant pain. I had gallbladder surgery to relieve a bile duct obstruction, which my doctors said was the source of the pain, but a week after the surgery the pain was back. Abdominal ultrasounds showed some scar tissue, but everyone assured me it wasn’t serious.

sies of a mass in the bile duct showed that I had pancreatic cancer. Although the news was devastating, I clung to the fact that my tumor was borderline resectable, and that I would be a good candidate for the Whipple

Living with cancer has given me an insight into life that I didn’t have before. While I still get nervous every 6 months as the date approaches for a new scan that will tell me whether the cancer is still in check, I generally feel very much at peace.

Nagging Feeling Still, I had a nagging feeling something wasn’t right. I knew that my aunt had died of pancreatic cancer just 2 months after being diagnosed, and I always felt anxious about having a family history of such a deadly cancer. Finally, right before Christmas in 2010, the cancer began to show itself. I had severe flu-like symptoms and nonstop vomiting for 12 hours that left me so sick and fatigued it was difficult to participate in our family’s holiday plans. Even after the vomiting subsided, I had lingering nausea and I became jaundiced. As soon as the holidays were over, I made an appointment to see my gastroenterologist. A CT scan showed another blockage in the bile duct. I was so poisoned by bilirubin, I had to be hospitalized for 8 days. Subsequent biop-

16, and a son, 5. Because my son is adopted, I feel an even greater responsibility to do everything I can to stay alive and be here to raise him. The experience has also brought my husband and me closer together.

—Margaret O’Donnell

procedure once the tumor was reduced in size with chemotherapy and radiation. I had 6 months of gemcitabine chemotherapy, followed by 25 rounds of radiation therapy. In October of 2011, I had the surgery and additional cycles of chemotherapy, and so far, my cancer remains in remission.

Taking Control Although having cancer has turned my life upside down, the experience hasn’t been all bad. I was working parttime as a hairdresser before my diagnosis, and now I relish being a full-time mom to my two children—a daughter,

I was always an anxious person, but once I got my cancer diagnosis I learned to rely more on my faith, and I no longer have any fear. I certainly don’t want to die, but I’m not afraid of death and that’s a wonderful feeling. My biggest worry is not being here for my children and husband. Having a life-threatening disease has also taught me to take more control of my life and to be more assertive when it comes to my care. I was unhappy with the first oncologist I saw because he didn’t always present information in the most positive light, so I sought out another opinion. It isn’t

that I was looking for rosy answers. I just wanted to feel like he was going to do everything in his power to fight for me. My new oncologist encourages me to be his partner in decisions about my care and welcomes my questions, and that gives me confidence. It also helps that not only do I respect him, but he respects me. Knowing that has made all the difference in my ability to cope with having cancer.

Accepting Mortality Living with cancer has given me an insight into life that I didn’t have before. While I still get nervous every 6 months as the date approaches for a new scan that will tell me whether the cancer is still in check, I generally feel very much at peace. I know it’s a cliché, but I didn’t realize what a great life I had until I was facing this terrible cancer. Now, everything is in perspective and I know I’ll get through whatever difficulties may lie ahead. The love I feel from my family and friends, and the support I get from my medical team have given me a new appreciation for life and an acceptance of mortality that I didn’t have before. How lucky I am to have such an abundance of love and unshakeable faith. n Margaret O’Donnell lives in Rochester Hills, Michigan.

Don’t Miss These Important Reports in This Issue of The ASCO Post Arti Hurria, MD, on Top Five Things to Know in Geriatric Oncology see page 1

Michael A. Carducci, MD, on Enzalutamide Monotherapy in Prostate Cancer see page 3

Hedy Lee Kindler, MD, on Pancreatic Cancer Research and Treatment see page 11

David B. Solit, MD, on Genomic Heterogeneity see page 38

Olufunmilayo I. Olopade, MD, FACP, on Genetics in Breast Cancer see page 41

Julie M. Vose, MD, MBA, on Treating Uncommon Cancers see page 75

Visit The ASCO Post online at ASCOPost.com


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Appointments Advocacy

Pancreatic Cancer Action Network Names 7-Year Survivor Chair of National Board of Directors

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he Pancreatic Cancer Action Network recently announced the appointment of Laurie MacCaskill to Chair of the National Board of Di-

rectors of the organization, effective July 1, 2013. Ms. MacCaskill is the first pancreatic cancer patient to hold this position. Since her diagnosis in

2006, Ms. MacCaskill has served as a volunteer and advocate for the Pancreatic Cancer Action Network. â&#x20AC;&#x153;Pancreatic cancer has been life-

changing for me in ways I never anticipated. The diagnosis was devastating, of course, but Iâ&#x20AC;&#x2122;ve since had the opportunity to work with amazing


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Appointments

people and witness how powerful we can be, even in the face of tremendous odds,” said Ms. MacCaskill. “As part of the Pancreatic Cancer Action Network, I have seen a groundswell across the country in the movement to defeat this disease. I am proud and honored to serve the organization in this new capacity and look

forward to even greater success in increasing the survival rate for people impacted by pancreatic cancer. People like me,” she said. “Laurie has been a valued advisor on our board since 2009, and I am thrilled to have the opportunity to work with her in her new role as Chair of our National Board of Directors,”

Laurie MacCaskill

Peter Kovler

Jeanne Ruesch

stated Julie Fleshman, President and CEO of the Pancreatic Cancer Action Network. “Not only does Laurie bring a wealth of professional knowledge and leadership, but firsthand perspective as a pancreatic cancer survivor.” Peter Kovler becomes the Immediate Past Chair after serving in the role for the last 3 years. The organization has also appointed Jeanne Ruesch to Vice Chair. Ms. Ruesch serves on the board in honor of her late husband, Otto J. Ruesch. n

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

www.ASCOPost.com

Phone: 631.692.0800 Fax: 631.692.0805

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724


The ASCO Post | JULY 25, 2013

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In the News Survivorship

More Than 98% of Childhood Cancer Survivors Have Chronic Health Conditions By Charlotte Bath

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ore than 98% of adult survivors of childhood cancer in a large clinically evaluated cohort had a chronic health condition, including a substantial number of previously undiagnosed problems that are more likely to occur in an older population. “These findings underscore the importance of ongoing health monitoring for adults who survive childhood cancer,” the investigators concluded in a study published in JAMA.1 The surprising finding of the study was not that survivors were experiencing problems, but that the conditions were so varied “across a spectrum of systems,” said the study’s lead author, Melissa Hudson, MD, in one of the media reports of the study.2 Dr. Hudson is Director of the Cancer Survivorship Division and Co-Leader of the Cancer Prevention and Control Program at St. Jude Children’s Research Hospital in Memphis. In an interview with The ASCO Post, she added, “It’s not just the conditions across many systems, but the spectrum of severity. At very young ages, many of the patients were showing subclinical or undiagnosed abnormalities that may become more clinically significant as they age. These findings emphasize the importance of survivors adhering to regular medical checkups with health-care providers who are informed about the health risks predisposed by treatment for childhood cancer.”

Accelerated Aging Process Late effects research has shown that adults who were treated for childhood cancers with cytotoxic approaches had organ system problems more likely to be found in older populations, according to Dr. Hudson. “Some of the functional measures and outcomes that we observed are more typical of individuals who are 60 years of age or older.” The median age of the 1,713 study participants, however, was 32 years old, with just 3.1% or 53 patients between the ages of 50 and 66 at recruitment and most in their 20s and 30s. All the study patients had been treated for childhood cancer at St. Jude and were enrolled in the St. Jude Lifetime Cohort Study (SJLIFE). The median time from diagnosis was 25 years, with a range of 10 to 47 years. All participants completed health

questionnaires that provided self-reported outcomes and information about their quality of life and health perceptions and health habits. “This is really important information, because we are going to able to understand how health habits have contributed to or modified the risk of these chronic health conditions,” Dr. Hudson explained. The standard laboratory assessment included blood counts, chemistries, and a battery of hormonal function tests, “to improve

productive disorders, 56.4% for cardiac conditions, and 48% for neurocognitive impairment. Lower rates were 13% for liver dysfunction, 9.6% for skeletal problems, 5% for kidney dysfunction, and 3% for abnormalities involving hematopoietic function. In many cases, the adverse health outcomes were subclinical and were first diagnosed as part of the SJLIFE evaluation. For example, 35.7% of those with abnormal lung function and 46.5% of

These findings underscore the importance of ongoing health monitoring for adults who survive childhood cancer. —Melissa Hudson, MD, and colleagues

our understanding about the impact of aging on their endocrine and reproductive organs,” she said. Strength, balance, stamina, and other measures of neuromuscular function were evaluated at the St. Jude human performance lab, run by study coauthor Kirsten K. Ness, PT, PhD, Associate Member of the St. Jude Faculty, and the results were compared with norms to assess risk for falls or other morbidities. Patients were also assessed for cognitive function. Systematic exposure-based medical assessments looked at late effect associated with specific treatments. The clinical evaluations were consistent with the risk-based screening and surveillance recommended by the Children’s Oncology Group (COG)3 but were expanded for this study. All patients also provided biologic specimens for genetic testing “that will help understand potential genetic factors that are contributing to their outcomes,” Dr. Hudson added.

Abnormal Pulmonary Function Ranks Highest Leading the list of adverse health outcomes was abnormal pulmonary function, with a crude prevalence rate of 65.2%. Other high rates were 62.1% for hearing loss, 62% for endocrine or re-

those with cardiac abnormalities were identified during the SJLIFE evaluation, underscoring the need for ongoing health monitoring. The study linked adverse outcomes to specific cancer treatments. The highest prevalence of abnormal lung function occurred among those who received lung radiation (74.4%, 95% confidence interval [CI] = 69.1%–79.2%), the authors reported, followed by those treated with bleomycin (73.3%, 95% CI = 61.9%–82.9%) and thoracotomy (53.2%, 95% CI = 44.1%–62.0%). Heart valve abnormalities were found in 56.7% (95% CI = 52.2%–61.1%) of survivors exposed to cardiac-directed radiation.

Second Neoplasms A total of 335 solid and 13 hematologic neoplasms occurred among 272 of the survivors. Second neoplasms include a spectrum of low-grade or benign conditions, like nonmelanoma skin cancer or meningioma, to highgrade invasive malignancies. Survivors with low-grade or indolent subsequent neoplasms may later develop invasive neoplasms. Therefore, it is important for survivors and their providers to be aware if their cancer history or treatment warrants early initiation of screening for common adult-onset cancers.

For example, women treated with chest radiation for cancer during childhood have a markedly increased risk of breast cancer. Because of this risk, breast cancer surveillance is recommended to begin at a much younger age (8 years after radiation or at age 25, whichever occurs last) than that recommended for women in the general population. Forty-four of the cancers were identified by the health evaluations conducted as part of the study. “The subsequent malignancies identified through imaging were all breast cancers, but the majority of the other cancers were detected on physical examination,” Dr. Hudson reported. “Typically, atypical skin lesions or palpable masses. So never underestimate the importance of a thorough physical examination.”

Quality-of-life Issues In the conclusion of the study report, the investigators pointed out that clinically focused monitoring is important not only “for conditions that have significant morbidity if not detected and treated early, such as second malignancies and heart disease, [but also] for those that if remediated can improve quality of life, such as hearing loss and vision deficits.” Dr. Hudson said, “We pay a lot of attention to those issues when patients are in the pediatric age range because it is so important for their progress in school and in achieving vocational and educational goals. I think we are appreciating that there is further decline in those systems as the patients are aging.” She noted that survivors themselves may not be aware of this further decline, and it may not be “on the radar for providers.” Some survivors undergoing evaluation “showed cognitive deficits by formal testing that are commonly observed after cancer therapies affecting the central nervous system. Many had not appreciated these abnormalities were a consequence of their previous cancer treatment,” Dr. Hudson said. “This lack of awareness may affect a survivor’s access to appropriate testing and remedial services that may improve their quality of life.” The most frequent deficits among survivors exposed to central nervous system treatments were in mathematics (29.2%), memory (25.4%), and processing speed (24.4%).


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In the News

Changes in Therapy As associations between specific treatments and long-term effects become better known, efforts have been made to reduce use of harmful treatments. “This has been among the changes that have been made to improve pediatric cancer treatments over the past 30 or 40 years,” Dr. Hudson said. It took years of following pediatric patients to understand some of the delayed effects of treatment, “like understanding the impact of cranial radiation on growth hormone, understanding the impact of radiation anywhere on the risk of subsequent malignancy development, particularly solid tumors, or understanding the impact of chest radiation on heart disease,” Dr. Hudson explained. “One of the major changes in childhood leukemia therapy,” pioneered at St. Jude, was to stop using cranial radiotherapy, “which was the mainstay of controlling or treating and preventing central nervous system leukemia in the old days,” Dr. Hudson said. Greater use of targeted treatments could also potentially reduce adverse outcomes for survivors, but these agents are relatively new, with little information on long-term follow-up. “Right now most of the information that’s available is more about acute toxicity. So we still have research to do to define long-term outcomes after these treatments,” Dr. Hudson said. “We can’t assume longterm survivors are safe. They need to be monitored as well, and we want to be sure that there are no other secondary effects that were not anticipated.” Another aim of the study is to characterize the risk in different patients, “so we can stratify the frequency and intensity of follow-up and screening based on the risk contributed not only by cancer treatment, but also by genetic factors, health habits, and other comorbid health conditions,” she said.

Creating Greater Awareness “Pediatric oncologists are very aware that many of our treatments predispose to these long-term health issues or late effects,” Dr. Hudson said. Medical oncologists are becoming increasingly aware as long-term survival has improved significantly for adultonset cancers. “It’s not practical to expect community providers to be experts in the health risks associated with pediatric cancer since survivors may be relatively uncommon in most practices. We disseminate information about cancer treatment–related health risks to com-

Encourage Questions about Late Effects of Treatment

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elissa Hudson, MD, of St. Jude Children’s Research Hospital in Memphis, and lead author of a study finding that 98.2% of adult survivors of childhood cancer had a chronic health condition, told The ASCO Post that she hoped that survivors’ awareness of the need for ongoing health monitoring was increasing. She based that hope not only on news reports of study results underscoring the importance of ongoing monitoring, but on the establishment of long-

parents.” Sometimes when patients came back for clinic visits, they would say that they didn’t realize the health problem they had could be related to cancer treatment they had received or even that they should be seeking long-term follow-up after treatment for childhood cancer, according to Dr. Hudson. Patients may not be aware that cancer treatment can have delayed effects on lung, heart, and cognitive function. “It takes ongoing education at various

Risk-based care integrates the cancer experience with other things that should be considered when seeing a primary care provider. —Melissa Hudson, MD

term follow-up programs or late-effect clinics that provide information and health evaluations for survivors. “Sometimes, it is just a matter of the patient personalizing the information, being ready to hear it and saying, ‘Yes, I understand this and now I need to seek the right type of follow-up,’” Dr. Hudson said. That presents an opportunity for physicians to elicit questions about possible late effects of treatment and encourage ongoing health monitoring.

Ongoing Education Even for patients enrolled in longterm follow-up programs, it is important to “remember, we are seeing these patients when they are young, and we are talking to their parents,” Dr. Hudson said. “You may not have as many opportunities to speak to that survivor; you may be talking more to the munity providers through the survivor at point of care,” Dr. Hudson said. “We want them to be aware that when they are seeing these survivors—especially survivors who have very complicated health histories, with relapses, or having had a bone marrow transplant or intensive multimodality therapy—they really need to consider all of those exposures during childhood and how that may impact their health long-term.” She continued, “We want providers to understand that the toxicity profile varies based on the specific chemotherapeutic agent or radiation treatment field. To anticipate health risks

times their after therapy course to set that foundation of this as a lifelong issue, that we need to continue to monitor them, even after we have changed therapy to what we think is safer,” Dr. Hudson said. “We have to remind them that even if they’ve had low-risk therapy and everything seems fine now, as they age, they might see some of these conditions manifest, and we want to be sure that somebody is continuing to track their health as they are getting older,” she noted.

Importance of Oncologists in Transferring Information Dr. Hudson stressed “the importance of oncologists helping to facilitate information transfer to the community providers who assume survivor care.” That information should include the details of the for a given patient, one needs to consider the age at treatment and doses and combinations of agents and modalities used to cure the cancer. In particular, it is pertinent to consider the organs in the radiation treatment field and the impact of treatment on organ function as the survivor is aging.” As Dr. Hudson said in the The Wall Street Journal,4 “Doctors may not be thinking about a heart-valve disorder in someone in his 30s, but if you had radiation to your chest at 10, this is something to think about.” n Disclosure: Dr. Hudson reported no potential conflicts of interest.

patient’s cancer history, the known health risks associated with the cancer and its treatment, and screening and surveillance recommendations or referrals to resources that are available to help guide screening and surveillance. While there is no recommended standard or minimum set of health risk assessments that would apply to all adult survivors of childhood cancer, follow-up for late effects should at least include “a good health history and physical exam,” Dr. Hudson said. Detailed discussions about health history are particularly important for survivors with complicated cancer experiences. “This might require a separately scheduled visit where patients can discuss their cancer history and cancer treatment as part of their overall health history and share information provided by their oncologist with their primary care physician.” Dr. Hudson stated. Research conducted through the Child Cancer Survivor studies, currently coordinated by St. Jude Children’s Research Hospital, and other cohort studies has shown that survivors are not currently receiving this type of follow-up care. “Risk-based care integrates the cancer experience with other things that should be considered when seeing a primary care provider—your family history, other comorbid conditions, and chronic health conditions that may have preceded or occurred after your cancer history,” Dr. Hudson said. “All those things need to be taken into account, as well as the former cancer history, because that is going to make a difference about what your health risks are as you begin to age.” n References 1. Hudson MM, Ness KK, Gurney JG, et al: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309:2371-2381, 2013. 2. Charlier T: Most survivors of childhood cancers suffer chronic health problems, St. Jude study finds. Commercial Appeal. June 11, 2013. 3. Children’s Oncology Group Longterm Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, version 3.0. Available at http://www.survivorshipguidelines.org. Accessed July 5, 2013. 4. Marcus AD: Childhood cancer’s health woes persist for years. Wall Street Journal. June 11, 2013.


OncOlOgy care PrOviders: Be sure to Proactively discuss

FerTiliTy PreservaTiOn

with All Cancer Patients of Child-Bearing Age

Patients are often overwhelmed or in crisis mode when newly diagnosed, and may not think of or know to ask questions about fertilityâ&#x20AC;&#x201D;making it even more important for oncology care professionals to start the fertility preservation conversation as early as possible.

Watch the new videos on how to broach this subject today!

new videOs on Male and Female Fertilit y Preservation

www.youtube.com/ascocancer

You do not need to be an expert in fertility preservation, but should be ready and able to assess reproductive risks and patient interest in fertility options.


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In the Literature

Emerging Clinical Data on Cancer Management LUNG CANCER Most Patients Receiving Radiotherapy for Incurable Lung Cancer Do Not Realize It Is Unlikely to Cure Them Surveying a population-based and health system–based cohort of patients receiving radiation therapy for incurable lung cancer (defined as stage IV or stage IIIB with malignant effusion at diagnosis) revealed that “64% did not understand that [radiotherapy] was not at all likely to cure them.” These results from the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) were reported in Journal of Clinical Oncology. Among 384 patients who completed surveys on their expectations about radiotherapy, 90% had stage�� IV disease and 82% had non–small cell lung cancer. Regarding expectations about treatment, 67% believed that radiotherapy was “very or somewhat likely to help them with problems they were having because of their cancer,” 78% thought that radiotherapy was “very or somewhat likely to help them live longer,” and 43% felt that radiotherapy was “very or somewhat likely to cure their cancer,” the investigators reported. “We did not observe significant differences in overall survival on the basis of patient expectations about the likelihood of [radiotherapy] helping them live longer or curing their cancer,” they added. Multivariate analysis, controlling for factors such as education and income, found that surveys completed by older patients and nonwhites were more likely to report inaccurate beliefs, while surveys completed by surrogates (because the patients themselves were too sick) were less likely to show inaccurate beliefs. Among the 285 patients in the cohort who also completed survey items concerning chemotherapy, 92% with inaccurate beliefs about cure from radiotherapy also had inaccurate beliefs about chemotherapy. The authors concluded that unrealistic expectations about the effectiveness of radiation therapy given to patients with incurable lung cancer indicate the need for clear and accurate information about the goal and limitations of palliative radiotherapy. “Patients cannot make well-informed decisions about their end-oflife care, taking into account risks and

benefits of treatment, if they hold inaccurate beliefs about the goals of care,” they pointed out. “Studies have shown that patients with advanced cancer who do not understand and overestimate their prognosis are more likely to pursue intensive therapies near the end of life. These therapies may reduce quality of remaining life and incur substantial costs for patients with limited life expectancy.” The investigators continued, “In particular, palliative [radiotherapy] requires daily visits for treatment, which can be burdensome for patients and families. It is possible that patients who understand that [radiotherapy] is not at all likely to result in cure might choose to forgo [radiotherapy] or pursue shorter courses of treatment. Although randomized studies suggest that short courses of [radiotherapy] are equally effective in many patients with poor prognosis, lengthier courses are more commonly given.” Chen AB, et al: J Clin Oncol. June 17, 2013 (early release online).

PROSTATE CANCER Use of Advanced Technologies Has Increased in Men at Low Risk of Dying from Prostate Cancer The use of advanced treatment technologies, such as intensity-modulated radiotherapy and robotic prostatectomy, has increased among men unlikely to die from prostate cancer, according to a retrospective analysis of data from almost 56,000 men diagnosed with prostate cancer between 2004 and 2009. Among these patients, the use of advanced treatment technologies for men unlikely to die from prostate cancer increased from 13%, or 129.2 per 1,000 patients diagnosed with prostate cancer, to 24%, or 244.2 per 1,000 patients diagnosed with prostate cancer (P < .001). “Aggressive direct-to-consumer marketing and incentives associated with fee-for-service payment may promote the use of these advanced treatment technologies,” the researchers noted in their report published in JAMA. The study compared the use of advanced treatment technologies to the prior standards of traditional externalbeam radiation therapy, open radical prostatectomy, and observation among

men with low-risk prostate cancer, those with a high risk of noncancer mortality, and those with both low-risk disease and a high risk of noncancer mortality. “The use of advanced treatment technologies for prostate cancer was common among patients with lowrisk disease and among those with a high risk of noncancer mortality,” the researchers reported. “The most common treatment modality was [intensitymodulated radiotherapy], which accounted for the greatest use among men who stand the least to gain in terms of survival. The increasing use of both [intensity-modulated radiotherapy] and robotic prostatectomy in populations unlikely to benefit from treatment was largely explained by their substitution for the treatments they aim to replace, namely [external-beam radiotherapy] and open radical prostatectomy.”

Key Data Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, the researchers identified 23,633 men who underwent intensity-modulated radiotherapy, 6,123 who had open radical prostatectomy, 5,881 who had robotic prostatectomy, and 3,926 who had external-beam radiotherapy, along with 16,384 men who had observation alone. In this cohort, the use of advanced treatment technologies increased from 32% to 44% among men with low-risk disease (P < .001) and from 36% to 57% among men with high risk of noncancer mortality (P < .001).

The use of these advanced treatment technologies among men with both low-risk disease and high risk of noncancer mortality increased from 25% to 34% (P < .001). “The absolute magnitude of the use of advanced treatment technologies in these populations has two important implications,” the authors noted. “First, both treatments are considerably more expensive than the prior standards. Thus, the implications of any potential overtreatment with these advanced treatment technologies are amplified in financial terms. Second, and perhaps more important, the implementation of these technologies in populations unlikely to benefit from treatment occurred during a time of increasing awareness about the indolent nature of some prostate cancers and of growing dialogue about limiting treatment in these patients,” they continued. “Our findings suggest that, even during this period of enhanced stewardship, incentives favoring the diffusion of these technologies outweighed those related to implementing a more conservative management strategy,” the authors commented. Jacobs BL, et al: JAMA 309:25872595, 2013.

Pain Is More Prevalent and Severe in Men with Metastatic Disease and Use of Docetaxel Men who have metastatic castration-resistant prostate cancer and have

©Edward Frascino/The New Yorker Collection/www.cartoonbank.com

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Emerging Clinical Data continued from page 107

used docetaxel reported a higher prevalence and greater severity of pain than docetaxel-naive patients, according to results of an anonymous survey conducted at five comprehensive cancer centers in the Prostate Cancer Clinical Trials Consortium. Overall, 461 patients with prostate cancer completed the survey, which included the Brief Pain Inventory (BPI), as well as questions about diagnosis, treatment, and analgesic use. Patients were asked to rate their worst pain in the last 24 hours and the last 7 days, on a scale of 0 to 10, with 0 being no pain and 10 being “pain as bad as you can imagine.” The “prevalence and severity of cancer-related pain and analgesic use were tabulated according to castration-resistant status and exposure to docetaxel chemotherapy,” the researchers wrote in Journal of Oncology Practice. Among the 147 patients with metastatic castration-resistant prostate cancer involving bone, 89 or 61% had been exposed to docetaxel and 58 or 39% had not. “Pain of any level was more common among docetaxel-exposed vs docetaxelnaive patients with [metastatic castrationresistant prostate cancer] (70% [62 of 89] vs 38% [22 of 58], respectively; P < .001). BPI score ≥ 4 was reported by 38% (34 of 89) of docetaxel-pretreated and 24% (14 of 58) of docetaxel-naive patients with [metastatic castration-resistant prostate cancer],” the researchers reported. “A striking finding of this study is the apparent underuse of analgesics, including narcotic analgesics, among the men with pain, consistent with other recent reports,” the investigators noted. Among patients with a worst BPI pain score ≥ 4 in the past 7 days, 40% reported no narcotic analgesic use. Among those with BPI scores ≥ 7, only 27% (6 of 22) reported use of a long-acting narcotic and 18% (4 of 22) reported no analgesic use. The five participating institutions were Memorial Sloan-Kettering Cancer Center, New York; Duke University Cancer Institute, Durham, North Carolina; Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore; The University of Texas MD Anderson Cancer Center, Houston; and Oregon Health & Science University Knight Cancer Institute, Portland. Autio KA, et al: J Oncol Pract. June 25, 2013 (early release online).

BREAST CANCER Two Studies Indicate Potential Predictors of Survival Benefit from Endocrine Therapy Two studies published in Journal of Clinical Oncology indicate that treatment-related symptoms and mammographic density reduction may predict whether a woman with hormone receptor–positive breast cancer will benefit from adjuvant endocrine therapy. In one study, women who had specific adverse events, particularly vasomotor symptoms, during their first year of endocrine therapy had improved disease-free and overall survival. In the other study, women who had a relative mammographic density reduction of more than 20% between baseline and the first-follow-up mammogram had a 50% reduced risk of death as a result of breast cancer. An editorial accompanying the two articles points out that a “patient might be more willing to tolerate” the considerable side effects of endocrine therapies “if she knows that she is obtaining benefit from the medication.”

Specific Adverse Events The International Tamoxifen Exemestane Adjuvant Multinational Trial Analysis investigated the relationship between survival outcomes and specific adverse events among 9,325 patients participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial, a randomized, phase III trial conducted in nine countries including the United States. Participating patients were postmenopausal women with estrogen receptor– and/or progesterone receptor–positive breast cancer eligible for adjuvant endocrine treatment. “Patients were randomly assigned to receive either exemestane 25 mg once daily for 5 years or tamoxifen 20 mg once daily for 2.5 to 3 years, followed by exemestane 25 mg once daily for 2.5 to 2 years (sequential regimen),” the researchers reported. The analysis included all adverse events reported in the first year of adjuvant endocrine therapy. Vasomotor symptoms were defined as “a subjective and transient sensation of heat, including hot flashes and night sweats.” Musculoskeletal adverse events “were all accounts of arthralgia, arthritis, arthrosis, myalgia, and bone pain.” Osteoporosis was not considered a musculoskeletal adverse events “due to the fact that os-

teoporosis is a long-term process, likely to take more than 1 year to become evident,” the investigators explained. Vulvovaginal symptoms included “all accounts of vaginal dryness/itching, vaginal discharge, dyspareunia, and endometrial and libido disorders.” Patients with specific adverse events vs those with nonspecific or no adverse events had better disease-free survival and overall survival. “The strongest effect on distant recurrence and survival outcomes was reported for [vasomotor symptoms]. A decreasing incidence of distant metastases, disease relapse, and death was noted in patients reporting increasing numbers of different specific [adverse events],” the researchers wrote. Multivariate hazard ratios for disease-free survival were 0.731 for vasomotor symptoms, 0.826 for musculoskeletal adverse events, and 0.769 for vulvovaginal symptoms. Multivariate hazard ratios for overall survival were 0.583 for vasomotor symptoms, 0.811 for musculoskeletal adverse events, 0.570 for vulvovaginal symptoms. “Outcomes were unrelated to treatment allocation,” the researchers stated. “Although our results must be considered hypothesis generating, our findings show an association between specific adverse effects caused by endocrine therapy and outcomes and may thus potentially be a valuable predictor and biomarker of treatment efficacy,” the investigators concluded. “Future prospective studies, however, are warranted to advance the personalization of treatment strategies for patients with breast cancer.”

Mammographic Density Reduction Tamoxifen recipients who had a relative density reduction of more than 20% between baseline and first follow-up mammogram showed a 50% reduced risk of breast cancer–related death (hazard ratio = 0.50; 95% CI = 0.27–0.93) compared with women who had stable mammographic density, according to results of a population-based case-control study in Sweden. The study involved 974 postmenopausal patients with breast cancer who had both a baseline and a follow-up mammogram. “On the basis of treatment information abstracted from medical records, 474 patients received tamoxifen treatment and 500 did not. Mammographic density was measured by using an automated thresholding method and expressed as absolute dense area,” the authors explained.

“Change in mammographic density was calculated as percentage change from baseline.” During a 15-year follow-up, 121 patients (12.4%) died from breast cancer. “In the tamoxifen-treated group, 35% of the women who died as a result of breast cancer had a reduction of [dense area] of 20% or more compared with 48% in women who did not die as a result of breast cancer (P = .017),” the investigators noted. “Among women treated with tamoxifen who experienced a decrease in [dense area] of 20% or more, the relative risk of death was 0.50 [95% CI = 0.27–0.93] compared with that of women treated with tamoxifen who had stable mammographic density.” The relationship between mammographic density change and survival did not reach statistical significance, but a trend for improved survival was seen with a decrease in dense area, the researchers noted. The association of mammographic density reduction with better long-term breast cancer–specific survival being found only in the tamoxifen group suggests that a change in dense area “could be a convenient biomarker for tamoxifen therapy response,” the investigators concluded. “If validated, mammographic density change has the potential to be an early marker for therapy response and provide clinicians with a tool for monitoring the effect of postsurgical adjuvant therapy beyond the current wait-andsee approach. In fact, given ongoing developments in automatic algorithms for mammographic density measurement, implementing this as a routine clinical tool could be cost-effective.” Henry NL, Stearns V: J Clin Oncol 31:2233-2235, 2013. Li J, et al: J Clin Oncol 31:2249-2256, 2013. Fontein DB, et al: J Clin Oncol 31:2257-2264, 2013.

LEUKEMIA Lenalidomide Induces Longlasting Responses in Elderly Patients Treatment with lenalidomide (Revlimid) as initial therapy induced longlasting responses in a phase II study of 60 patients with chronic lymphocytic leukemia (CLL). “Overall, 35 patients (58%) patients had responses lasting more than 36 months and were considered long-term responders,” the researchers wrote in Blood. Best responses among long-term re-


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In the Literature

sponders were 25 complete remissions (71% of patients), including five patients with no evidence of residual disease at bone marrow evaluation (minimal residual disease–negative complete remissions), and 10 partial remissions (29% of patients). At a median followup of 4 years, median time to treatment failure had not been reached and overall survival was 82%. All of the long-term responders are alive, the researchers noted, and 25 of the long-term responders are still on therapy. “Treatment consisted of 5 mg of lenalidomide daily by mouth, continuously. After two 28-day cycles, the dose of lenalidomide could be escalated by increments of 5 mg per cycle to 25 mg daily,” the investigators explained. Previously reported results showed an overall response rate of 56% with 2-year overall survival of 88% and progression-free survival of 60%. “Because response duration and longterm survival are important clinical endpoints, we sought to report the long-term outcome of this trial,” the authors wrote. “As patients continued on therapy with lenalidomide, we compared the quality of responses at 18 months and after 36 months. Twelve patients with a [partial remission] improved their response to a [complete remission], 8 patients with stable disease improved their response to [partial remission], and 2 additional patients achieved [minimal residual disease]-negative [complete remission],” the investigators reported. Hematologic toxicity led to dose reductions. Ten long-term responders discontinued lenalidomide, six because of toxicity, two due to moderate neuropathy, and one each due to deep venous thrombosis, persistent fatigue, moderate weight loss, and immune thrombocytopenia. Other reasons for discontinuation were progression, sepsis, second malignancy (invasive squamous cell carcinoma of the skin), and change of institution. “Recent reports have suggested a possible correlation between treatment with lenalidomide and the development of second cancers in patients with multiple myeloma,” the authors noted. “In our series only 1 patient developed an invasive skin cancer, but the size of this study and the available follow up time are insufficient to derive accurate information on the occurrence of other cancers.” Strati P, et al: Blood. June 25, 2013 (early release online).

RISK FACTORS Some Excess Cancer Risk in Men May Be Related to Greater Height More than one-third of the excess risk for cancers among men may be due to factors associated with height, according

to data from the Vitamins and Lifestyle (VITAL) study. As reported in the Journal of the National Cancer Institute, these factors include the “number of susceptible cells in a specific organ or growthinfluencing exposures in childhood.” Using the Surveillance, Epidemiology, and End Results (SEER) cancer registry, a total of 3,466 can-

cers of anatomic sites that men and women have in common were identified among 65,308 VITAL volunteers aged 50 to 76 years. The mean height for men was 70.67 inches vs 64.67 inches for women. Men were also heavier than women, exercised more, consumed more alcohol and red meat continued on page 110

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About the Author Mario E. Lacouture, MD Associate Member Memorial Sloan-Kettering Cancer Center New York, NY Mario E. Lacouture, MD, is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. His clinical focus is the recognition and management of the side effects and conditions of the skin, hair, and nails that may arise in cancer patients and survivors as a consequence of surgery, chemotherapy, radiation, or transplantation. His research focuses on exploring new skin treatments that do not interfere with the effectiveness of anticancer medications.


T:10.25" S:9.5" PAGE 110

The ASCO Post | JULY 25, 2013

In Memoriam

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Keith Amos, MD, Surgical Oncologist, Dies at 42

Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

October 8, 1970 – June 17, 2013

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]

K

eith Amos, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center, died recently in Edinburgh, Scotland, where he was on a Dr. Claude Organ, Jr., Travel Award from the American College of Surgeons. Dr. Amos is survived by his wife, Ahaji, and three young daughters.

Passionate About Education, Screening, Disparities Dr. Amos was a member of the University of North Carolina School of Medicine, the Department of Surgery, the Division of Surgical Oncology, and

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

Keith Amos, MD

vard University, and completed surgery residency at Washington University in Saint Louis. He performed a surgical oncology fellowship at MD Anderson

[Dr. Amos] is remembered for his passion in visiting communities to talk about cancer, the importance of screening for cancer, and cancer disparities.

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

the UNC Lineberger Comprehensive Cancer Center. He is remembered for his passion in visiting communities to talk about cancer, the importance of screening for cancer, and cancer disparities. Dr. Amos was recruited to University of North Carolina in 2007. He earned his medical degree from Har-

Cancer Center in Houston. During his career at the University of North Carolina, Dr. Amos focused his energy on all aspects of the multidisciplinary UNC Breast Center in Chapel Hill, Raleigh and across the state. A memorial service for Dr. Amos was held on June 29, 2013. n

1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Emerging Clinical Data

but not others “indicate there are multiple biologic and behavioral mechanisms that vary by anatomic site that may explain the sex differences in cancer risk,” the authors stated. “One postulated mechanism related to height is that taller individuals may be at increased risk of cancer because of a larger number of cells and higher rate of cell divisions within tissues,” they continued. “Consistent with this hypothesis, for instance, a case–control study reported a strong association between melanoma risk and body surface area, as measure of skin cell mass at risk of malignant transformation. Proposed mechanisms contributing to the association between height and cancer risk, perhaps by influencing the number of proliferating cells and/or other pathways, include genetic factors, energy intake in early life, and exposure to sex and growth hormones.” n Walter RB, et al: J Natl Cancer Inst 105:860–868, 2013.

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).]

continued from page 109

and fewer servings of fruits and vegetables, smoked more in their lifetime, and were more educated. “Men had a 55% increased risk of cancer at shared sites (HR = 1.55; 95% confidence interval [CI] = 1.45 to 1.66),” the researchers reported. “When height was accounted for, 33.8% (95% CI = 10.2% to 57.3%) of the excess risk for men was explained by the height differences between sexes. The proportion mediated by height was 90.9%, 57.3%, and 49.6% for kidney, melanoma, and hematologic malignancies, respectively, with little evidence that height mediates the sex difference for gastrointestinal tract, lung, and bladder cancers. For comparison, more than 35 lifestyle and medical risk factors only explained 23.1% of the sex difference in cancer risk at shared sites,” the researchers noted. Observations that some cancers, such as thyroid and breast cancers, are less common among men and that height is associated with some cancers

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade  1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13  (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade  2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate >  10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 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. The data below reflect exposure to Avastin in 4599  patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23  doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median  60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184  first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8  doses of Avastin, 163  glioblastoma patients who received a median of 9  doses of Avastin, and 337  mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363  patients with metastatic breast cancer (MBC)


"

T:10.25" S:9.5" AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy.  Among patients requiring surgery on or within 60  days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Congestive Heart Failure (CHF) The incidence of Grade   ≥  3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The  safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade  3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

a

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. 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. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged  ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20  mg/kg IV) was associated with headache in nine of 16  patients and with severe headache in three of 16 patients.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

03/13 AVA0000765905 Initial U.S. Approval: February 2004 Code Revision Date: March 2013 Avastin® is a registered trademark of Genentech, Inc. © 2013 Genentech, Inc.

S:12.5"

Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). [See Warnings and Precautions (5.8).]

Arm 2 IFL+ + Avastin (n = 392) 87%

T:13" S:12.5"

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

a

Arm 1 IFL+ + Placebo (n = 396) 74%

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)


To confront a common threat across approved indications...

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Because anti-angiogenesis matters Avastin is designed to directly inhibit the VEGF ligand to specifically inhibit angiogenesis1*

VEGF=vascular endothelial growth factor. *The mechanism of action of Avastin has been elucidated primarily in preclinical models. Its clinical significance is unknown.

Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,† the incidences of Avastinrelated adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Rhinitis — Dry skin — Back pain — Headache — Proteinuria — Rectal hemorrhage — Exfoliative dermatitis — Hypertension — Taste alteration — Lacrimation disorder Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

©2013 Genentech USA, Inc.

All rights reserved.

AVA0000488403

Printed in USA.

(5/13)

Avastin is not approved for use in combination with irinotecan.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. Reference: 1. Avastin Prescribing Information. Genentech, Inc. March 2013.

www.avastin.com


TAP Vol 4 Issue 12