July 2015

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Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • July 2015 • Vol. 10, No. 7

SOLID TUMORS Report From ASCO Meeting:

First trial for liver metastases in colorectal cancer shows benefit .........

9

HEMATOLOGIC DISEASE Report from ASCO Meeting:

New immunotherapy may change treatment landscape for multiple myeloma ...............................

12

CURRENT PRACTICE On the Spot

Genomics in clinical oncology practice ............

14

Editorial Board Commentary

Maurie Markman, MD: Invasive Biopsies for Research Purposes: Time for a Discussion .....

17

numbers U.S. Daily Spend

daily | Average cost of a U.S. biologic

$2

Chicago—Results from the international Phase III GADOLIN trial show that obinutuzumab plus bendamustine followed by obinutuzumab maintenance is an effective treatment option for patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL) who are refractory to rituximab. This treatment appears to at least double progression-free survival (PFS) compared with bendamustine monotherapy.

“This represents the first randomized controlled trial data that demonstrate the utility of a novel anti-CD20 monoclonal antibody in patients with rituximab-refractory lymphoma,” see GADOLIN, N page 10

by the

$45

GADOLIN Called Practice-Changing Trial for Indolent NHL

daily | Average cost of a chemical drug

Source: Am Health Drug Benefits 2013;6(8):469478, PMID: 24991376.

The Many Challenges But Promise of Big Data

Report From ASCO Meeting:

Combination Immune Therapy Yields Big Benefit in Melanoma Chicago—In previously untreated patients with metastatic melanoma, the combination of ipilimumab and nivolumab provided a nearly 60% increase in progression-free survival (PFS) relative to ipilimumab alone.

Drawn from a Phase III trial called CheckMate 067, the data were characterized as setting a new treatment standard.

“Based on the results of the nivolumab alone and nivolumab plus ipilimumab arms relative to ipilimumab and the prior study comparing pembrolizumab to ipilimumab, it is my opinion that ipilimumab alone can no longer be considered a standard first-line immunotherapy for patients with advanced see MELANOMA, page 4

Breast cancer cells. New therapy promising for endocrine-resistant disease; story on page 4.

Arlington, Va.—A plethora of oncology patient information is stored in various electronic health record (EHR) systems, but accessing it and using it wisely to monitor trends and treatment outcomes remains challenging, oncologists say.

To illustrate the shortcomings of stored medical data, oncologist Amy Abernethy, MD, PhD, shared the story of her patient “Janet.”

In 2009, Janet, a 37-year-old emergency room nurse, came to see Dr. Abernethy, then a melanoma specialist at Duke Cancer Institute, in Durham, N.C. Janet, whose mother died from melanoma, had a stage IIIB melanoma on her right arm, about 3 mm in size and partly ulcerated. She had pain in her arm after node dissection. Her likely treatment plan was high-dose interferon for one month, followed by a moderate dose for 11 months.

Based on data available at that time, Dr. Abernethy said she could only answer some of Janet’s questions. She could predict Janet’s risk for death (about 47%) and manage her pain, but “I was not good at crystallizing her story from the research evidence available in front of me,” Dr. Abernethy, now chief medical officer and senior vice president for oncology at Flatiron Health, a health technology firm in New York City, told attendees at the Association of Community Cancer Centers’ 2015 annual meeting.

Dr. Abernethy didn’t know the impact of Janet’s family history, how treatment would affect her future fertility or what her quality of life would be. Additionally, see BIG DATA, page 18

NOW Available Essential Oncology™

Multiple Myeloma Renju Raj, MD Parmeswaran Hari, MD To download the Essential Oncology app go to: essentialoncology.com

65 Cancer Types

The New Standard for Bone Marrow Biopsies Starts Here Larger specimens with a better patient experience.1, 2 For blood-borne cancer patients and their treating oncologists, a manually performed bone marrow biopsy is a critical, but often painful, procedure for diagnosis and treatment monitoring. The procedure is often physically taxing on clinical staff who must obtain a sample of adequate size and quality. Ultimately, the accuracy of the diagnosis determined by pathology is directly related to the integrity of this specimen.

The ARROW® OnControl® Powered Bone Marrow Biopsy System is used for obtaining bone marrow samples in major cancer centers throughout the country. With the ARROW OnControl System, you can be confident in developing treatment plans based on the diagnosis you receive: • Larger specimens provide more usable area for diagnosis • Reduced insertion pain,1 less overall pain,3 and helps promote patient compliance3, 4 • Shorter procedure time improves efficiency4 Relative size comparison of manual sample to a sample obtained using the ARROW® OnControl® System

Procedure times decrease dramatically1 Comparison of mean time to sample on first attempts Manual procedure Powered procedure

Manua nual Needle Core Sa Co ample

55% % Fast ter Faster

ARROW OW OnControl System’s Core Sample Sy Both sample s sizes from same healthy subject, same provider. Sample sizes are most representative of sample means in a published healthy subject study.

The ARROW OnControl Bone Marrow Aspiration and Biopsy Systems should only be used by clinicians familiar with the complications, limitations, indications, and contraindications of bone marrow aspiration and bone marrow biopsy.

1. Swords RT, Anguita J, Higgins RA, et al. A prospective randomized study of a rotary powered device (OnControl) for bone marrow aspiration and biopsy. J Clin Pathol 2011; 64(9): 809-13. doi:10.1136/jclinpath-2011-200047. * 2. Reed LJ, Raghupathy R, Strakhan M et al. The OnControl bone marrow biopsy technique is superior to the standard manual technique for hematologists-in-training: a prospective, randomized comparison. Hematology Reports 2011; 3(e21). doi:10.4081/hr.2011.e21. * 3. Miller LJ, Philbeck TE, Montez DF, et al. Powered bone marrow biopsy procedures produce larger core specimens, with less pain, in less time than with standard manual devices. Hematology Reports 2011; 3:e8. * 4. Berenson JR, Yellin O, Blumenstein B, et al. Using a powered bone marrow biopsy system results in shorter procedures, causes less residual pain to adult patients, and yields larger specimens. Diagnostic Pathology 2011; 6:23.* * Research sponsored by Teleflex Incorporated or its affiliates, including Vidacare LLC Teleflex, Arrow, Never Settle and OnControl are trademarks or registered trademarks of Teleflex Incorporated or its affiliates. © 2015 Teleflex Incorporated. All rights reserved. MC-001096 Rev 1

TELEFLEX 3015 Carrington Mill Boulevard, Morrisville, NC 27560 Toll Free: 866.246.6990 Phone: +1.919.544.8000 TELEFLEX.COM

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center Penn State University Hershey, PA

Breast Cancer Andrew Seidman, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Hematologic Malignancies

Betty Ferrell, RN, PhD

Joseph P. DeMarco, PhD

Cancer Treatment Centers of America Zion, IL

City of Hope National Medical Center Duarte, CA

Cleveland State University Cleveland, OH

Jennifer R. Brown, MD, PhD

Michele Neskey, MMSc, PA-C

Paul J. Ford, PhD

Dana-Farber Cancer Institute Harvard Medical School Boston, MA

University of Texas, MD Anderson Cancer Center Houston, TX

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Harry Erba, MD, PhD University of Alabama Birmingham, AL

Mayo Clinic Rochester, MN

Richard Stone, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Cathy Eng, MD

Saad Z. Usmani, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Levine Cancer Institute Charlotte, NC

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD

Michael J. Fisch, MD, MPH

Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

University of Texas, MD Anderson Cancer Center Houston, TX

Steven Vogl, MD Ronald M. Bukowski, MD

Medical Oncologist New York, NY

Taussig Cancer Center Cleveland Clinic Foundation Cleveland, OH

Gynecologic y g Cancer

William S. Breitbart, MD

Cancer Treatment Centers of America Philadelphia, PA

Memorial Sloan-Kettering Cancer Center New York, NY

Steven D. Passik, PhD Edward S. Kim, MD

Millennium Health San Diego, CA

Levine Cancer Institute Carolinas HealthCare Charlotte, NC

Joseph V. Pergolizzi Jr., MD

Lung g Cancer,, Emesis

Johns Hopkins University School of Medicine Baltimore, MD

Richard J. Gralla, MD Albert Einstein College of Medicine New York, NY

Prostate Cancer Michael A. Carducci, MD Johns Hopkins Kimmel Cancer Center Baltimore, MD

Matt Brow McKesson Specialty Health, The US Oncology Network, Washington, DC

Sara S. Kim, PharmD

Infection Control Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

MELANOMA continued from page 1

melanoma,” asserted Michael B. Atkins, MD, the deputy director of Georgetown University’s Lombardi Comprehensive Cancer Center, in Washington, D.C., who was the invited discussant for this trial at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), where the data were presented during the plenary session (abstract LBA1). The study, which was published simultaneously in The New England Journal of Medicine (May 31. [Epub ahead of print], PMID: 26027431), was supported by Bristol-Myers Squibb.

In this study, presented by Jedd D. Wolchok, MD, PhD, the chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan-Kettering Cancer Center, in New York City, 945 previously untreated patients with unresectable stage III or IV melanoma were randomized to the CTLA-4 checkpoint inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb) alone, the PD-1 checkpoint inhibitor nivolumab (Opdivo, BristolMyers Squibb) alone, or a combination of the two. Both have indications for melanoma, but they had not been evaluated in combination in a Phase III trial.

After a median follow-up of slightly more than a year, the PFS rates were 2.9 months with ipilimumab alone, 6.9 months with nivolumab alone, and 11.5 months with the combination. These translated into favorable hazard ratios (HR) for the combination relative to ipilimumab alone (0.42; P<0.001) and for nivolumab alone relative to ipilimumab alone (0.57; P<0.001). The combination showed a numerical advantage over nivolumab alone in an exploratory analysis (HR, 0.74; significance not assessed).

The PFS advantage of the combination

These results are ‘the latest in a series of breakthroughs’ that have dramatically changed the prognosis of a cancer for which the median survival just five years ago was six to nine months.

—Michael B. Atkins, MD treatment over ipilimumab alone was consistent across a large number of subgroups, including BRAF mutation status and PD-L1 expression. However, greater than 5% PD-L1 expression was a factor in relative PFS rates. In patients whose tumors had greater than 5% PD-L1 expression, the median PFS was 3.9 months in the ipilimumab alone group but 14 months in both the combination group and the nivolumab-alone group. In patients with less than 5% PD-L1 expression, the median PFS was 2.8 months with ipilimumab alone, 5.3 months with nivolumab alone, and 11.2 months with the combination.

Investigator-assessed objective response rates and complete response rates were higher with the combination treatment (57.6% and 11.5%) relative to nivolumab alone (43.7% and

8.9%) and ipilimumab alone (19% and 2.2%). Higher objective response rates were observed in patients with tumors expressing greater than 5% PD-L1 relative to those expressing less than 5% PD-L1, particularly with the combination (72.1% vs. 54.8%) and nivolumab alone (57.5% vs. 41.3%). In patients randomized to ipilimumab alone, the difference in objective response rates between those with tumors expressing greater than 5% PD-L1 and those with tumors expressing less than 5% PD-L1 was narrower (21.3% vs. 17.8%).

The combination was less well tolerated than either immunotherapy alone.

Discontinuations due to adverse events (AEs) occurred in 36.4% of patients in the combination arm versus 7.7% of those receiving nivolumab alone and 14.8% of those receiving ipilimumab alone.

The grade 3 or higher AEs that occurred more commonly with the combination relative to nivolumab alone and ipilimumab alone, respectively, included diarrhea (9.3% vs. 2.2% and 6.1%), rash (4.8% vs. 0.6% and 1.9%), fatigue (4.2% vs. 1.3% and 1.0%), vomiting (2.6% vs.

0.3% and 0.3%) and liver enzyme abnormalities (6.1% vs. 1.0% and 0.6%). However, immune-modulatory agents— used in nearly half of patients receiving nivolumab alone, more than half of those receiving ipilimumab alone and nearly 85% of those receiving both agents— were effective in modifying the intensity of these AEs, according to Dr. Wolchok.

Overall survival data from this trial are pending, but, as noted by Dr. Atkins, the data are already sufficiently compelling to suggest a new standard of care.

According to Dr. Atkins, more work needs to be done on biomarkers to predict response and to explore whether alternative ipilimumab schedules or substitution of other immunotherapies for ipilimumab could improve the therapeutic effectiveness of this combination. However, he considered these results to be “the latest in a series of breakthroughs” that have dramatically changed the prognosis of a cancer for which the median survival just five years ago was six to nine months.

—Ted Bosworth Dr. Wolchuk reported financial relationships with Bristol-Myers Squibb, EMD Serono, GlaxoSmithKline, Janssen, Jounce Therapeutics, Medimmune, Merck, Polaris, Polynoma Potenza Therapeutics, Vesuvius and Ziopharm Oncology. Dr. Atkins reported financial relationships with Alkermes, Amgen, Bristol-Myers Squibb, C-Cam, Costim, Genentech, GlaxoSmithKline, Infinity, Lilly, Merck, Neostem, Novartis, Pfizer and X4.

Report From ASCO Annual Meeting:

New Therapy Identified for Endocrine-Resistant Breast Ca Chicago—Adding palbociclib to fulvestrant improved median progressionfree survival (PFS) by 5.5 months in women with hormone receptor (HR)positive, HER2-negative breast cancer who had progressed on endocrine therapy, according to results of the Phase III PALOMA-3 trial.

“Resistance to endocrine therapy presents a major clinical challenge in breast cancer,” said Nicholas Turner, MD, PhD, an academic consultant medical oncologist at Royal Marsden Hospital, in London, who presented the study at the annual meeting of the American Society of Clinical Oncology (abstract LBA502). “Palbociclib in combination with fulvestrant is an effective treatment option for women whose cancer

Table. Comparison of AEs In Phase III PALOMA-3 Trial AE (any grade), %

Palbociclib + Fulvestrant

Placebo + Fulvestrant

Neutropenia

79

3

Leukopenia

46

4

Anemia

26

10

Thrombocytopenia

19

0

Fatigue

38

27

Alopecia

15

6

Upper respiratory infection

19

16

AE, adverse event

progressed on prior endocrine therapy,” Dr. Turner said.

Palbociclib (Ibrance, Pfizer) is an orally active selective inhibitor of cyclindependent kinase (CDK) 4/6 that inhibits cell proliferation and DNA synthesis.

The drug has been shown to be active in cell line models of endocrine therapy resistance and is synergistic with fulvestrant (Faslodex, AstraZeneca). In February 2015, the FDA granted accelerated approval to palbociclib in combination with letrozole as a first-line therapy for women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer. Palbociclib is the first commercially available CDK4/6 inhibitor.

PALOMA-3, which was simultaneously see PALOMA-3 TRIAL, page 8

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

Dual Targeted Rx Tested in Breast, Ovarian Cancers PARP inhibitor, P13K inhibitor combined approach found feasible for BRCA-mutated cases Philadelphia—Substantial response rates were achieved in early-phase trials in women with high-grade serous ovarian or triple-negative breast cancers when a PARP inhibitor and a P13K inhibitor were given as combined treatment.

Toxicities were manageable, providing evidence that the synergy seen with this strategy in the experimental setting may be viable in the clinic.

In this study, the PARP inhibitor, olaparib (Lynparza, AstraZeneca), which already has an indication for advanced germline BRCA (gBRCA ( )-mutated ovarian cancer, was combined with the investigational P13K inhibitor BKM120 (buparlisib). Based on animal data, the P13K renders BRCA-mutated cancers more susceptible to olaparib, providing a potential synergy for the combination, explained Ursula A. Matulonis, MD, the director and program leader of medical gynecologic oncology at Dana-Farber Cancer Institute’s Susan F. Smith Center for Women’s Cancers, in Boston.

In an initial study, the goal was to identify maximally tolerated doses of the two agents together, according to Dr. Matulonis, who presented the findings at the 2015 annual meeting of the American Association for Cancer Research (AACR; abstract 8972). There were 46 patients in

this dose-escalation phase. An expanded experience now includes safety and overall response rate results for 46 ovarian and 24 triple-negative breast cancer patients.

Seventy-seven percent of the ovarian cancer group and 58% of the breast cancer group were gBRCA carriers.

The safety profiles of these agents differ, but the most common dose-limiting toxicities for these agents used together were hyperglycemia, transaminitis and depression. Nausea, fatigue, diarrhea and anorexia were common but generally occurred at a severity of grade 2 or lower.

The dose most likely to move forward is 300 mg of olaparib twice daily (lower than the 400 mg twice-daily dose used for monotherapy) combined with 50 mg of buparlisib once daily (about half that used in several ongoing clinical trials in other cancers).

Even in this dose-escalation trial that likely resulted in suboptimal drug exposure in at least some patients, the response rates were encouraging.

Although no complete responses were seen, the partial response rates were 26% and 21% in the ovarian and breast cancer groups, respectively. Stable disease was achieved in approximately 50% of the patients in both groups. Although only about 33% of the breast cancer and 17%

of the ovarian cancer patients were carriers of wild-type BRCA, some responses also were observed in this group.

Response in wild-type BRCA carriers is important, said Dr. Matulonis, adding that it is believed that gBRCA mutations produce cancers that rely on the DNA repair enzyme PARP to preserve their ability to proliferate. This may explain why PARP inhibition is particularly effective in BRCA carriers. However, the initial data suggest that the presence of gBRCA mutations may not be essential.

“We need to do further analysis to identify biomarkers that we can use to more effectively identify the patient population that will be most positively affected by the olaparib/BKM120 combination,” Dr. Matulonis said.

Overall, these data provide reassurance that two targeted therapies functioning via different pathways can be combined with acceptable tolerability. The responses so far are consistent with the potential synergy of this particular combination.

According to Dr. Matulonis, the data provide bench-to-bedside encouragement that pathways with potentially complementary effects can be combined.

The work toward combining two pathway inhibitors in high-grade epithelial ovarian and triple-negative breast cancers

is “exciting,” particularly as the results presented by Dr. Matulonis suggest “early evidence of clinical benefit,” according to Jung-Min Lee, MD, an assistant clinical investigator in the Women’s Malignancies Branch at the National Cancer Institute’s Center for Cancer Research, in Bethesda, Md. However, Dr. Lee suggested that it is an early step. “It will be important to follow up to see the long-term safety and to identify a subset of women who respond to this novel combination,” she said. “It will also be important to see whether this early activity signal can be seen with olaparib and a different P13K inhibitor, BYL719, combination.” The data “will help us understand the genomic landscape of a patient’s tumor,” she said, which, in turn, has the potential to lead to novel ways “to improve our patient’s quality and quantity of life.”

—Ted Bosworth Dr. Matulonis reported a financial relationship with AstraZeneca. Dr. Lee reported no relevant financial relationships.

Metastatic Castration-Resistant Prostate Cancer

Olaparib Response Better in Pts With DNA Repair Mutations Philadelphia—Deletions in DNA repair genes were highly accurate in predicting response to the PARP inhibitor olaparib in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC), according to a recent biomarker study. In addition to identifying a promising therapy for patients with advanced mCRPC, the study may provide the first molecular treatment stratification of this population.

Whether somatic or germline, defects in DNA repair genes provide “a high biomarker specificity” as well as specificity for response to olaparib (Lynparza, AstraZeneca), reported Joaquin Mateo, MD, from the Institute of Cancer Research and the Royal Marsden NHS Trust, in London, United Kingdom. In this study, which was presented at the 2015 annual meeting of the American Association for Cancer Research (AACR; abstract 8311), the response rate was 32.7% among unselected mCRPC patients but 86.7% among those with DNA repair gene deletions.

This ongoing Phase II, multicenter study involves multiple steps. In the first

step, 50 unselected patients with mCRPC were treated with olaparib 400 mg twice daily. The primary end point was response rate, defined as an objective response by RECIST assessment, a 50% reduction in prostate-specific antigen level or a circulating tumor cell count reduction from over 5 to below 5. The second step is a preplanned analysis of response in patients whose tumors have mutations in DNA repair genes, which the authors hypothesized to be potential biomarkers of benefit.

Of the 49 evaluable patients, putatively deleterious mutations in DNA repair genes were identified in 15 (30.6%). Most of the mutations were in the BRCA2 and ATM M genes, but mutations in other genes, such as CHEK2 and members of the Fanconi anemia complementation group, were observed. The presence of these mutations corresponded strongly with response to olaparib.

“All seven patients with BRCA2 loss and four of the five patients with ATM-truncating mutations responded to olaparib,” Dr. Mateo reported. This included responses in those with inherent germline mutations as well as those with acquired

somatic mutations. Major and durable responses have been concentrated in the subgroup with DNA repair mutations, some lasting longer than six months.

The high rate of response in mCRPC patients with defects in DNA repair genes is consistent with the expected activity of olaparib. PARP is an enzyme that is important in DNA repair, so it is presumed that its inhibition would treat cancers that are most dependent on PARP to preserve their ability to survive and divide.

BRCA-mutated cancers are among these.

Olaparib is already FDA-approved for the treatment of advanced ovarian cancer in patients with BRCA mutations.

The data from the study provide strong support for the role of olaparib in mCRPC, a disease with limited options for patients who no longer respond to drugs that inhibit androgen activity, such as abiraterone (Zytiga, Janssen) or enzalutamide (Xtandi, Astellas).

In this study, all patients had received a prior course of docetaxel and almost all patients had received abiraterone. Nearly 30% had received enzalutamide, and nearly 60% had been treated with cabazitaxel

(Jevtana, Sanofi). Olaparib was generally well tolerated. The most common grade 3 or higher adverse events were anemia and fatigue, occurring in 20% and 12%, respectively, of the patients. Dose reductions to 300 mg were required in 26% of the patients, with a second dose reduction required in three patients.

The data from this study provide another demonstration of how molecular signatures can single out patients most likely to respond to a specific targeted agent pathway, according to William Nelson, MD, PhD, the director of Johns Hopkins University’s Sidney Kimmel Comprehensive Cancer Center, in Baltimore. In comments made at the AACR meeting, Dr. Nelson suggested that the same principles likely will be applied to other cancers, but these data outline promise for new options for mCRPC patients who no longer derive benefit from androgen suppression.

—Ted Bosworth Drs. Mateo and Nelson reported no relevant financial relationships.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

Study Addresses Clinical Dilemma in Bladder Cancer Orlando, Fla.—Patients with bladder cancer who underwent cystectomy benefit from adjuvant chemotherapy when neoadjuvant chemotherapy had not been used, according to a large retrospective study presented at the 2015 Genitourinary Cancers Symposium (abstract 292).

Patients who received adjuvant chemotherapy had a 30% to 40% lower chance of death at five years.

“Neoadjuvant chemotherapy is the preferred approach based on the available level of evidence. However, for patients who do not receive neoadjuvant chemotherapy, these data lend further support to consideration of adjuvant chemotherapy,” said investigator Matthew Galsky, MD, an associate professor of medicine, hematology and medical oncology at Mount Sinai’s Icahn School of Medicine, in New York City.

not release survival data until patients have been followed for five years.

To be included in the analysis, patients were required to have urothelial histology as well as pathologic T3 stage and/or node-positive

disease. Patients were not included if they had metastases or had received neoadjuvant chemotherapy or radiation.

The patients in the observation cohort had to have survived longer than 30 days from cystectomy to ensure eligibility for adjuvant

chemotherapy.

Of 5,653 patients who met eligibility criteria, 1,293 received adjuvant chemotherapy and 4,360 were observed.

“Adjuvant chemotherapy was defined as the receipt of multiagent chemotherapy within 90 days of cystectomy,” Dr. Galsky said. The median follow-up period for patients alive in both cohorts was approximately six years.

The investigators used logistic see BLADDER CANCER, R page 9

®

makes all the difference

‘For patients who do not receive neoadjuvant chemotherapy, these data lend further support to consideration of adjuvant chemotherapy Matthew Galsky, MD For patients with bladder cancer undergoing a cystectomy, level 1 evidence supports the use of neoadjuvant chemotherapy. When neoadjuvant therapy is not provided, it has been unclear whether clinicians should use adjuvant chemotherapy. Early trials of adjuvant chemotherapy in patients with bladder cancer often used suboptimal regimens, were underpowered, and, at times, were associated with methodological flaws.

Recent clinical trials of adjuvant chemotherapy have closed early due to poor accrual. “All of these trials have fueled controversy regarding the role of adjuvant chemotherapy in bladder cancer, with some practice guidelines endorsing the practice and other guidelines recommending against it,” Dr. Galsky explained.

Because it is unlikely that a randomized trial will provide a definitive answer, given poor enrollment, Dr. Galsky and his colleagues conducted an observational study. They compared adjuvant chemotherapy with observation in patients with locally advanced bladder cancer who underwent radical cystectomy between 2003 and 2007, using data from the National Cancer Data Base (NCDB). This resource includes information on approximately 70% of cancer cases in the United States. The year 2007 was selected as the upper limit, because the NCDB does

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

Mixed Results for RT Dose Escalation in Prostate Cancer Orlando, Fla.—In the largest randomized study to date comparing doseescalated radiation with standard-dose radiation in patients with prostate cancer, dose escalation significantly improved outcomes, including relapse rates, but did not improve overall survival (OS).

Results from the Phase III Radiation Therapy Oncology Group (RTOG) 0126 trial, presented at the Genitourinary Cancers Symposium (abstract 4), also provided great detail on the adverse event rates that patients can expect.

“Dose escalation to 79.2 Gy for intermediate-risk prostate cancer did not improve the overall or disease-specific survival. However, dose escalation did improve local control, distant metastases–free and biochemical disease–free survival [DFS] rates,” and was associated with less use of salvage therapy, said Jeff M. Michalski, MD, MBA, a radiation oncologist at Washington University’s Siteman Cancer Center, in St. Louis.

Dose-escalated radiation therapy in prostate cancer patients is included in the National Comprehensive Cancer Network’s guidelines and commonly is used in the United States. Five clinical trials, with study populations ranging from 300 to 850 patients, have shown that dose escalation improves biochemical DFS rates, but these studies have failed to identify a benefit in OS. The researchers wondered whether a larger trial would identify a survival benefit, and thus launched the randomized RTOG 0126 trial. The

Table. Clinical Outcomes in the RTOG 0126 Trial

a

Outcome

70.2 Gy in 39 Fractions

79.2 Gy in 44 Fractions

P Value

5-y biochemical failure,a %

40

25

<0.0001

10-y biochemical failure,a %

45

30

<0.0001

5-y local progression, %

2

1

<0.0059

10-y local progression, %

8

4

<0.0059

5-y distant metastasis, %

3

2

0.026

10-y distant metastasis, %

8

5

0.026

Patients needing salvage therapy, %

20.6

13.5

0.002

American e ca Society Soc ety for o Radiation ad at o Oncology O co ogy definition de to

trial analyzed data from roughly 1,500 patients who received three-dimensional conformal radiation therapy (CRT) or intensity-modulated radiation therapy (IMRT). An equal number of patients received a minimum target volume prescription of either 70.2 Gy in 39 fractions or 79.2 Gy in 44 fractions.

All patients had histologically confirmed stage T1b-T2b prostate adenocarcinoma. The patients were required to have a Zubrod performance status of 0 to 1 and negative lymph nodes. Patients with distant metastases and prior hormonal treatment were excluded. Patients were stratified by risk group (Gleason score of 6 and prostate-specific antigen test [PSA] ≥10 but <20, or Gleason

score of 7 and PSA <15) and treatment type (CRT or IMRT). The two arms were balanced with respect to tumor stage, Gleason score, serum PSA and study stratification, Dr. Michalski said.

Approximately one-third of patients in both arms received IMRT. The median follow-up was seven years for all patients and 7.6 years for survivors.

Although there was no difference in OS or time to prostate cancer death, patients who received dose-escalation radiation therapy had better outcomes in terms of biochemical failure rates, local progression, distant metastasis and need for salvage therapy than patients who received 70.2 Gy (Table). Dr. Michalski said the difference in biochemical failure

PALOMA-3 TRIAL continued from page 4

published in The New England Journal of Medicine (2015. June 1 [Epub ahead of print], PMID: 26030518), enrolled 521 women with HR-positive, HER2negative metastatic breast cancer who had received no more than one prior chemotherapy regimen for advanced cancer and had progressed on prior endocrine therapy within the past 12 months. Patients were randomized to receive fulvestrant in combination with palbociclib or a placebo. The two trial arms were balanced with respect to the presence of visceral metastases, sensitivity to prior endocrine therapy and menopausal status.

The primary end point, PFS, was significantly longer in patients receiving palbociclib (9.2 vs. 3.8 months; hazard ratio, 0.422; 95% confidence interval, 0.318-0.560; P<0.000001), and the benefit was seen in all prespecified subgroups, including pre- and postmenopausal patients. The most common adverse events (AEs), reported more

The study ‘provides support for combination of fulvestrant plus palbociclib in the second-line setting.’

—Eric Winer, MD often in patients receiving palbociclib, were hematologic, including grade 3/4 neutropenia (62% vs. 1%) and grade 3/4 leukopenia (26% vs. 1%) (Table), but the two treatment arms had the same low rate of febrile neutropenia.

Patients who received palbociclib had similar rates of serious AEs (14% placebo vs. 9.6% palbociclib) and discontinuations due to AEs (2.6% palbociclib vs. 1.7% placebo).

Clinicians not involved with the study were impressed with the trial results. “This study confirms the

findings from the front-line randomized Phase II trial that led to accelerated approval,” said Eric Winer, MD, the director of the Breast Cancer Treatment Center at Dana-Farber Cancer Institute, in Boston. “I suspect that this will lead to a full approval in the near future,” he predicted.

The study “provides support for combination of fulvestrant plus palbociclib in the second-line setting,” said Dr. Winer, noting that palbociclib “can be used in either in the first-line or second-line setting, and it can be used with

was “striking” using both the American Society for Radiation Oncology (ASTRO) and Phoenix definitions, both of which showed a hazard ratio of 0.59.

The rates of acute gastrointestinal (GI) and genitourinary (GU) adverse events were similar in the two arms, but patients who received dose escalation had higher rates of late grade 2+ and grade 3+ GI toxicities, as well as late grade 2+ GU toxicities. Previous studies have shown statistically significant increases in GI toxicities in patients receiving dose-escalation therapy, but data on GU toxicities have been unclear, never reaching statistical significance.

The new study identified a 5% increase in late, grade 2+ GU toxicities with dose escalation ((P=0.001).

According to D. Andrew Loblaw, MD, a radiation oncologist at Sunnybrook Health Sciences Centre, in Toronto, Canada, who was not involved with the study, “RTOG 0126 is an important study. Dose-escalation therapy has already been adopted in the community, and we knew that there were higher GI toxicities associated with the higher dose. The study is informative that there may also be higher GU toxicities, and there’s unlikely to be an overall survival advantage.”

—Kate O’Rourke Dr. Michalski reported no relevant financial relationships. Dr. Loblaw reported relationships with Elekta and GE Healthcare.

either an AI [aromatase inhibitor] or fulvestrant.” However, he pointed out that there are no data for using palbociclib in patients who have developed disease progression on palbociclib, and “it should not be used in this setting.”

Two other CDK4/6 inhibitors are being investigated in Phase III trials in advanced ER-positive breast cancer. Ribociclib (Novartis) is being tested with letrozole or fulvestrant, and abemaciclib (Lilly) is being combined with fulvestrant or a nonsteroidal aromatase inhibitor.

Noting that although there is “great optimism for CDK4/6 inhibition in general,” with palbociclib being one of the three agents being studied, Dr. Winer cautioned that “we have yet to see a survival advantage with these drugs. With time,” he added, “hopefully, we will see that.”

—Kate O’Rourke Dr. Turner reported financial relationships with AstraZeneca and Pfizer. Dr. Winer reported financial relationships with Genentech/Roche, Novartis and Verastem.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

Report From ASCO Annual Meeting:

Multimodality Trial for Liver Metastases in CRC Shows Benefit Chicago—In patients with colorectal cancer (CRC) and liver metastases, the addition of liver-directed radiation therapy controls metastatic progression, according to the first Phase III trial to test any strategy directed at the hepatic component in this population. In the experimental arm, which tested selective internal radiation therapy (SIRT), there was no significant advantage relative to chemotherapy alone for overall progression-free survival (PFS), but there was a significant improvement in liver disease PFS. With the addition of SIRT, “we did achieve a major improvement in PFS of 7.9 months, representing a 31% reduction in the risk of progression within the liver,” reported Peter Gibbs, MBBS, a medical oncologist at the Royal Melbourne Hospital, in Melbourne, Australia. The results of this trial, called SIRFLOX, were presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 3502).

SIRT in this multinational trial consisted of yttrium 90–labeled resin microspheres infused directly into the hepatic artery. It was evaluated on top of a modified FOLFOX6 (5-fluororacil, leucovorin and oxaliplatin) regimen, which was administered to all participants in the study. In patients randomized to SIRT, the radiation therapy was given one

BLADDER CANCER continued from page 7

regression analysis to calculate propensity scores, defining an individual’s probability of being assigned to adjuvant chemotherapy versus observation based on patient-level variables (e.g., age, gender, comorbidity index, socioeconomic variables), facility-level variables (e.g., facility location and type, distance to facility, cystectomy volume) and tumor-level variables (e.g., pathologic T stage, nodal status, margin status). Patients who received adjuvant chemotherapy were more likely to be young and to have private insurance, positive surgical margins and positive lymph nodes.

At five years, overall survival was increased in patients receiving adjuvant chemotherapy (36% vs. 26%). Survival was improved using all three propensity-score adjusted models: stratification by quintiles (hazard ratio [HR], 0.72), weighting (inverse probability of treatment weighting; HR, 0.72) and matching (HR, 0.62) ((P<0.0001 for all). The benefit for adjuvant chemotherapy was seen regardless of performance status,

time, on day 3 or 4 of the first cycle of chemotherapy. Bevacizumab (Avastin, Genentech) was permitted by investigator discretion in either arm, but the intention to offer bevacizumab was established prior to randomization.

After a median follow-up of 36.1 months, the overall median PFS—the primary end point of the study—was comparable between patients who received SIRT and those who did not (10.7 vs. 10.2 months; P=0.43). However, liver PFS was 20.5 months for patients who received SIRT versus 12.6 months for those who did not. This more than seven-month advantage translated into a hazard ratio (HR) that was significantly different,

favoring SIRT (HR, 0.69; P=0.002).

SIRT was associated with an increased rate of adverse events (AEs), particularly hematologic toxicities, but Dr. Gibbs characterized the overall incidence and burden of AEs as “acceptable.” The most common grade 3 or higher AEs were neutropenia (40.7% with SIRT vs. 20.5% without) and thrombocytopenia (9.8% with SIRT vs. 2.6% without). Grade 3 or higher febrile neutropenia occurred in 6.1% of patients who received SIRT versus 1.9% of those who did not. Grade 3 or higher gastric ulcers (3.7% vs. 0%) and ascites (2.8% vs. 0%) also were more common with SIRT. SIRFLOX is one of a series of three trials evaluating the effect of SIRT on top of conventional chemotherapy in metastatic CRC. Data from SIRFLOX will be combined with those from the other two, FOXFIRE and FOXFIRE Global, to evaluate effects of this strategy on overall survival (OS). Analyses also are preplanned for quality of life (QoL) and the cost–benefit of adding SIRT. Noting that liver metastases are the predominant cause of death in metastatic CRC, Dr. Gibbs indicated that these data provide guidance for considering SIRT with the current standard of chemotherapy plus a biologic.

Despite the lack of benefit for overall

Table. Recent Analyses Showing OS Benefit With Adjuvant Chemotherapy in Bladder Cancer Patients Overall N/ Adjuvant Group N

HR for OS

Literature-based meta-analysis of nine randomized controlled trials

945/475

0.77

Clin Cancer Res 2010;16 (17):44614467, PMID: 20651056

Retrospective cohort study from 11 high-volume centers

3,947/932

0.85a

BJU Intt 2014;Aug 28. doi:10.1111, PMID: 25168574

Population-based retrospective cohort study

2,802/541

0.71

2015 Gastrointestinal Cancers Symposium, abstract 292

Population-based retrospective cohort study

5,653/1,293

0.72

Citation

Study Design

Eur Urol 2014;66(1):42-54, PMID: 24018020

a

Cancer-specific survival HR, hazard ratio; OS, overall survival

age (<70 or >70 years), gender, node status and number of nodes examined (<15 or >15).

“This is a clinically relevant study,” said Ashish Kamat, MD, the director of urologic oncology training and an

attending surgeon at the University of Texas MD Anderson Cancer Center, in Houston, who was not involved with the study. “In patients who don’t get neoadjuvant chemotherapy and present after surgery with advanced disease

PFS, “SIRT does appear to have a role in combination with FOLFOX chemotherapy for local control of liver metastases,” agreed Ricky A. Sharma, MB, PhD, a professor in the Department of Oncology at Oxford University, in the United Kingdom. As the ASCO-invited discussant, Dr. Sharma cautioned that improved PFS “comes at a cost” of an appreciable rate of hematologic and gastrointestinal side effects, but he called the improvement in local control “robust” and “impressive.”

According to Dr. Sharma, the value of SIRT as a standard of care will become clearer when the OS data are mature, but he suggested that SIRT is a good example of the effort to employ multimodality strategies to improve outcome in metastatic CRC and other malignancies.

Citing data suggesting that radiation and surgery contribute more often to cancer cures than chemotherapy, he said he believed that “interventional oncology,” a term he used to describe the combination of modalities to improve outcomes, deserves more attention.

—Ted Bosworth Dr. Gibbs reported financial relationships with Alchemia, Amgen, Bayer, Merck, Pfizer, Roche and Sirtex. Dr. Sharma reported financial relationships with Biocompatibles, Cancer Research Technology, Roche, Sirtex and Vertex.

on pathology, there has always been a question about whether to provide adjuvant chemotherapy,” Dr. Kamat said. “A study like this, that looks at existing data and involves careful statistical analyses, is useful to guide practitioners to say ‘yes, I should have a discussion with my patients about adjuvant chemotherapy.’”

Dr. Galsky conceded that the study was limited, in that it was retrospective and the NCDB does not include chemotherapy details (e.g., regimen type or duration) or information on recurrence or cancer-specific survival. However, the study provided evidence from the real world, and the findings were similar to those from recent meta-analyses and retrospective studies that have shown a survival benefit for adjuvant chemotherapy in patients with bladder cancer, with hazard ratios ranging between 0.71 and 0.85 (Table). “While not definitive proof,” Dr. Galsky said, “what is striking about these studies is the consistency of the results.”

—Kate O’Rourke Drs. Galsky and Kamat reported no relevant financial relationships.

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

Report From ASCO Annual Meeting:

Adding Ibrutinib Is Beneficial in Previously Treated CLL Chicago—The addition of ibrutinib reduces the risk for death or disease progression over that provided by bendamustine and rituximab (BR) alone in previously treated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to results of a Phase III trial. The addition of ibrutinib was relatively well tolerated, supporting a change in practice.

“These results demonstrate that ibrutinib plus BR is superior to the current standard of care, which is BR alone, in

previously treated CLL/SLL patients,” reported Asher Chanan-Khan, MD, the chair of hematology/oncology at Mayo Clinic in Jacksonville, Fla., who presented the results of this study, called HELIOS, at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA7005).

Ibrutinib (Imbruvica, Pharmacyclics/ Janssen), a Bruton tyrosine kinase (Btk) inhibitor, has demonstrated promise in previous CLL/SLL studies, but HELIOS is the first randomized, placebo-controlled

trial in which the addition of ibrutinib was compared directly with chemotherapy alone. In this study, which involved centers in 21 countries, 578 previously treated patients with CLL or SLL were randomized to receive a conventional regimen of BR, with 420 mg of ibrutinib or placebo. Patients remained on ibrutinib or placebo after completing six cycles of BR until disease progression.

The primary end point was progressionfree survival (PFS).

For PFS, which was validated by an

GADOLIN continued from page 1

said Laurie Sehn, MD, MPH, a medical oncologist at the BC Cancer Agency, in Vancouver, Canada, who presentd the findings at the 2015 annual meeting of the American Society of Clinical Oncology (abstract LBA8502).

Grzegorz Nowakowski, MD, a hematologist/oncologist at Mayo Clinic in Rochester, Minn., who was not involved with the research, called GADOLIN “a practice-changing study for patients with rituximab-refractory disease.”

He added that the obinutuzumab regimen used in the trial “provides significant [PFS] benefit, and it doesn’t do it at increased toxicity.”

Although an increasing number of chemotherapy options are available for NHL, advanced-stage iNHL remains incurable.

Adding rituximab (Rituxan, Genentech) to chemotherapy during induction, followed by maintenance has significantly improved outcomes in patients with iNHL, but patients with rituximabrefractory disease have limited treatment options. “Bendamustine was shown to be effective in this setting; however, the median [PFS] is short, averaging seven to nine months,” Dr. Sehn said.

In the GADOLIN trial, 413 patients with rituximab-refractory CD20+ iNHL were randomized to receive obinutuzumab (Gazyva, Genentech)—a monoclonal antibody already approved for use in combination with chemotherapy for chronic lymphocytic leukemia—plus bendamustine (Treanda, Cephalon) (n=194), or bendamustine alone (n=202). Patients in the obinutuzumab arm who achieved a complete response, partial response or stable disease (n=143) received maintenance therapy with obinutuzumab for two years or until disease progression. Patients were excluded from the

Table. Common Grade 3/4 AEs in GADOLIN Trial AE, %

Obinutuzumab + Bendamustine

Bendamustine

Grade 3/4 neutropenia

33

26

Grade 3/4 thrombocytopenia

11

16

Anemia

8

10

Infusion-related reactions

11

6

≥1 serious AE

38

33

≥1 grade 3/4 AE

67

62

≥1 AE leading to dose modification

50

41

AE, adverse event

trial if they had exposure to bendamustine in the past two years or exposure to monoclonal antibodies besides rituximab in the past three months.

Patient characteristics and pretreatment characteristics at baseline were similar in the two arms. About 80% of patients were refractory to both rituximab and alkylators, and roughly 80% of patients had follicular lymphoma. The median number of prior lines of therapy was two.

The investigators assessed response

by computed tomography scan postinduction, every three months for two years, and then every six months. At the primary interim analysis, 46 of the 143 patients who had started maintenance therapy were still on it and 35 had completed maintenance.

The primary end point was PFS, as assessed by an independent radiology facility. The facility-assessed median PFS was 14.9 months in the monotherapy arm and had not been reached in patients receiving obinutuzumab

independent review committee (IRC), the hazard ratio (HR) of 0.201 (P ( <0.0001) represented an 80% reduction relative to BR alone. At 18 months, PFS rates for the ibrutinib and placebo groups were 79% and 24%, respectively.

“The advantage of ibrutinib was noticeable as early as four months into the assessment of disease response,” Dr. Chanan-Khan reported. He noted that a subgroup analysis confirmed a consistent advantage of ibrutinib over BR alone when patients were stratified

plus bendamustine after a median follow-up of 21 months (hazard ratio, 0.55; P=0.0001). By investigator assessment, the median PFS was significantly higher among patients receiving obinutuzumab (29.2 vs. 14 months; P<0.0001).

There were no differences in response rates between the two arms. Rates of adverse events (AEs), serious AEs, grade ≥3 AEs, deaths and withdrawals from therapy were similar in both arms (Table).

Dr. Nowakowski said the fact that there was no difference in response rates raises the question of how much of the improvement is caused by the maintenance therapy versus the induction therapy, especially since the PFS survival curves begin to separate at the end of induction therapy. “Since data is very limited on the duration of rituximab resistance, one wonders how would the control arm look like if maintenance rituximab was used,” Dr. Nowakowski said.

He also pointed out that based on Medicare average sales price, the experimental arm would cost approximately $95,000 more than the bendamustinealone arm ($157,608 vs. $65,677). However, this does not take into account the cost of subsequent therapy in patients who relapse in the bendamustine arm.

“You need an analysis of the whole cost of caring for the patient, because it is very likely that patients who relapse early require subsequent, and sometimes more aggressive, therapies, such as transplant, etc.,” Dr. Nowakowski noted.

“The costs of treating with bendamustine alone could be much higher.”

—Kate O’Rourke Dr. Sehn reported a financial relationship with Genentech. Dr. Nowakowski reported financial relationships with Celgene and MorphoSys.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY LY 2015 • CLINICALONCOLOGY.COM

by age, previous lines of therapy, bulky disease, IgVH H mutational status, or o tumors with or without an 11q deletion.

Ibrutinib also prroduced significantly high her objective response rates (ORR), whether assessed by the investigators i or the h IRC. On IRC evaluation, these rates were 82.7% and 67.8% (P ( <0.0001) for ibrutinib and placebo, respectively. The median overall survival (OS) has not been reached in either treatment arm after a median follow-up of 17 months, but the more than 35% improvement in survival has produced a trend favoring ibrutinib (HR, 0.63; P=0.0598). This trend was observed even though 90 of the placebo patients (31%) crossed over to ibrutinib after disease progression. Also notably, minimal residual disease (MRD) was achieved in 12.8% of patients receiving ibrutinib versus 4.8% of those receiving placebo (P ( =0.0011). Of patients who achieved a complete response (CR) on either therapy, about half achieved MRD. The addition of ibrutinib was associated with a modest cost in terms of adverse events (AEs). Most AEs overall

‘T ‘The advantage of ibrutinib was noticeable no as early as four months into the assessment a of disease response.’

—Asher Chanan-Khan, MD and m most grade 3 or higherr AEs were related d to BR. Any differences in which grade 3 or higher events were more common with ibrutinib were modest; these included diarrhea (2.1% vs. 1.4%), pyrexia (3.5% vs. 1.7%) and headache (1.7% vs. 0%).

There were, however, two AEs specifically linked to ibrutinib. Bleeding of any grade occurred in 31% of ibrutinib-treated patients versus 14.6% of placebo patients, but the difference in major hemorrhage was more modest (3.8% vs. 1.7%). Atrial fibrillation occurred in 7.3% of patients taking ibrutinib versus 2.8% of those in the placebo group. Grade 3 or higher atrial fibrillation occurred in 2.8% and 0.7% of the patients in the ibrutinib and placebo groups, respectively. Dr. Chanan-Khan noted that a previous history of atrial fibrillation was not a predictor of atrial fibrillation with ibrutinib.

Although the trial suggests that the addition of ibrutinib improves outcomes

relative to BR alone, the ASCO-invited discussant, Lloyd E. Damon, MD, the director of hematologic malignancies and bone marrow transplant, at the University of California, San Francisco, brought a different perspective. In his remarks, he compared data from a study that employed ibrutinib alone presented at the 2014 ASCO and recently published (Blood ( 2015;125[16]:2497-2506, PMID: 25700432) with the data just presented evaluating ibrutinib in combination with BR. The benefits were very similar.

Essentially, the HELIOS study asked whether ibrutinib improves outcomes when added to BR, “but I would turn this question on its head,” Dr. Damon said. Based on evidence that ibrutinib achieves the same activity when used alone, “the better question is what is the contribution of BR immunochemotherapy to ibrutinib.”

When data on ibrutinib monotherapy are compared with that from the HELIOS trial, the PFS and ORR rates

are about the same, although Dr. Damon pointed out that patients in the monotherapy study had, on average, more lines of prior treatment.

Although Dr. Damon considered the HELIOS data useful for deciding treatment strategies for patients with advanced CLL, he said that he is looking forward to studies evaluating whether immunochemotherapy can be omitted altogether.

—Ted Bosworth Dr. Chanan-Khan reported no relevant financial relationships. Dr. Damon reported financial relationships with Actelion, Boston Scientific, Gilead and Sunesis.

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

Report From ASCO Annual Meeting:

New Treatment for Multiple Myeloma on the Horizon Chicago—Roughly a year after the immunotherapy agent elotuzumab (Bristol-Myers Squibb/AbbVie) received breakthrough therapy designation from the FDA, the drug is poised to change the treatment landscape of multiple myeloma. At the 2015 annual meeting of the American Society of Clinical Oncology, researchers from the ELOQUENT-2 trial reported that adding elotuzumab to dexamethasone and lenalidomide (Revlimid, Celgene) improved median progression-free survival (PFS) by four months in patients with relapsed/refractory multiple myeloma (abstract 8508).

“Based on this randomized Phase III trial, we hope that we will soon have a new treatment option,” said lead author Sagar Lonial, MD, a professor and the executive vice chair in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and chief medical officer at Emory’s Winship Cancer Institute, in Atlanta.

The ELOQUENT-2 investigators randomized patients with relapsed/ refractory multiple myeloma who had received one to three prior lines of therapy to lenalidomide/dexamethasone alone (n=325) or with elotuzumab, a

novel immunostimulatory monoclonal antibody, with a dual mechanism of action that targets both tumor cells and immune-mediated natural killer cells (n=321). Prior lenalidomide exposure was allowed in 10% of the study population. All the patients received premedication to mitigate infusion reactions before elotuzumab administration.

Roughly one-third of patients had a deletion 17p mutation and 10% had a t(4;14) translocation, which are associated with a poor prognosis. Roughly half of the study population had received a stem cell transplant, and one-third were refractory to their most-recent line of therapy. Patients had received a median of two prior lines of therapy.

Patients receiving elotuzumab had a significantly improved PFS (median, 19.4 vs. 14.9 months; hazard ratio, 0.70; P=0.0004). The overall response rate was higher in the elotuzumab arm (70% vs. 66%; P=0.0002). The benefit of elotuzumab was consistent across key subgroups, including high-risk patients and elderly patients. Dr. Lonial noted that the difference between the elotuzumab and control groups appeared to become more pronounced over time. Separation of the curves and the maintenance

of benefit over time have been observed with other immune-based approaches.

Nearly Equivalent Adverse Effects Patients receiving elotuzumab had higher rates of all grades of infection (81% vs. 28%) as well as grade 3/4 infection (74% vs. 24%), but Dr. Lonial pointed out that if adjustment is made in the incidence of infectious complications for the duration of therapy, the absolute incidence per year of exposure is the same. Based on such an analysis, he noted, “the incidence of toxicity across the board is relatively similar between the two arms.”

Infusion reactions occurred in 10% of patients receiving elotuzumab, but there were no grade 4/5 infusion reactions. Only 1% of patients discontinued from the study due to an infusion reaction. Elotuzumab did not have any adverse effects on overall health-related quality of life.

Jeffrey Wolf, MD, the director of the Multiple Myeloma Program at the University of California, San Francisco’s Helen Diller Family Comprehensive Cancer Center, said the ELOQUENT-2 data showing improved PFS are encouraging

and suggest that elotuzumab “may have a role in extended control of disease after initial response.”

Dr. Wolf pointed out that there is a tail on the PFS curve for patients receiving elotuzumab, “implying a cohort of patients with an extended benefit.” Given those results, he noted, elotuzumab may prove to be “a good candidate for maintenance therapy.” He added that “very importantly, there is very little additional toxicity with the addition of elotuzumab, making it an easy drug to add to other combinations.”

Dr. Wolf said that “it will be interesting to see how elotuzumab fares against the coming anti-CD38 antibodies,” such as daratumumab (Genmab), being tested in clinical trials for myeloma.

ELOQUENT-2 has since been published in The New England Journal of Medicine (2015 Jun 2. [Epub ahead of print], PMID: 26035255).

—Kate O’Rourke Dr. Lonial reported financial relationships with Bristol-Myers Squibb, Celgene, Janssen, Millennium, Novartis, and Onyx. Dr. Wolf reported financial relationships with Amgen, Celgene, Janssen, Millennium and Onyx.

EBV-Specific T Cells Offer Potential New Immunotherapy Philadelphia—A novel immunotherapy that employs Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes has been associated with high rates of extended survival in patients with EBVassociated lymphoproliferative disorder (EBV-LPD). Because of the dismal prognosis typical of this disease, the treatment has been given a breakthrough designation by the FDA. “In the absence of effective therapy, [EPV-LPD] patients have an average survival time of only 16 to 56 days,” reported investigator Richard J. O’Reilly, MD, the chief of the Pediatric Bone Marrow Transplantation Service at Memorial Sloan-Kettering Cancer Center (MSKCC), in New York City.

Presenting data from two ongoing, early studies of the new immunotherapy at the 2015 annual meeting of the American Association for Cancer Research (AACR; abstract 8841), Susan E. Prockop, MD, said the studies evaluated 57 EBVpositive transplant patients. Most of them were being treated for diffuse large B-cell lymphomas. In the first study, known as 95-024, the median patients age was 21 years; 28 of the 39 patients had failed prior treatment with rituximab (Rituxan, Genentech). In the other

study, known as 11-130, the median age of the 18 patients was 52 years, and rituximab treatment was unsuccessful in all of them.

The majority of patients in 95-024 received EBV cytotoxic T lymphocytes derived from the blood of the transplant donor. The remaining patients and all of the patients in 11-130 received EBV cytotoxic T lymphocytes from third-party healthy donors. Up to five infusions of the cells were administered.

Both types of EBV cytotoxic T lymphocytes proved active, according to Dr. Prockop, an assistant attending oncologist in MSKCC’s Transplantation Service.

In the 11-130 study, half of the 18 patients achieved a complete response (CR). The nonprogression rate was 72% when the CRs were combined with three partial responses (PR) and one patient with stable disease. Progression-free survival (PFS) at one year was 66.7%, and overall survival (OS) at two years was 71.8%. In the 95-024 study, the CR rate was 59%, and the nonprogression rate was 69% when one PR and three cases of stable disease were included.

“Patients who have achieved CR had no relapses of EBV-LPD,” Dr. Prockop reported. Conversely, nonresponders

in these studies typically died within months of treatment due to disease progression.

The decision to offer third-party EBV cytotoxic T lymphocytes, which have the advantage of being immediately available, to all of the patients in the second clinical study was based on evidence that they were just as effective as transplant-derived EBV cytotoxic T lymphocytes in the first study.

“Strikingly, the one-year OS rates were 50% and 49% for rituximab-refractory patients treated with third-party and transplant donor-derived EBV [cytotoxic T lymphocytes], respectively,” Dr. Prockop said.

Dr. O’Reilly noted that clinical responses become evident seven to 14 days after treatment is initiated. This is attributed to the time required for in vivo expansion of cells. He said the group is “rigorously pursuing the development of biomarkers or other tests to predict responses earlier.”

So far, the new immunotherapy has been associated with low toxicity. Specifically, there have been no cases of cytokine release syndrome or graftversus-host disease that require systemic therapy.

The concept of creating EBV-specific T cells is not new, but the approach now being developed for clinical use may make this more routinely viable, according to Helen Heslop, MD, the interim director of the Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children’s Hospital, in Houston. “Studies over the last 20 years from several groups have shown that donor-derived, EBV-specific T cells can effectively treat EBV lymphoma, but the original manufacturing methodologies were lengthy, limiting broader application,” said Dr. Heslop, who has written on managing EBV in transplant patients. “More recent studies have evaluated faster manufacturing methodologies or the use of third-party banks, and this report is interesting since the Sloan-Kettering team has confirmed equivalent activity from the banked cells. This makes the therapy available to a wider group of patients.”

—Ted Bosworth Drs. O’Reilly, Prockop and Heslop reported no relevant financial relationships. MSKCC and Atria Pharmaceuticals have an option agreement to further develop T cell banks.

To get new biotech or novel therapies to market takes starting at the beginning. It takes a partner with the experience, resources and expertise to advance promising ideas into fully realized solutions. It takes a global healthcare solutions leader dedicated to enhancing patient care through end-to-end solutions for manufacturers, pharmacies and providers. It takes persevering upstream and executing downstream. It takes AmerisourceBergen.

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

On the Spot With Colleen Hutchinson

Genomics in Clinical Oncology Practice T

his edition of On the Spott focuses on genomics and its clinical application in oncologic patient care. While genomic research and gene testing have achieved meaningful and significant advances

recently, we are still at the dawn of this area of science. This article focuses on the practical issues that oncologists face as genomic research and gene testing rapidly become an integrated component of

oncologic care.

Thanks to each of this column’s participants for sharing their views on the benefits and challenges of genomics in the oncology setting.

P ARTICIPANTS Robert J. Green, MD, MSCG Community oncologist Vice President of Oncology Flatiron Health New York, NY

Prudence Lam, MD Medical oncologist Director of the Genetics & Cancer Prevention Clinic Mount Auburn Hospital Cambridge, Massachusetts Physician-Investigator Cancer Biology Program Beth Israel Deaconess Medical Center Boston, Massachusetts

Matthew F. Kalady, MD Associate Professor of Surgery Krause-Lieberman Endowed Chair in Colorectal Surgery Co-Director of the Comprehensive Colorectal Cancer Program Cleveland Clinic Cleveland, Ohio

Nadine Tung, MD Director Cancer Genetics and Prevention Program Beth Israel Deaconess Medical Center Breast cancer medical oncologist Beth Israel Deaconess Medical Center Dana-Farber Harvard Cancer Center Boston, Massachusetts

Thomas Abraham Samuel, MD Oncologist Departments of Medicine-Breast Oncology and Hematology/Oncology Cleveland Clinic Florida Weston, Florida

As we consider oncologist/ hematologist readiness and education in genomics, it is fair to state that there is a rift between available genetic technology and realistic, proper application of it into the clinician’s workflow—patient selection, test administration, test result interpretation, and insurance coverage/payment options.

Thomas Abraham Samuel, MD: Agree. I believe that there is a rift between the rapid advancement of genetic assessment products and physician education about the proper use of these tests, especially among primary care providers. However, I also believe that when used properly, these genetic panels can provide great information to both providers and patients about future screening and prevention interventions.

The best mechanism to manage this gap in the short term is for providers to refer patients to highly specialized genetic assessment programs with dedicated genetic counselors, where proper genetic testing and appropriate education can be provided. In the long run, physician and provider understanding of genetic testing needs to be included on certification exams and incorporated into continuing education requirements.

Prudence Lam, MD: Disagree. There are enough data and knowledge about genetic testing at this time to help us prevent cancers and detect them early—and although oncologists like to treat cancers, this truly is their ultimate goal. There is still much more to be done, but we can already do a lot of good with what we have.

As we grow into “expanded” panels, there is much more uncertainty. This means both patients and physicians will have to become more comfortable with the unfamiliar. We will need to continue to try to find answers to these growing question marks to continue to help our patients navigate their surveillance paths. This is a greater challenge in regions of the country where genetic testing is not as readily available and there is a greater lack of knowledge of what to do with what is found from these increasingly complicated genetic test results. Insurance companies are lagging behind in understanding how genetic testing can be helpful in preventing cancers that are costly to treat, so there also is some disparity related to who gets covered for testing and who does not.

Robert J. Green, MD: Agree. The advancement of our ability to derive information by sequencing malignant tumors is incredibly exciting—and yet, this creates

a number of challenges for oncologists. Many questions remain unanswered about whom to test, what to do with the information, when and if off-label use of drugs for various targets is indicated, and how to effectively get patients into clinical trials. But with these challenges come enormous opportunities and that these questions will be answered.

Nadine Tung, MD: Agree. Other than for a handful of well-recognized, high-penetrant cancer susceptibility genes, criteria for performing genetic testing for other, moderate-penetrant genes are not well established.

Additionally, the risk and clinical spectrum of associated cancers is not well known. This makes identifying patients who are appropriate for cancer susceptibility panel testing difficult and counseling patients with identified genetic changes challenging. Pretest counseling is a crucial part of the process, but it is timeconsuming and complicated, particularly when many genes are being tested for at one time. Additionally, most clinicians lack sufficient knowledge to interpret and act on the results of many genetic tests.

It is essential that only clinicians with adequate genetic training use these tests because there is significant potential for harm if results are misinterpreted. For example, clinicians may overestimate the risk associated with mutations in lower-risk genes, and this could lead to inappropriate prophylactic surgery.

Similarly, a negative genetic test result for mutation in a single, low-penetrant gene may lead to a false sense of reassurance since a strong cancer family history may be caused by mutations in multiple lower-penetrance genes. Different coverage rules for genetic testing among insurance carriers make gene panel testing complicated and make providers struggle to determine which panels are covered for which patients.

The new trend toward expanded genetic panels is misleading and potentially harmful.

Dr. Samuel: On the fence. I believe that expanded genetic panels provide much greater information and guidance regarding future risks that a patient may face. However, since long-term, prospective, interventional outcomes (whether increased screening or proactive risk reduction methods) based on genetic assessments are lacking for most genetic mutations, this is one of those situations where knowing about a risk may be more important than doing something about it. Therefore, at the present time, patients need to be educated about genetic risk assessments to gain an awareness about malignancy development. If such awareness causes increased anxiety, patients need to be counseled about the risk of potentially avoiding

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.NEWS

Best advice to new medical students who plan to specialize in clinical oncology

Advice to community oncologists who want to become more involved in oncology association leadership and general research/publication

Thomas A. Samuel, MD Too soon to know, but so far has been a negative experience

Be prepared to read, adjust and grow with your patients

Advocate for your patients with better research and care

Communication, patient advocacy and coordinated care

Robert J. Green, MD

Opportunity to provide health insurance to the uninsured

Incredibly interesting and rewarding career

Don’t be afraid to say yes

Cooperation, communication and collaboration

Prudence Lam, MD

Some “urban” patients say they can get mammograms for the first time

Be ready to teach and enroll in a good business school course on how insurance/reimbursements come into play with medical decision making!

Yes, do it. This is important!

A powerful machine when working as a team

The science drives the care

Build relationships with the cooperative groups; collaborate

Open, cooperative

Speaker

Affordable Care Act

Matthew F. Kalady, MD Ambitious, challenging, uncertain

genetic assessments in this situation. Unfortunately, it is a “chicken or egg” problem, that is, should we perform genetic tests that may have no meaningful, current clinical impact yet might increase awareness and early diagnosis of a problem, or should we avoid risk assessment, which can result in diagnoses at more advanced stages? Ultimately, genetic testing only should be offered by professionals who are well versed in communicating these complex concerns to patients at risk.

Dr. Lam: Disagree. I think the answer to this will be determined by whether you are the type of person that believes that “knowledge is power” or “a little knowledge is a dangerous thing.” I tend to believe the former, especially in this case, because we know that gene mutations that are tested on these panels are significant enough to at least act on. As long as we continue to have reasonable actions to suggest to our patients based on these test results, then I think we are doing good for our patients.

cancer susceptibility genes is less expensive and more efficient than testing for each gene sequentially. In the case of hereditary breast cancer, approximately 4% of breast cancer patients who test negative for a BRCA1 or BRCA2 mutation will be found to have a mutation in another cancer susceptibility gene. In some of these cases, this information may lead to screening for cancers for which the individual is at increased risk, which would not have otherwise been appreciated based on family history alone. Additionallly, the information may alert the clinician that the woman is at higher risk for a second breast cancer and additional screening may be indicated (e.g., breast magnetic resonance imaging). However, this occurs in the minority of cases for which a gene panel is ordered. For many genetic changes, the associated risks are not clear, and that is why only clinicians with genetic expertise should be ordering such panels.

In five to 10 years, every cancer patient will and should undergo gene testing that will individualize care.

Matthew F. Kalady, MD: On the fence. The expanded genetic panels are clearly a double-edged sword. They serve as an excellent choice to decipher underlying causes of suspected hereditary cancer syndromes and have defined utility. They often are cheaper than ordering individual gene tests and thus often are ordered preferentially. As with anything else, however, the power or danger of the tool relies on those who order and interpret it. If you order these, you must be careful that you will know how to interpret the results and how you should act on them. Often the test will reveal a genetic variant of unknown significance or a gene mutation that was unexpected or completely unrelated to the disease for which the test was ordered. You must be prepared to appropriately counsel the patient on the results and potentially take action. In the hands of the unprepared or uneducated, the results could be more harmful or stress-provoking to patients.

Dr. Tung: On the fence. Routine genetic testing (germline and somatic testing) will be indicated if the information improves treatment. For example, many breast cancer patients with BRCA1 and BRCA2 mutations are not recognized because clinicians fail to recommend genetic testing. Routine BRCA1/2 testing for all patients with newly diagnosed breast cancer would alleviate the burden of having to remember genetic testing criteria and would increase the detection of BRCA1 and BRCA2 mutations in small families or those with unknown family histories. Recognizing patients with certain germline mutations will become increasingly important if this information is used to predict future cancers and to individualize cancer treatment (e.g., use of platinum chemotherapy or PARP inhibitors). Similarly, routine somatic genetic testing of cancers will be indicated if studies demonstrate that tailoring therapy to specific mutations is superior to standard therapies. Hopefully, this will be true!

Dr. Green: Disagree. The key is the proper use of both the testing and the results generated. Yes, there are certainly circumstances when genomic sequencing of patients may not yield useful information. But our role as oncologists is to set expectations and use the information appropriately.

Dr. Lam: Agree. I think it is quite possible that every cancer patient will be undergoing either blood or tissue testing to look for gene mutations. I think cancer treatment in the future will indeed be less focused on the type of organ involved, and more on the type of gene mutation that does or does not exist.

Dr. Tung: On the fence. For patients with a family history of colon cancer, simultaneous testing for colon

Dr. Green: On the fence. Although we have made great advancements in our understanding of the genomic

Dynamic between oncologist and oncologic surgeon

makeup of tumors and have found useful treatments and interventions based on this information, whether it will be helpful for all patients and all tumors remains to be seen. I believe it will play a role, but it’s not clear whether it will play a role for everyone.

Dr. Kalady: Disagree. I think the time is coming when most patient tumors or patients will be tested with the thought of driving personalized care. Unfortunately, we are likely more than five to 10 years away to saying that “every” cancer patient will be tested.

Technological and scientific advances continue to allow broad scale high-throughput genetic and epigenetic analysis that leads to unprecedented knowledge of genetic contributions to disease. There are some major victories in personalized care. Examples include the use of colorectal cancer microsatellite instability to determine the effectiveness of adjuvant 5-fluorouracil–based regimens, and the use of KRAS mutation testing to guide the use of anti-EGFR therapies. The goal is to eventually be able to offer directed therapy based on tumor or patient factors, but that may be beyond 10 years out.

Dr. Samuel: Agree. With the rapid proliferation of various genetic testing products from multiple providers and competition causing price indices for genetic testing to drop, the likelihood will be that all cancer patients will undergo some form of genetic testing to guide treatment as well as prevention and screening approaches. However, is not yet clear that all genetic testing will have relevance for every patient. The better question to ask is whether and should all patients without cancer undergo genetic risk screening. If so, who will select these patients, what tests will be performed and who will perform these analyses? Better yet, who will pay for it?

It has not been clearly established whether the clinician or the patient using personal gene data should make the call regarding treatment, such as preventive surgery, in the health care setting.

Dr. Kalady: Agree. Who initiates the drive or the decision for genetic work-up has become blurred in recent years. Traditionally, it seems that patients looked more to doctors to make all decisions and it was more the norm to follow recommendations see ON THE SPOT, T page 16

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ON THE SPOT continued from page 15

blindly. As the Internet and hand-held devices have exploded, providing access to seemingly endless instant information (not all of it accurate), patients are becoming more empowered. There are definitely instances when patients come into my clinic and tell me what they want done. Sometimes I agree; sometimes I do not. Ultimately, decisions regarding surgery, and all aspects of patient care, should be a joint decision between the physician and the patient.

Dr. Tung: Disagree. These decisions should always be made jointly by the informed patient and educated clinician. The clinician must accurately understand the risks associated with genetic changes and convey those risks clearly. Certainly, preventive surgery should not be offered if the risk for cancer is not sufficiently high. But how high that risk must be to justify surgery is a personal decision. Many patients choose preventive surgery because they overestimate their risk for cancer. This decision is analogous to treatment with chemotherapy for breast cancer. We do not offer chemotherapy for DCIS [ductal carcinoma in situ] but for a 5 mm, HER2-positive breast cancer, we often offer the choice of chemotherapy to a patient after an informed discussion about risks and benefits.

Dr. Lam: At first, I thought “disagree,” then I thought about this more and switched to “agree,” and now I’m going with “on the fence.” Traditionally, I think most physicians felt that it was the job of the doctor to make the decisions, but now it is more the patient who is the one “in charge” of making treatment decisions. It is our job as physicians to help them make their decision, but it is still their decision. However, we’re quickly now doing more tumor testing for genetic mutations and sometimes these are automatically ordered without the patient’s knowledge. We then base our decisions of what drugs to use, what treatment regimen to choose based on the presence or absence of a certain mutation. Patients may or may not know or have explained to them all of the intricacies that have gone into a certain treatment decision. They may not want to know. These conversations get longer and more complicated, and whether this is helpful or detrimental is unknown. I think this is different from blood testing of a patient who does not yet have cancer and who is trying to decide how best she or he wants to monitor for and/or prevent certain cancers.

Dr. Samuel: On the fence. This is a complex statement, and I can see how one can answer it in any particular way. Although it is the patient’s ultimate responsibility to decide to move forward with either prevention or screening recommendations based on genetic risk assessments, a clinician should provide context and guidance using evidence-based data to help patients make a sophisticated decision to their benefit. In fact, I do not believe that this is a binary discussion, where it is either the clinician or the

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

patient, but rather it is the clinician and d the patient who make the final decision regarding management.

Expectations about what genetic testing can do broadly outpace its actual capability at this moment.

Dr. Lam: Agree. With the exception of the BRCA gene mutation result, genetic testing cannot predict with generally more than a 50% chance the likelihood of getting a cancer. It can only tell doctors and patients that they may be at increased risk for getting a cancer. Armed with this information, we can try to come up with a plan to prevent a cancer, but patients may still develop a cancer despite our best efforts. And for those who already have a cancer, it can only help with driving the direction of cancer treatment. Patients still come in who think that testing for a specific gene mutation will tell them whether or not they will get cancer, or if they already have cancer, that we can target and, therefore, somehow eradicate their cancer. We use “targeted” treatments and patients still can succumb to their cancers. There is a ton of education that needs to be done, with both physicians not in the field and with our patients. The story is just getting more and more complicated.

Dr. Kalady: Agree. Although there have been tremendous strides with genomic medicine and personalized care in recent years, currently clinical application to patient care is still lagging behind the expectations.

Dr. Samuel: Agree. Does reality ever match expectations? Although most patients perceive genetic testing as a roadmap to their future health care, the truth is that genetic testing only provides statistical risk assessments and probabilities regarding their health care outcomes. It would be wise for both patients and providers to understand this nuance and make appropriate management decisions based on these probabilities.

Dr. Tung: Agree. The promise of personalized medicine has led some patients to expect tailored, precise cancer therapy, but this has not yet been realized for the vast majority of tumors with somatic mutations.

Likewise, the genetic basis for the majority of hereditary breast cancer remains unknown even after multiplex gene panel testing.

The “Angelina Jolie effect”— significant increased testing for gene mutations—does more harm than good to the medical field and to the field of cancer genetics.

Dr. Kalady: Disagree. Any action that raises awareness about cancer risk is a win for the medical field.

I applaud Ms. Jolie for being proactive and using

her fame to open discussion about a very real and pressing issue. The subsequent increase in genetic testing theoretically should only come from those who meet criteria to be tested. That puts the onus on physicians and genetic counselors to be properly educated on these issues and be prepared to discuss them with patients.

Dr. Lam: Disagree. Patient after patient tells me that she had never heard of genetic testing until she heard about Angelina’s story. Some of these women—and men—are those who have significant family histories of cancers and had simply always thought, prior to Angelina, that they were destined to get cancer.

Whether we like her or the roles she’s played or not, she’s reached people we’ve been trying to reach for years. She’s bridged the nonmedical world with the medical and has made genetic testing and the possibility of getting certain cancers something we can talk about openly with our patients, and only in that way, try to prevent or detect early. I use her story as a teaching tool.

Dr. Samuel: Disagree. I believe that Ms. Jolie’s decision to go public with her personal genetic risk has increased public awareness regarding genetically driven malignancies. This has led to greater screening and patient education regarding the nature of genetic predispositions to malignancies, especially with regard to breast and ovarian cancer. By beginning and advancing the conversation regarding genetic analysis and risk assessment, we are better able to prevent malignancies. I am now often seeing patients for consideration of genetic testing because of this increased awareness—patients who, even if they don’t have a genetic predisposition, are undergoing breast cancer risk assessments so that better screening and prevention methods can be instituted.

It also increases the opportunity for these patients to have focused education regarding cancer screening and prevention.

Dr. Tung: Disagree. Awareness of genetic testing for BRCA1 and BRCA2 mutations is important. Identifying carriers who should undergo risk-reducing salpingo-oophorectomy improves survival, and screening breast MRIs and prophylactic mastectomies allow for earlier detection and prevention of breast cancer.

Many mutation carriers are not identified because physicians fail to refer those for whom testing would be appropriate. As long as the results are interpreted correctly—for example, variants of uncertain significance are not treated as mutations—the benefit of increased genetic testing outweighs the harms.

Colleen Hutchinson is a medical communications consultant based in Philadelphia and can be reached at colleen@cmhadvisors.com.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

Invasive Biopsies for Research Purposes: Time for a Discussion EDITORIAL BOARD COMMENTARY Maurie Markman, MD Cancer Treatment Centers of America Drexel University College of Medicine Philadelphia, Pennsylvania

disease is not required for entry into the Phase III trial and there is no evidence that any molecular biomarker predicts the benefits of this agent, the company sponsor is requiring that all patients entered into the trial undergo a biopsy to explore the hypothesis that a “yet to be determined” genomic/proteomic profile may be able to predict clinical utility.

The only clearly defined area available

to biopsy is a small, but enlarging, retroperitoneal lymph node. The patient desires to participate in this study in the hope that she will be randomized to the “experimental regimen” (2:1 randomization to this study arm).

To summarize, if the patient elects to enter this trial, she will be required to undergo an invasive, interventional radiographic procedure, the results

17

of which are openly acknowledged to have no impact on her current or future management. Further, the primary end point of this trial (an improvement in overall survival associated with the experimental regimen) will not be affected by the information obtained from the biopsy of this (or any other) patient entered into the trial.

There are several questions that should be considered by the interested parties: • Is it ethical to mandate a potentially dangerous biopsy in a clinical see BIOPSIES, S page 18

T

he performance of invasive biopsies in cancer patients to obtain tissue for laboratory analysis is increasingly an exploration of the molecular profile of a cancer to discover useful biomarkers that may help predict the clinical utility of a given antineoplastic agent.

This commentary is not about all such biopsies, but rather the more invasive procedures (excluding analysis of serum or plasma, skin and bone marrow biopsies, and excision of small, superficial lymph nodes). Also not considered are invasive procedures where the intent is to search for molecular abnormalities that may be of value in the management of the patient undergoing the biopsy.

Rather, the sole focus here is on individual investigator-initiated or industrysponsored trials in which scientific justification exists to obtain tissue for the purpose of attempting to discover a biomarker that may benefit future generations of patients, with no expectation that the information will directly benefit the patient undergoing the procedure.

I anticipate that there are different perspectives regarding the appropriateness of performing biopsies in this setting.

Some may feel that there is no controversy here, meaning that there is nothing wrong with performing such invasive biopsies as long as the patient fully understands that the procedure is being undertaken solely for research purposes and that there is no chance she or he will directly benefit from any information generated. Others may be concerned and feel that potentially harmful invasive biopsies should rarely, if ever, be undertaken in the absence of the potential for any direct benefit to the individual cancer patient, even if one acknowledges the theoretical benefit to future patients.

A simple hypothetical case may help focus the issue: A 53-year-old woman with chemotherapy-refractory metastatic colon cancer is being considered for inclusion in a Phase III registration study of a novel targeted antineoplastic.

The patient has no other serious medical issues. Single-arm Phase II data have suggested provocative evidence of clinical activity (eg, unexpected, objective partial responses and prolonged “stable disease” observed). While measurable

Cases in Hyponatremia

Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

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Expiration Date: November 11, 2015

Faculty

Goal

Michael L. Moritz, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD Ron and Nancy McFarlane Distinguished Professor and Chair Division of Practice Advancement and Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia.

2 Describe the comorbidities and causes commonly associated with hyponatremia and their significance in treatment.

3 Summarize current evidence and best practices in the management of hyponatremia.

4 Explain how to mitigate adverse events secondary to treatment of hyponatremia.

5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

This activity is jointly provided by Global Education Group and Applied Clinical Education.

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka America Pharmaceutical Inc.

Distributed via CMEZone

18

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BIG DATA continued from page 1

although Janet wanted her information to help others, that could only happen if she were part of a clinical trial, and only 3% to 4% of U.S. cancer patients qualify for trials, Dr. Abernethy said. Before Janet ultimately died, she asked Dr. Abernethy to share her story.

“The majority of what we do as clinicians doesn’t ever make it into the future history,” she said. “In Janet’s terms, because she was not in a clinical trial, her data would not get entered into the data record for the future, nor can all of the stories of caring for patients like Janet inform the care of other Janets in the future. This is a challenge we need to solve.”

Making sense of this mass of data has been a growing focus for many groups, Dr. Abernethy said, noting that the field of oncology has been a forerunner in the development of registries and databases. “We’re very proud of our ability to do large-scale clinical trials, but they miss the majority of patients whom we see,” she noted. Individual institutions have been working on data warehouses that compile information into one big cauldron to analyze, but these data

CLINICAL ONCOLOGY NEWS • JULY 2015 • CLINICALONCOLOGY.COM

trial eligibility, personalized treatment and other tasks. Current EHRs track so-called “structured” data points, such as serum sodium and other laboratory test results, but they’re not always easy to search, Dr. Abernethy said. Much more relevant information is found in so-called “unstructured” data, such as handwritten documents or radiology reports, in which key points are hidden and much more time-consuming to pull out, she said. The company’s idea was to use technology-enabled abstraction, a method of compiling the structured and unstructured data into a common, easy-to-use platform.

The company has several software products for oncology practices, including the free OncoEMR, a cloud-based oncology-specific EHR for cancer clinics, and OncoAnalytics, an EHR-agnostic analytics portal that administrators and physicians can use to explore and analyze their practice data. According to Dr. Abernethy, more than 200 cancer centers and over 1,700 clinicians nationwide are using these products.

Participating practices use the products for a range of purposes, Dr. Abernethy told Clinical Oncology News, with OncoEMR employed to document patients’ medical histories and track

‘There’s a lot of promise with big data, and the trick will be merging big data with small data from your own personal practice. It remains to be seen how that will play out.’

—John Sprandio, MD

warehouses don’t connect to each other. She said perhaps EHRs can play a role here and “actually be a mechanism for good,” rather than always being “the bane of our existence.”

Dr. Abernethy and her colleagues at Flatiron wanted to create a foundation of linked, patient-level data that easily could be analyzed to support clinical

data points along their care, review lab or radiology test results, and better identify patients in need of financial assistance programs. OncoAnalytics allows clinicians to monitor the overall population seen in a practice, such as the number of breast cancer patients, their comorbidities and what locations they visit.

Northwest Medical Specialties, a hematology/oncology and infectious diseases practice in Tacoma, Wash., has used OncoAnalytics for about a year, and in March began using OncoEMR. “A lot of our focus in the last couple of years has been on data and how to access it,” the group’s CEO, Mark Nelson, PharmD, said in an interview. Dr. Nelson and his group had limited research resources but wanted to more easily identify its population’s cancers and stages to pinpoint what type of studies to pursue.

They also wanted to better recognize patients eligible for existing clinical trials and elicit data points to provide evidence of quality care to insurers.

He and his colleagues did have access to those data before, he said, but through a more cumbersome process. The OncoEMR and OncoAnalytics software are enabling them to look more quickly for trends. “It has enormous potential at the global aggregate level but also enormous potential at the local level,” he said.

John Sprandio, MD, the founder of Consultants in Medical Oncology and Hematology, a nine-physician practice in Drexel Hill, Pa., has been using OncoAnalytics for about seven months.

BIOPSIES

to potentially receive an antineoplastic agent that may potentially improve her or his outcome (survival, existing cancer-related symptoms, overall quality of life)?

• Who should be responsible for paying for the procedure itself and all related costs (eg, additional time spent in the hospital, additional monitoring, any laboratory testing required specifically for the procedure, travel time to the appointment by the patient and family, required time off work by the

patient or family for the performance of the procedure)?

• Who will assume liability for any complications associated with this purely “research test”: the company sponsor, the investigators and their institutions, any third-party insurer, or the patient and her or his family)?

• What is the role of the institutional review board (either individual institutional or central) in ensuring that these questions are addressed and appropriately answered?

Individual institutions have been working on data warehouses that compile information into one big cauldron to analyze, but these data warehouses don’t connect to each other. Perhaps EHRs can play a role here and ‘actually be a mechanism for good,’ rather than always being ‘the bane of our existence.’

—Amy Abernethy, MD, PhD

continued from page 17

trial, the outcome of which will not be determined by the biopsy results and in which there is no possibility the patient will directly benefit from the results of the procedure?

• Is it realistic to believe that truly adequate “informed consent” can be obtained from patients in this setting, when there is an understandably strong desire by the individual

He told Clinical Oncology News that he appreciates being able to more easily track new referrals and practice trends.

“There’s a lot of promise with big data,” he said, “and the trick will be merging big data with small data from your own personal practice. It remains to be seen how that will play out.”

Another practice, Michiana Hematology Oncology, which operates seven community cancer centers in Indiana, uses the Flatiron products and also participates in a local health information exchange, said Kim Woofter, RN, chief operating officer. In addition, the group hired a local firm to build a custom platform to compile data from payroll, finance and other areas into their practice analytics. With this custom platform, Ms. Woofter said, “I can tell you for every regimen what it truly costs to execute, including the supplies, staff time, and the lighting and electricity costs.” Having the combined systems and accurate data also has helped her negotiate payor contracts.

—Karen Blum

At a time of unprecedented progress in the management of malignant disease based on our increasing knowledge of the fundamental drivers of cancer growth, spread and resistance, and the clear need to develop innovative strategies to accelerate progress in this arena, it is absolutely critical that we never forget it is the individual cancer patient who is at the true core of this effort. Patients who are asked to become “research subjects” deserve answers to these questions.

■

Dr. Abernethy is an employee of Flatiron Health. None of the other sources reported any relevant financial relationships.

JULY 2015

CLASSIFIEDS

Fellowship-Trained Breast Surgeon Near Baltimore/D.C. Metro Areas Wellspan Health, a sophisticated medical community in south central Pennsylvania is seeking a Fellowship Trained Breast Surgeon. Join a large, wellrespected medical group of over 700 providers with low physician turnover. WellSpan is a top-rated integrated health system and tertiary care center with a collaborative culture and focus on a high-quality patient care.

Position details: Ideal candidate will be board certified in General Surgery and fellowship trained at a certified breast surgery program WellSpan York Hospital is a 600-bed level one trauma center Surgical Oncology team currently includes two surgeons and one CRNP New grads are welcome and will be mentored by this experienced team Shared call within the Surgical Oncology practice No general surgery call York Hospital has 20 ORs. We enjoy specialty support of excellent specialists including: mammography team, medical and radiation oncologists and plastic surgeons Opportunities for resident teaching and research Position may include one day per week outreach to Lancaster County Competitive salary and excellent benefits including retirement plan and relocation. Malpractice with tail coverage is also included.

About the York Community: York is a family oriented community with excellent schools, a low cost of living and abundant outdoor and cultural activities Centrally located among several major metropolitan areas, including Baltimore, Washington D.C. and Philadelphia If you value a strong sense of community, the more palatable pace of suburban/rural living, and the convenience of a workplace close to home, you’ll realize the advantages of considering WellSpan as part of your future.

Please contact Ann Reid at 717-812-4377 or e-mail at areid2@wellspan.org

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