TAP Vol 6 Issue 12

ASCO 2015 News

1, 3–9, 12–14

| Value in Cancer Care

14

| Checkpoint Inhibitors in NSCLC

VOLUME 6, ISSUE 12

30, 31

JULY 10, 2015

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

ASCO Plenary Report

Survivors of Childhood Cancer Living Longer, Largely Due to Treatment Improvements

Biosimilars: Questions Remain

By Caroline Helwick

By Richard J. Boxer, MD, FACS

S

urvivors of childhood cancers can expect longer lives than their peers of 30 years ago. Improvements in the care of children with cancer have reduced the long-term mortality rate, according to an analysis of 34,000 participants in the Childhood Cancer Survivor Study.1 Cumulative all-cause late mortality at 15 years dropped from 10.7% in the 1970s to 7.9% in the 1980s and to 5.8% in the 1990s, according to Gregory T. Armstrong, MD, a pediatric oncologist at St. Jude Children’s Research Hospital, Memphis, who shared the good news at the 2015 ASCO Annual Meeting Plenary Session.

“The improvement in the cure rate for childhood cancers is one of the success stories of modern medi-

cine; however, these individuals are still at risk for late effects and mortality.

The punch line of this story is that deaths due to late effects and other health-related causes have dropped,” Dr. Armstrong said at a press briefing during the Gregory T. Armstrong, MD Annual Meeting.

“Survivors in more recent eras have a significant reduction in late mortality attributable to fewer deaths from treatment-related causes, including subsequent malignancies and cardiac deaths,” he noted. “The strategy of reducing the intensity of therapy to lower the occurrence of late effects—along with the promotion of early detection and improved treatment of late effects—has now translated to extend the life span of survivors.” continued on page 9

Health Information Technology

How CancerLinQ™ Can Benefit People Living With Cancer s regular readers of The ASCO Post know, ASCO is developing an exciting new health information learning system called CancerLinQ™, which will exponentially enlarge our understanding of cancer therapy far beyond what we’ve achieved with our system of clinical trials. Cancer clinical trials have led the way to countless new therapies; without them, cancer care would never evolve. Unfortunately, clinical trials are a woefully inefficient—and insufficient—source of information.

continued on page 72

Dr. Boxer is Visiting Professor of Urology and Scholar in Residence (Business of Science Center) at the David Geffen School of Medicine at UCLA. He is also Professor of Clinical Urology at the University of Wisconsin–Madison.

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

MORE IN THIS ISSUE

By Jim Omel, MD

A

B

iosimilars are biologic drugs that are similar to an already established “reference” or “innovator” biologic drug product and can be manufactured when an original biologic drug product’s patent expires. Reference to the innovator product is an integral component of approval for a biosimilar. The U.S. Food and Drug Administration (FDA) requires licensed biosimilar and interchangeable biologic products to meet the agency’s rigorous standards of safety and efficacy.

Everyone is aware of our dismal 3% adult cancer trials accrual rate, but it has been that tiny fraction of 3% of patients willing to participate in clinical studies that has allowed us to advance new treatments. What about the other 97% of patients treated for cancer? How can their treatment and outcomes add to our overall cancer wisdom? CancerLinQ promises to unlock the wealth of data stored in individual patient electronic health records and provide us with answers.

CancerLinQ promises to unlock the wealth of data stored in individual patient electronic health records and provide us with answers.

—Jim Omel, MD

Outcome Information Tool CancerLinQ is not a clinical trial, but rather, an outcome information tool designed to increase our understanding of cancer and its treatment and improve patient outcomes.

Oncology Meetings Coverage ASCO Annual Meeting ����� 1, 3–9, 12–14 American Society of Gene and Cell Therapy Annual Meeting ���������� 15–18 National Cancer Policy Forum ��������� 21–22 Leonard Saltz, MD, on Value in Cancer Care ���������������������������������� 14 Direct From ASCO ������������������ 34, 36–37 Integrative Medicine ����������������������� 40–41 Women in Oncology: Clara Bloomfield, MD, FASCO ������ 50–51 In Memoriam ���������������������������� 54–55, 74

continued on page 48

Send your comments to editor@ASCOPost.com

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The ASCO Post | JULY 10, 2015

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

George W. Sledge, MD Indiana University

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

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Joseph S. Bailes, MD Texas Oncology

Hagop M. Kantarjian, MD MD Anderson Cancer Center

Laurence H. Baker, DO University of Michigan Health System

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Jamie Von Roenn, MD American Society of Clinical Oncology Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

International Editors Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Rakesh Chopra, MD Artemis Healthsciences Institute Gurgaon, Haryana, India

Philip D. Bonomi, MD Rush University Medical Center

Stuart Lichtman, MD Memorial Sloan-Kettering Cancer Center Commack, New York

Nagi El-Saghir, MD American University of Beirut, Lebanon

Richard Boxer, MD University of Wisconsin School of Medicine

Michael P. Link, MD Stanford University Medical Center

Harold J. Burstein, MD Dana-Farber Cancer Institute

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Douglas W. Blayney, MD Stanford University Medical Center

Robert W. Carlson, MD National Comprehensive Cancer Network Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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PAGE 3

ASCO Annual Meeting Breast Cancer

Ado-Trastuzumab Emtansine Fails to Replace Standard of Care in First-Line Metastatic Breast Cancer

By Caroline Helwick

R

esults are now in for the phase III MARIANNE trial. Although ado-trastuzumab emtansine (formerly known as T-DM1, Kadcyla) proved noninferior to trastuzumab (Herceptin) plus a taxane in the first-line metastatic breast cancer setting, it performed no better than the standard of care.1

ASCO Annual Meeting.

Ado-trastuzumab emtansine was better tolerated, in some respects, and maintained health-related quality of life longer. Therefore, Dr. Ellis maintained that it is “an alternative treatment option to trastuzumab/taxane in previously untreated HER2-positive patients.”

T-DM1 and T-DM1 plus pertuzumab demonstrated a noninferior progression-free survival compared to trastuzumab/taxane, but they were not found to be superior to it.

—Paul Ellis, MD

“T-DM1 and T-DM1 plus pertuzumab demonstrated a noninferior progression-free survival compared to trastuzumab/taxane, but they were not found to be superior to it,” said Paul Ellis, MD, of Guy’s Hospital and Sarah Cannon Research Institute, London, presenting the results at the 2015

MARIANNE Rationale When MARIANNE was designed in 2009, trastuzumab in combination with a taxane was “far and away the commonest standard of care” in patients with untreated HER2-positive metastatic breast cancer, Dr. Ellis noted.

Ado-trastuzumab emtansine had

shown strong activity in phase II studies in treated and untreated disease, with a favorable safety profile. A subsequent randomized phase II study comparing ado-trastuzumab emtansine against trastuzumab in combination with a taxane in untreated patients showed encouraging efficacy and excellent tolerability.2 Furthermore, the combination of ado-trastuzumab emtansine and pertuzumab (Perjeta) had demonstrated preclinical synergy and activity in a phase Ib/II study.3 These findings led to the international randomized MARIANNE trial, which enrolled 1,095 previously untreated patients with locally advanced or metastatic breast cancer. It evaluated three arms: trastuzumab plus docetaxel or paclitaxel (physician’s choice; trastuzumab/taxane); ado-trastuzumab emtansine plus placebo; and ado-trastuzumab emtansine plus pertuzumab.

The primary endpoint was assessment of progression-free survival by independent review, with determinations of both noninferiority and superiority.

There were independent comparisons

between ado-trastuzumab emtansine vs trastuzumab in combination with a taxane and ado-trastuzumab emtansine/ pertuzumab vs trastuzumab in combination with a taxane.

Noninferiority Demonstrated Median progression-free survival was 13.7 months with trastuzumab in combination with a taxane compared with 14.1 months for ado-trastuzumab emtansine (hazard ratio [HR] = 0.91, P = .31) and 15.2 months for adotrastuzumab emtansine/pertuzumab (HR = 0.87, P = .14). This outcome met the noninferiority boundary.

By prestratified subgroups, no significant differential effects were observed. However, numerical trends favoring ado-trastuzumab emtansine were observed among patients who had received adjuvant taxanes and HER2directed therapy (HR = 0.75) or any prior taxane (HR = 0.69).

At this first interim analysis, Dr. ­Ellis noted that the overall survival curves “essentially overlapped,” and median continued on page 4

EXPERT POINT OF VIEW

S

tudy discussant Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, commented, “Neither T-DM1 [Kadcyla] nor T-DM1 plus pertuzumab [Perjeta] proved to be superior to the old standard of care, taxane plus trastuzumab [Herceptin]. MARIANNE was a valiant trial, but THP (taxane, trastuzumab, and pertuzumab) remains our first-line standard of care, with T-DM1 a preferred second-line option.”

Dr. Modi emphasized that toxicity and health-related quality of life did appear more favorable with the adotrastuzumab emtansine–containing regimens. In particular, rates of grade 3/4 neutropenia, febrile neutropenia, and diarrhea were lower in these arms, as was the occurrence of alopecia, and patient-reported outcomes remained positive for much longer. “It would be very informative to reassess these toxicities based on the taxane delivered,” she offered, “knowing that weekly paclitaxel has a very low febrile neutro-

penia rate and may be the preferred partner.”

vival advantage for T-DM1 or T-DM1 plus pertuzumab in the first-line meta-

MARIANNE was a valiant trial, but THP (taxane, trastuzumab, and pertuzumab) remains our first-line standard of care, with T-DM1 a preferred second-line option.

—Shanu Modi, MD

She also questioned why pertuzumab provided no additional benefit, since in CLEOPATRA, the addition of this drug greatly improved survival, compared with an HT (trastuzumab [Herceptin] and taxane) arm.1 The role of pertuzumab in adjuvant breast cancer is being explored further in the phase III ­APHINITY trial, she added.

Assessing the future for ado-trastuzumab emtansine, Dr. Modi suggested, “Given no progression-free sur-

static setting, it is unlikely to show a survival advantage in the early-stage setting (neoadjuvant or adjuvant).” A number of adjuvant trials, however, are currently testing its potential in early-stage patients.

Unanswered Questions Regarding the treatment of HER2positive advanced breast cancer in general, Dr. Modi said a number of questions remain unanswered: What

is the value of combining therapies? Is there an optimal combination? Does every case warrant multiple targeted agents? Can we avoid chemotherapy for some patients? What is the ideal trial setting for evaluating these treatments, and what are the right endpoints in these trials?

Based on current evidence, she concluded, “For the time being, taxane/trastuzumab/pertuzumab remains our preferred first-line therapy for HER2-positive metastatic breast cancer, and our treatment guidelines for 2015 remain unchanged.” n

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

Reference 1. Swain SM, Kim SB, Cortés J, et al: Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): Overall survival results from a randomised, doubleblind, placebo-controlled, phase 3 study.

Lancet Oncol 14:461-471, 2013.

The ASCO Post | JULY 10, 2015

PAGE 4

ASCO Annual Meeting Breast Cancer

Anastrozole and Tamoxifen: Both Options for Ductal Carcinoma in Situ

By Alice Goodman

A

nastrozole was found to be at least as safe and effective as tamoxifen in preventing breast cancer recurrence in women with ductal carcinoma in situ, in the large NSABP B-35/

treated with lumpectomy and radiation for ductal carcinoma in situ, like the women in this study. Other studies have compared the two drugs in more invasive forms of cancer.

It [tamoxifen or anastrozole] is a personal choice that a woman should make with her physician about the relative benefits of a reduced chance of recurrence, with respect to the differing safety profiles.”

—Richard G. Margolese, MD

SWOG-35 study.1 Among all women in the trial, however, the 10-year breast cancer–free interval rates were higher in women taking anastrozole than tamoxifen (93.5% vs 89.2%).

This is the first study to compare an aromatase inhibitor vs tamoxifen in ductal carcinoma in situ, the earliest form of breast cancer sometimes considered precancer. Breast cancer– related death is uncommon in women

He emphasized that adverse events are uncommon with these drugs— from 1% to 3% of all women treated.

“Depending on the drug, the side effects are different. It is a personal choice that a woman should make with her physician about the relative benefits of a reduced chance of recurrence, with respect to the differing safety profiles,” Dr. Margolese commented at a press conference.

Other experts at the 2015 ASCO Annual Meeting, where these data were presented, were quick to note that this study expands the options for treatment of ductal carcinoma in situ and does not represent one standard of care.

“The good news is tamoxifen and anastrozole are both very effective, but it seems that women have better chances of staying well with anastrozole. Women will need to discuss the risks and benefits of both drugs with their doctors, because the side-effect profiles differ,” said lead author Richard G. Margolese, MD, Professor of Surgical Oncology, Jewish General Hospital, McGill University, Montreal, Canada.

Study Details

ado-trastuzumab emtansine and 21.2 months with ado-trastuzumab emtansine/pertuzumab, compared with 12.5 months with trastuzumab in combination with a taxane.

just 3.6 months for the control arm, vs 7.7 months with ado-trastuzumab emtansine and 9.0 months with adotrastuzumab emtansine/pertuzumab.

“This suggests that health-related quality of life was prolonged in patients treated with T-DM1,” Dr. Ellis suggested.

Ado-trastuzumab emtansine was tolerated as well as—and in some respects better than—the control arm. Grade ≥ 3 adverse events were observed in 54.1% of the trastuzumab in combination with a taxane cohort, 45.4% of the ado-trastuzumab emtansine arm and 46.2% of the ado-trastuzumab emtansine/pertuzumab arm. Adverse events leading to discontinuation of any treatment component occurred in 29.7%, 18.3%, and 19.1%, respectively.

Grade ≥ 3 neutropenia, febrile neutropenia, and diarrhea were much more common with trastuzumab in combination with a taxane than with either ado-trastuzumab emtansine regimen, whereas hypertension, anemia, thrombocytopenia, and liver enzyme elevations were greater in the ado-trastuzumab emtansine arms. Pertuzumab did not

The study randomized 3,104 postmenopausal women with hormone receptor–positive ductal carcinoma in situ to treatment with 5 years of daily tamoxifen or anastrozole. Prior to randomization, all women had been treated with lumpectomy and radiation and were stratified by age: < 60 years vs ≥ 60 years.

At an average follow-up of 8.6 years,

114 cancers were identified in the tamoxifen group vs 84 in the anastrozole group. The 10-year breast cancer– free rates by age were similar in older women: 92.2% for anastrozole vs 88.2% for tamoxifen. There was a larger difference among younger women: 94.9% with anastrozole vs 88.2% with tamoxifen, but this difference was not explainable by body mass index, death due to other causes, or compliance. “We are still looking for other reasons [for this difference],” Dr. Margolese said. “It is a stimulus for further research.”

Overall, there was a 45% relative risk reduction for invasive recurrences with anastrozole, he continued. The number of recurrences was 60 in the tamoxifen group vs 30 in the anastrozole group.

The numbers of recurrent ipsilateral or contralateral ductal carcinoma in situ cases were relatively small and not statistically significant between the two treatment arms, but the number of contralateral invasive cancers was significantly reduced in the anastrozole arm.

There were eight deaths due to breast cancer in the tamoxifen group and five deaths in the anastrozole group. continued on page 5

Ado-Trastuzumab Emtansine continued from page 3

overall survival has not been reached in any arm. Events were recorded in 123 patients in the control arm, 115 in the ado-trastuzumab emtansine arm, and 115 in the ado-trastuzumab emtansine/ pertuzumab arm.

Objective responses were lowest with ado-trastuzumab emtansine (59.7%), compared with trastuzumab in combination with a taxane (67.9%) and ado-trastuzumab emtansine/pertuzumab (64.2%). However, patients who responded to ado-trastuzumab emtansine (either arm) had a much longer duration of response: 20.7 months with

Quality-of-Life Benefits According to the Functional Assessment of Cancer Therapy–Breast Trial Outcome Index, health-related quality of life (a secondary endpoint) was also maintained longer in ado-trastuzumab emtansine–containing arms. The median time to a clinically meaningful decrease from baseline (≥ 5 points) was

Ado-Trastuzumab Emtansine in Metastatic Breast Cancer ■■ The international phase III MARIANNE trial compared ado-trastuzumab emtansine and ado-trastuzumab emtansine plus pertuzumab with trastuzumab plus a taxane in patients with advanced or metastatic breast cancer.

■■ The trial proved noninferiority for the ado-trastuzumab emtansine arms, but they were not superior to the standard of care.

■■ Toxicity and health-related quality of life were overall better in the adotrastuzumab emtansine arms than in the control arm.

“dramatically” add to these toxicities, but the drug did increase diarrhea. Alopecia was rare with ado-trastuzumab emtansine, Dr. Ellis noted. n

Disclosure: Dr. Ellis has received travel, accommodations, and expenses from Roche Pharma AG.

References 1. Ellis PA, Barrios CH, Eiermann W, et al: Phase III, randomized study of trastuzumab emtansine ± pertuzumab vs trastuzumab + taxane for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study. 2015 ASCO Annual Meeting. Abstract 507. Presented June 1, 2015.

2. Hurvitz SA, Dirix L, Kocsis J, et al: Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 31:1157-1163, 2013.

3. Miller KD, Diéras V, Harbeck N, et al: Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. J Clin Oncol 32:1437-1444, 2014.

ASCOPost.com | JULY 10, 2015

PAGE 5

ASCO Annual Meeting Lenvatinib/Everolimus: Robust Combination in Metastatic Renal Cell Carcinoma

By Alice Goodman

T

he combination of lenvatinib (Lenvima) plus everolimus (Afinitor) significantly extended progression-free survival compared with everolimus alone

Robert Motzer, MD

in metastatic renal cell carcinoma, according to a randomized phase II trial.1 Median progression-free survival for patients who received the combination was 14.6 months, significantly longer than 5.5 months for everolimus alone (P < .001),

Anastrozole and Tamoxifen continued from page 4

As for expected side effects, there was a slight increase in the cases of uterine cancers with tamoxifen vs anastrozole: 17 cases vs 8 cases. The average annual rate of the number of new osteoporotic fractures per 1,000 women was increased in women receiving anastrozole (69 vs 50 events), but this difference was not statistically significant.

“Severe adverse events were uncommon in general and less common with anastrozole. Events of concern with tamoxifen are thromboembolism and uterine cancer,” he said.

Dr. Margolese did not report in de-

which is currently a National Comprehensive Cancer Network–recommended second-line therapy for unresectable or advanced or metastatic renal cell carcinoma.

“The combination of lenvatinib and everolimus was superior to everolimus in previously treated metastatic renal cell carcinoma patients. Progression-free survival was longer—and response rates were higher—with the combination, and study results suggest that the combination will have a survival benefit over everolimus.

This speaks to the high level of efficacy for the combination in this study. Further study of the combination of lenvatinib and everolimus is warranted,” said lead author Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

Targeted therapy with a tyrosine kinase inhibitor is the current standard of

EXPERT POINT OF VIEW

“T

his combination [lenvatinib and everolimus] is a potential game-changer in metastatic renal cell carcinoma. We’ve studied other combinations to no avail; for example, bevacizumab [Avastin] plus everolimus had no advantage over everolimus alone. Other combinations are too toxic, such as sunitinib plus bevacizumab. These results are potentially exciting. We have no other approved combinations in metastatic renal cell carcinoma,” said Sumanta K. Pal, MD, Researcher and Co-Director, Kidney Cancer Program, City of Hope, Duarte, California.

Sumanta K. Pal, MD

“Typically, we expect progression-free survival of around 5 months, and the combination achieved median progression-free survival approaching 15 months.

These are encouraging results and continued on page 6

continued on page 6

tail on quality of life and other side effects in the trial, including arthralgias and myalgias, which are commonly experienced by women taking aromatase inhibitors. He said a separate analysis of these events would be reported in the future.

Additional Comments “In my view, this does not set a single standard of care for all women with ductal carcinoma in situ,” said ASCO expert Don S. Dizon, MD, Clinical Co-Director of Gynecologic Oncology, Massachusetts General Hospital Cancer Center, Boston.

“The main take-away point is that we now have a new breast cancer preven-

tion option for women treated with ductal carcinoma in situ.”

“Until now, the only option for adjuvant medical treatment of ductal carcinoma in situ was tamoxifen. The availability of both drugs means there are choices, and we can individualize therapy,” Dr. Dizon stated at a press conference.

“Patients will make this choice depending on what motivates them. For some women with ductal carcinoma in situ, the main fear is recurrence. For others, the fear of toxicity is more important,” Dr. Dizon noted.

The formal discussant of this trial, ­Joseph Sparano, MD, of Montefiore Medical Center and Albert Einstein College of Medicine, New York, said:

“Anastrozole and probably other aromatase inhibitors are a good option for preventing ipsilateral recurrence and contralateral breast cancers in women with ductal carcinoma in situ. Anastrozole is probably more suitable for younger patients who are postmenopausal and have a history of thromboembolism.” n Disclosure: The study was funded by the National Institutes of Health. Drs. Margolese and Sparano reported no potential conflicts of interest.

Reference 1. Margolese RG, Cecchini RS, Julian TB, et al: Primary results, NRG Oncology/NSABP B-35. 2015 ASCO Annual Meeting. Abstract LBA500. Presented May 30, 2015.

EXPERT POINT OF VIEW

“T

his is an important study. We’ve known for some time that the aromatase inhibitors tend to be better than tamoxifen for postmenopausal women with hormonally sensitive invasive breast cancer. The NSABP B-35 trial asked the same question in ductal carcinoma in situ. These data, which now follow patients for a mean of 8.6 years, suggest that anastrozole may be better than tamoxifen in preinvasive disease when looking at breast cancer–free interval, particularly in younger postmenopausal women,” said Anees B. ­Chagpar, MD, Director, The Breast Center, Smilow

Anees B. Chagpar, MD

Cancer Hospital, Yale University School of Medicine, New Haven.

Dr. Chagpar pointed out that the data show that aromatase inhibitors were similar to tamoxifen across most endpoints,

with the exception of contralateral invasive cancers. “This would fit with the concept that perhaps there is a chemopreventive effect in this setting,” she said.

“The side-effect profiles of the two agents are different, and although the authors were not able to show significant differences for many of the categories of symptoms they evaluated, at least these data provide us with another potential agent in our tool box for patients with hormone receptor–positive ductal carcinoma in situ,” Dr. Chagpar commented.

She said that some “intriguing” questions remain: “Why do younger wom-

en benefit more from anastrozole? It doesn’t seem to be related to body mass index or compliance, according to the authors who struggled with this question as well,” Dr. C ­ hagpar continued.

She remains unconvinced of the clear superiority of anastrozole over tamoxifen or vice versa. “Particularly with a low event rate, I think it is safe to say that anastrozole is at least equivalent to tamoxifen in this setting. It really should be a conversation a woman has with her doctor,” she concluded. n Disclosure: Dr. Chagpar reported no potential conflicts of interest.

The ASCO Post | JULY 10, 2015

PAGE 6

ASCO Annual Meeting Genitourinary Cancer

Lenvatinib/Everolimus continued from page 5

care for metastatic renal cell carcinoma.

Lenvatinib, a new, powerful tyrosine kinase inhibitor, has potent selectivity and a binding mode that differs from that of other tyrosine kinase inhibitors. Lenvatinib simultaneously inhibits vascular endothelial growth factor receptors (VEGFR-1, -2, -3), fibroblast growth factor receptors (FGFR 1-4), RET, KIT, and platelet-derived growth factor receptors (PDGFR), and it is the first tyrosine kinase inhibitor to have these p­ roperties.

Lenvatinib is currently approved in the United States for the treatment of refractory differentiated thyroid cancer.

Currently, no combination therapy has been approved for metastatic renal cell carcinoma anywhere in the world.

Study Details Between March 2012 and July 2013, the international, prospective, open-label, phase II study randomized 153 patients with metastatic renal cell carcinoma who progressed on one prior VEGF-targeted therapy to receive lenvatinib, everolimus, or the combination of both drugs. Patients were treated until progressive disease or unacceptable toxicity.

All patients had measurable disease and disease progression within 9 months of stopping their prior therapy.

No crossover was allowed in the trial.

At the 2015 ASCO Annual Meeting, Dr. Motzer presented an updated overall survival analysis up to December 2014.

“Patients enrolled in the trial were typical metastatic renal cell carcinoma pretreated patients balanced for Memo-

Sumanta K. Pal, MD continued from page 5

the best margin of improvement we have seen within the confines of a randomized controlled trial in pretreated patients,” he added.

The toxicities need to be better characterized, he continued, but they are acceptable for moving to a phase III trial. A phase III trial is being considered, but the design is yet undetermined.

Dr. Pal commented that with this combination, as with all new drugs in oncology, it is important to determine the relevant targets and identify biomarkers to establish which groups of patients will preferentially benefit. n Disclosure: Dr. Pal has received consulting fees from Pfizer, Novartis, and Genentech.

rial Sloan Kettering risk factors. All patients had prior VEGF treatment, most commonly with sunitinib followed by pazopanib [Votrient],” Dr. Motzer said.

Median progression-free survival was 14.6 months with the combination, 7.4 months with lenvatinib alone, and 5.5 months with everolimus alone,

representing a 60% reduction in disease progression favoring the combination over everolimus and a 39% reduction in disease progression favoring lenvatinib alone over everolimus.

The highest overall response rates were observed with the combination: 43%, followed by 27% with lenvatinib alone and

6% with everolimus alone. The median duration of response was 13.1 months for the combination therapy arm.

“At the time of data cutoff, a trend was observed favoring the combination for overall survival,” Dr. Motzer said. Median overall survival was 25.5 months for the combination, 18.4

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; JULY 10, 2015

PAGE 7

ASCO Annual Meeting months for lenvatinib alone, and 17.5 months for everolimus alone. The updated overall survival analysis in December 2014 showed a significant difference favoring the combination over everolimus alone (P = .024).

All patients had at least one treatment-emergent adverse event. Adverse

events were more frequent in the combination therapy arm but were manageable with dose reduction, Dr. Motzer said.

Lenvatinib was associated with more grade 3 diarrhea, fatigue, nausea, and vomiting. The most common treatment-related grade 3 or higher adverse events were diarrhea, hyper-

tension, and fatigue. Relatively few grade 4 adverse events were reported with the combination treatment. There were two grade 5 events, one in each of the lenvatinib-containing arms. n Disclosure: Dr. Motzer is a consultant for Pfizer; has received research funding (institutional) from Bristol-Myers Squibb, Eisai,

Genentech/Roche, GlaxoSmithKline, Novartis, and Pfizer; and travel expenses from BristolMyers Squibb and GlaxoSmithKline.

Reference 1. Motzer R, et al: 2015 ASCO Annual Meeting. Abstract 4506. Presented June 1, 2015.

The ASCO Post | JULY 10, 2015

PAGE 8

ASCO Annual Meeting UAB Study on Lay Navigation Program Shows Trend Toward Cost Savings

R

esearchers from the University of Alabama (UAB) at Birmingham presented preliminary findings of an observational study indicating a rapid decline in Medicare costs and patient resource utilization during implementation of a lay nav-

igation program. The study was presented at this year’s ASCO Annual Meeting.1 In 2012, the UAB Comprehensive Cancer Center created the Patient Care Connect Program, a lay patient navigation initiative with the support of a

$15 million Health Care Innovation Challenge Grant Award from the Centers for Medicare and Medicaid Innovation. The Patient Care Connect Program was designed to pair a trained nonclinical lay navigator with a patient with cancer

to help him through his cancer journey.

“The goals of the program are to reduce unnecessary emergency room visits and inpatient intensive care unit days, encourage evidence-based clinical pathways, adopt earlier use of hospice care, reduce use of chemotherapy in the last 2 weeks of life, and provide the highest quality of life for people diagnosed with cancer,” said Edward Partridge, MD, Director of the UAB Comprehensive Cancer Center and Principal Investigator of the Study.

Edward Partridge, MD

“Our trained navigators help address the barriers patients often have with identifying resources for their care and empower them to recognize clinical symptoms, become more knowledgeable about their disease and treatment, and when necessary engage in end-oflife discussion with their providers,” said Gabrielle Rocque, MD, Assistant Professor in the UAB Division of Hematology and Oncology and Medical Director of the Patient Care Connect Program.

About the Study Researchers examined 30,589 Medicare patients receiving cancer care across the Network from January 1, 2012 through December 31, 2014. The study evaluated health-care utilization with hospitalizations, emergency department visits, intensive care admissions, and hospice admissions for all eligible Medicare patients. In addition, during implementation, the study analyzed the cost to Medicare for the overall medical care.

The results of the study indicate a dramatic trend toward a clinically significant reduction in health-care utilization and Medicare costs, with substantial impact during initial phase, survivorship, and the last 6 months of life.

“Certainly this study has its limitations in that some of these trends cannot be fully attributed to the Patient Care Connect Program,” Dr. Rocque noted.

Disclaimer: Drs. Partridge and Rocque reported no potential conflicts of interest.

Reference 1. Rocque GB, et al: ASCO Annual Meeting. Abstract 6502. Presented May 29, 2015.

ASCOPost.com | JULY 10, 2015

PAGE 9

ASCO Annual Meeting Plenary Session

Childhood Cancer Survivors continued from page 1

Study Details

The federally funded Childhood Cancer Survivor Study evaluated long-term health outcomes in 5-year survivors of childhood cancer (leukemia, lymphoma, central nervous system malignancies, Wilms tumor, neuroblastoma, as well as soft-tissue and bone sarcomas). Subjects from 31 participating centers were diagnosed between 1970 and 1999 and followed for an average of 21 years after diagnosis. During the study period, 12% of patients died, and 41% of these deaths were from causes other than their cancer, including other health-related conditions as well as late effects of cancer therapy.

Some of the details presented by Dr. Armstrong at the Annual Meeting follow: • Over the 30-year period, all-cause mortality 15 years from diagnosis dropped from 10.7% to 5.8% (P < .001).

• Mortality due to recurrence or progression of the primary cancer dropped from 7.1% to 3.4% (P < .001).

• Late mortality due to specific childhood cancers significantly decreased.

This included a reduction from 2.8% to 1.9% (P < .001) for acute lymphoblastic leukemia (ALL); from 4.2% to 2.1% for Hodgkin lymphoma (P = .02); and from 2.2% to 0.4% for Wilms tumor (P < .001).

• The cumulative incidence of deaths from health-related causes not related to recurrences (but potentially related to late effects) dropped from 3.5% to 2.1% (P < .001).

the most intensive regimens for the highest risk patients, has included the elimination of cranial radiotherapy in many patients with ALL; response-based therapy—reduced dose or no radiation at all—for many patients with Hodgkin lymphoma; and reduced radiotherapy dose/volume and reduced anthracycline exposure in the treatment of localized Wilms tumor, he noted.

For example, cranial radiotherapy was

The improvement in the cure rate for childhood cancers is one of the success stories of modern medicine.

—Gregory T. Armstrong, MD

• The incidence of deaths from subsequent neoplasms dropped from 1.8% to 1.0% (P < .001); cardiac-related deaths dropped from 0.5% to 0.1% (P = .001); and lung-related deaths dropped from 0.5% to 0.1% (P = .4).

Improvements From Treatment Modifications These results have been driven by treatment refinements in the clinic, especially a reduction in the intensity of treatment for patients with favorable prognoses. Risk stratification, reserving

delivered to 85% of pediatric patients with ALL in the 1970s, but it is given to 19% or fewer today. In the 1970s, 78% of patients with Wilms tumor received abdominal radiotherapy, compared with 43% today. Similar trends are seen for anthracycline exposure.

“Additionally, there have been improvements in screening and early detection of late effects, treatment of late effects, and supportive care,” Dr. Armstrong noted. n Disclosure: Dr. Armstrong reported no potential conflicts of interest.

Reference 1. Armstrong GT, Yasui Y, Chen Y, et al: Reduction in late mortality among 5-year survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. 2015 ASCO Annual Meeting. Abstract LBA2. Presented May 31, 2015.

Results of the Childhood Cancer Survivor Study ■■ The Childhood Cancer Survivor Study has been evaluating outcomes in 5-year survivors of childhood cancers since 1994.

■■ Over the 30-year period, allcause mortality 15 years from diagnosis dropped from 12.4% to 6.0% (P < .001).

■■ Mortality due to recurrence or progression of the primary cancer dropped from 7.1% to 3.4%, and the cumulative incidence of deaths from healthrelated causes not related to recurrences (but potentially related to late effects) dropped from 3.5% to 2.1% (both P < .001).

■■ The improvements largely stem from reductions in radiation and anthracycline exposure.

EXPERT POINT OF VIEW

“W

e have had remarkable success in treating patients with cancer. Millions of survivors are a testament to this success. But the ‘cost of cure’ borne by our patients is substantial in terms of diminished quality and quantity of life,” commented the formal discussant of the study ­Michael P. Link, MD, Lydia J. Lee Professor in Pediatric Cancer, Stanford University School of Medicine.

but many of the lessons are applicable to all our patients.”

“ASCO Plenary Sessions usually focus on exciting new therapies that have the prospect of adding incrementally to our goal curing cancer. Dr. Armstrong’s presentation allows us to examine another important aspect of cancer care: survivorship,” he said. “It reminds us that cumulative advances have translated into a growing population of cancer survivors, who are the beneficiaries of our past efforts.”

Consequences of Cures

Michael P. Link, MD

Dr. Link applauded the investigators of the Childhood Cancer Survivor Study for imparting another “important lesson learned from pediatric oncology.” He noted, “There is good news here for children with cancer,

Since 1990, deaths from cancer in the United States have dropped 22% and patients surviving cancer are living longer. Children and young adults cured of cancer have a lifetime ahead of them during which to develop the potential health-related side effects of the therapies that cured them and to suffer their consequences.

Nearly two-thirds of long-term childhood cancer survivors have at least one chronic condition, and in more than one-fourth of cases, it is

severe or life-threatening. “We accept this collateral damage, much like we accept that civilian deaths are the regrettable price of winning a war,” Dr. Link commented.

Launched in 1994, the Childhood Cancer Survivor Study has been instrumental in identifying these late effects through a retrospective cohort study.

More than 250 peer-reviewed manuscripts and other publications hare “catalogued the price of cure,” he said.

The study has documented that survivors of childhood cancers, compared with national age-adjusted cohorts, have 10-fold excess mortality and 6.4-fold excess second cancers.

In addition, these survivors are at increased risk of cardiac, pulmonary, and endocrine diseases, as well as obesity and psychosocial issues.1

Refining Therapies Challenged with finding ways to reduce these late effects and improve the quality of life of survivors, pediatric oncologists adjusted treatment protocols that would reduce the inten-

sity of treatments for select, good-risk patients. The aim has been to retain the treatment components believed necessary for cure while eliminating those contributing only toxicity.

“The question remained: Did these modifications actually move the needle on the cost of cure? The good news here,” he said, “is there is a statistically and clinically significant decrease over time in all-cause mortality, nonrecurrence mortality, and mortality related to second malignancies and cardiac and pulmonary disease.”

Dr. Armstrong’s study, he continued, “is a gratifying validation of 3 decades of refining therapies to accomplish cures while lowering the cost of cure.”

Treatment stratification will continue to be refined, based on a growing understanding of host and tumor genetics. Meanwhile, he said, oncologists have an obligation to continue to refine therapies to balance efficacy against toxicity. “Cure,” Dr. Link emphasized, “is not enough.” n Disclosure: Dr. Link reported no potential conflicts of interest.

Š 2015 Celgene Corporation

03/15

US-CELG140284c

IN MULTIPLE MYELOMA

RESIDUAL DISEASE AND IMMUNE DYSFUNCTION FORM A GROWING RISK OF RELAPSE An increased understanding of multiple myeloma has helped advance myeloma care over the past several decades.1,2 Despite a significant improvement in 5-year relative survival rates, patients still experience multiple periods of relapse and remission.2,3 Do residual disease and immune dysfunction form a cycle that complicates our strategies?

EVEN WITH THE ACHIEVEMENT OF A COMPLETE RESPONSE, 100 MILLION MYELOMA CELLS MAY REMAIN.4

~

The majority of patients with multiple myeloma have persistent levels of residual disease (minimal residual malignant cells) that are below the sensitivity of most protein and bone marrow diagnostic tests.5-7 Even in patients who achieve a complete response (by current International Myeloma Working Group criteria), residual disease may persist.4 In addition, dominant and minor clones continue to evolve, putting the patient at increased risk for relapse.8,9

IMMUNE DYSFUNCTION ALLOWS RESIDUAL DISEASE TO PROLIFERATE, FURTHER WEAKENING THE IMMUNE SYSTEM, AND MAY CAUSE A CYCLE OF DISEASE THAT RESULTS IN RELAPSE.5, 9-14 Myeloma tumor cells crowd out healthy cells in the bone marrow, leading to a compromised immune system and decreased immune surveillance—the immune system’s ability to identify and eliminate tumor cells.9-13 When immune surveillance is impaired, residual cells may proliferate and evolve, permitting a cycle that can lead to relapse.9,10,13

CONTINUOUS SUPPRESSION OF RESIDUAL DISEASE AND SUPPORT OF IMMUNE FUNCTION ARE IMPORTANT CONSIDERATIONS WHEN CREATING A LONG-TERM STRATEGY.13,15,16

References: 1. Kumar SK, et al. Leukemia. 2014;28:1122-1128. 2. National Cancer Institute Surveillance, Epidemiology, and End Results Program. SEER cancer statistics review 1975-2011. Available at http://www.seer.cancer.gov. Accessed October 22, 2014. 3. Hajek R. Multiple myeloma – a quick reflection on the fast progress. InTech; 2013. Available at http://www.intechopen.com/books/multiple-myeloma-a-quick-reflection-onthe-fast-progress. Accessed December 12, 2014. 4. Poon ML, et al. Cancer Therapy. 2008;6:275-284. 5. Hart AJ, et al. Biol Blood Marrow Transplant. 2012;18:1790-1799. 6. Rajkumar SV, et al. Blood. 2011;117:4691-4695. 7. Martinez-Lopez J, et al. Blood. 2014;123:30733079. 8. Keats JJ, et al. Blood. 2012;120:1067-1076. 9. Morgan GJ, et al. Nat Rev Cancer. 2012;12:335-348. 10. Katodritou E, et al. Am J Hematol. 2011;86:967-973. 11. Braga WM, et al. Clin Dev Immunol. 2012;2012:Mar 27 EPub. 12. Kyle RA, et al. N Engl J Med. 2004;351:18601873. 13. Pratt G, et al. Br J Haematol. 2007;138:563-579. 14. Favaloro J, et al. Leuk Lymphoma. 2014. May 12:1-8. [Epub ahead of print].

15. Roschewski M, et al. Blood. 2013;122:486-490. 16. Pessoa de Magalhães RJ, et al. Haematologica. 2013;98:79-86.

The ASCO Post | JULY 10, 2015

PAGE 12

ASCO Annual Meeting Hematology

Pacritinib for Myelofibrosis: Effective in Patients With Thrombocytopenia

By Caroline Helwick

A

n emerging JAK inhibitor, pacritinib, appears not only effective in a broad population of patients with myelofibrosis but also among a subset with very low platelet counts, investigators from the global phase III PERSIST-1 trial reported at the 2015 ASCO Annual Meeting.1

Ruben A. Mesa, MD

“There is a huge unmet clinical need for patients with myelofibrosis,” said Ruben A. Mesa, MD, Deputy Director of the Mayo Clinic Cancer Center, Scottsdale, Arizona. “Symptoms of myelofibrosis have a substantial negative impact on both patient quality of life and overall survival.”

This need is especially felt among patients with very low platelet counts (< 50,000/µL), who tend to have shorter survival and are at increased risk for leukemic transformation. The one Food and Drug Administration (FA)-approved agent, the JAK inhibitor ruxolitinib ( Jakafi), is not considered safe for patients with low platelet counts, Dr. Mesa indicated. “There’s nothing for this population that is really efficacious,” he noted.

“Individuals with counts < 50,000/µL are likely getting it in modest doses that probably impact efficacy.”

Pacritinib inhibits JAK2 and FLT3, whereas ruxolitinib inhibits JAK1 and JAK2. The drugs also have different effects on cytokines and on the spleen, he explained.

“Current treatments have not demonstrated the ability to simultaneously improve splenomegaly, symptoms, and cytopenias in myelofibrosis patients,” he pointed out.

“Pacritinib has activity in persons who do not have current treatments available, in particular, those with significant thrombocytopenia,” he said.

“The endpoint with pacritinib was vastly superior in both the intent-to-treat and evaluable treatment arms. There were no responders in the best available treatment arm. The efficacy was similar in the broader group with < 100,000/µL.”

PERSIST-1 Details The phase III PERSIST-1 trial enrolled 327 patients with myelofibrosis (primary myelofibrosis, postpolycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis), randomizing them to pacritinib or “best alternative therapy,” which included a range of offlabel treatments. These treatments did not include ruxolitinib due to safety concerns in patients with very low platelet counts, who were part of the study population. Patients in the study had not previously received ­r uxolitinib.

The primary endpoint was the proportion of patients achieving at least a 35% spleen volume reduction at week 24 by centrally reviewed magnetic res-

EXPERT POINT OF VIEW

L

loyd Damon, MD, Professor of Medicine at the University of California, San Francisco, discussed the study and noted that although ruxolitinib ( Jakafi) is associated with a fair amount of anemia and thrombocytopenia, pacritinib did not increase these conditions in PERSIST-1. In fact, treatment was associated with a reduction in the need for transfusions. The lack of such toxicity allows pacritinib to be given to patients with low platelet counts, for whom ruxolitinib is not indicated or is used at a lower and possibly less effective dose.

Lloyd Damon, MD

For these reasons, he said, “Pacritinib is a very important agent for patients with advanced disease.”

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

New JAK Inhibitor for Myelofibrosis ■■ The phase III PERSIST-1 trial evaluated the JAK inhibitor pacritinib in patients with myelofibrosis, finding it to be significantly more effective than best alternative therapy.

■■ A significant reduction in spleen volume was observed at 24 weeks in 25.0% of the pacritinib arm, vs 5.9% of the control arm (P = .0001) in the evaluable population.

■■ Significant splenic shrinkage was observed with pacritinib, with no increase in toxicity, in the subset of patients with very low platelet counts: 33.3% vs 0% (P = .0370), respectively.

■■ Pacritinib also reduced the need for transfusions and improved symptoms.

onance imaging or computed tomography. Secondary endpoints included the proportion achieving at least a 50% reduction in total symptom score at 24 weeks using the Myeloproliferative Neoplasm Symptom Assessment Form.

In this population, 32% of patients had a platelet count < 100,000/µL, and 15% had a platelet count < 50,000/µL; 75% were JAK2 V617F-positive.

The median duration of treatment was 16.2 months in the pacritinib arm and 5.9 months with the best available treatment. In the control arm, 74.5% received active treatment in the control arm (25.5% were watch and wait), including erythropoietinstimulating agents, immunomodulatory drugs, hydroxyurea, and others.

Primary Endpoint Met “This study demonstrated that pacritinib was well tolerated and induced significant and sustained spleen volume reduction and symptom control, even in patients with severe thrombocytopenia,” Dr. Mesa reported. “Pacritinib therapy also resulted in red blood cell transfusion independence in a significant proportion of patients.”

At 24 weeks, significant spleen shrinkage was observed in 19.1% of the pacritinib arm, compared with only 4.7% of the control arm (P = .0003), in the intent-to-treat analysis, and in 25.0% vs 5.9% (P = .0001) of the evaluable population (who both had baseline and 24-week assessments).

Additional Benefits In other endpoints, additional benefits were observed with pacritinib, as described here for the evaluable patient population: • Among patients with the lowest platelet counts, spleen shrinkage of at

least 35% was observed in 33.3% vs 0% (P = .0370); • Among patients dependent on red blood cell transfusions, transfusion independence was achieved by 25.7% vs 0% (P = .04); • Among all patients, a significant reduction (at least 50%) in Total Symptom Score at 24 weeks was observed in 40.9% vs 9.9% (P < .0001); • In the very low platelet subset, this reduction in symptoms was observed in 31.8% vs 11.1% (P = .3791).

Overall survival data are premature, but a landmark analysis at week 24 found that spleen shrinkage was associated with improved survival in the pacritinib arm but not in the control arm. “This highlights the importance of splenic reduction in impacting outcomes,” according to Dr. Mesa.

The most common toxicities with pacritinib were diarrhea, nausea, and vomiting, which were generally mild and resolved within 1 week. Few patients discontinued the drug due to side effects.

The ongoing phase III PERSIST-2 trial is exploring pacritinib in patients with low platelet counts due to their disease or therapy. n Disclosure: The study received funding from CTI BioPharma Corp. Dr. Mesa has received honoraria from and served as a consultant or advisor to Novartis and also has received research funding from Celgene, CTI, Gilead Sciences, and Incyte.

Reference 1. Mesa RA, Egyed M, Szoke A, et al: Results of the PERSIST-1 phase III study of pacritinib versus best available therapy in primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia-myelofibrosis. 2015 ASCO Annual Meeting. Abstract LBA7006. Presented May 30, 2015.

ASCOPost.com | JULY 10, 2015

PAGE 13

ASCO Annual Meeting Neuro-oncology

Investigators Update PVS-RIPO Data in Glioblastoma

By Caroline Helwick

A

t the 2015 ASCO Annual Meeting, Annick Desjardins, MD, Associate Professor of Neurology at Duke University Medical Center, presented a brief update on the ongoing study of oncolytic PVS-RIPO in glioblastoma, which now includes 24 patients.1 The median age of enrolled patients is 57, most have a good performance status, all received radiation therapy and temozolomide, and 42% also received bevacizumab (Avastin).

hyperglycemia in three patients and hypophosphatemia, fatigue, pneumonia, skin infection, and a thromboembolic event in one patient each.

“At dose level −1, we are seeing many fewer inflammation issues (such as seizures and weakness) than we saw in other dose cohorts, and efficacy is just

as good,” Dr. Desjardins said.

The investigators started bevacizu­ mab in patients who appear to require continued on page 14

It’s what’s inside that counts.

At dose level −1, we are seeing many fewer inflammation issues than we saw in other dose cohorts, and efficacy is just as good.

—Annick Desjardins, MD

As of May 19, 2015, 11 patients had died. Median survival was 12.5 months, the 6-month survival rate was 82.7%, and the 12-month survival rate was 56%, Dr. Desjardins reported.

Of the 24 patients, 9 have been treated at the optimal dose level, and they are anticipated to have longer survival. Only one has reached the 6-month mark, however, so “it’s too early to tell,” she said.

The survival data for all patients at all dose levels are shown in Table 1 (page 14). The study continues to enroll at “dose level minus 1” (−1).

Adverse Events Most adverse events have been related to secondary inflammatory response and prolonged steroid use, she said. Grade ≥ 3 neurologic adverse events have included hemiparesis in six patients (14.3%) and steroid myopathy, intracranial hemorrhage upon catheter removal, and seizure in one patient each. Grade ≥ 3 hematologic toxicity has included lymphopenia in six patients. Other toxicities include

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1. Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023-1031. ©2015 Foundation Medicine, Inc. Foundation Medicine® and FoundationOne® are registered trademarks.

The ASCO Post | JULY 10, 2015

PAGE 14

ASCO Annual Meeting Plenary Session

Cost of Immunotherapy Projected to Top $1 Million per Patient per Year

By Caroline Helwick

I

f new immunotherapy combinations were administered to the half a million Americans dying of cancer each year, the nation’s price tag for treating them— for just 1 year—could top $174 billion, according to projections by Leonard Saltz, MD, Chief of Gastrointestinal Oncology and Chair of the Pharmacy and Therapeutics Committee at Memorial Sloan Kettering Cancer Center. Dr. Saltz offered his perspective on value in cancer care at the Plenary Session of the 2015 ASCO Annual Meeting.

“We must acknowledge that there must be some upper limit to how much we can, as a society, afford to pay to treat each patient with cancer,” Dr. Saltz said.

tients. As one who worries how we will make them available and minimize disparities, I have a major problem—and that is that these drugs cost too much.”

He cited the current per-mg costs to be $28.78 for nivolumab and $157.46 for ipilimumab; the other anti–PD-1 (programmed cell death protein 1) agent, pembrolizumab (Keytruda), costs $51.79/mg. “To put that into perspective, that’s approximately 4,000 times the cost of gold,” Dr. Saltz said.

In the clinic, therefore, the cost of

year and 589,430 deaths—giving $295,000 worth of drugs to each patient with metastatic disease would cost $173,881,850,000, Dr. Saltz projected.

“That’s $174 billion in 1 year for drugs treating patients with metastatic disease—no adjuvant therapy—for 1 year only,” he emphasized.

Dr. Saltz also questioned the need to use pembrolizumab at a dose of 10 mg/ kg—far higher than its U.S. Food and Drug Administration (FDA)-indicated dose of 2 mg/kg every 2 weeks. The

As a clinician, I want these drugs and others like them to be available for my patients. As one who worries how we will make them available and minimize disparities, I have a major problem—and that is that these drugs cost too much.

Cost-of-Care Crisis Many of the attention-grabbing studies presented at the 2015 ASCO Annual Meeting pertained to immunotherapies, which are being evaluated in a growing number of tumor types. Dr. Saltz pointed out how these exciting new drugs are clearly accentuating the cost-of-care crisis.

As one example, Dr. Saltz focused on the CheckMate 067 trial of nivolumab (Opdivo) plus ipilimumab (Yervoy) in advanced melanoma, presented at the Plenary Session by Jedd ­Wolchok, MD, which yielded a median progression-free survival rate of 11.4 months, compared with 6.9 months for nivolumab alone and 2.9 months for ipilimumab alone.1 “A median progression-free survival of 11.4 months is truly remarkable, for a disease that 5 years ago was thought virtually untreatable,” Dr. Saltz said. “As a clinician, I want these drugs and others like them to be available for my pa-

treating an “average-sized” (80 kg) American patient with the combination of nivolumab plus ipilimumab for advanced melanoma would exceed $295,500. Treatment with nivolumab alone would be $103,220, and ipilimumab alone—to achieve a median remission of less than 3 months—would cost $158,252.

Rounding the cost of treatment up to about $300,000 for the individual patient with a 20% copay, the patient’s responsibility would be approximately $60,000, Dr. Saltz pointed out.

Taking this nationally—with 1.6 million cancer cases expected this

PVS-RIPO Data

Table 1: Dose Escalation, Current Survival Status, and Dose-Limiting Toxicities

—Leonard Saltz, MD

monthly cost for the higher-dose regimen is $83,500, he calculated, and this dose (10 mg/kg every 2 weeks) was evaluated in at least five studies presented at the 2015 ASCO Annual Meeting, he noted.

Single-agent treatment, at this dose, for a 75-kg patient who needs 26 doses per year, generates a per-patient price tag of $1,009,944, Dr. Saltz estimated.

“This is unsustainable,” he said.

Solving the Problem Potential solutions to escalating drug costs have been bandied about for years now, and Dr. Saltz reiterated

them. Two important changes are to allow the FDA, the “gatekeeper,” to consider price in the approval process and to allow the Centers for Medicare and Medicaid Services, as the major purchaser of drugs, to negotiate prices with industry, he said.

Dr. Saltz emphasized that there must be an upper limit to how much society will pay to treat cancer; that discussions of value and cost must be encouraged within industry, government, patients, and “amongst ourselves”; and that alternative payment strategies that do not incentivize on the cost of drugs must be adopted. “There’s a tipping point that we have to be willing to search for,” he said.

Meanwhile, he urged ASCO members to discuss patients’ concerns regarding cost and finances and understand and explore the limitations of their insurance coverage. If the current trend continues, he noted, by 2028, a full 100% of household income will be required to cover the cost of insurance premiums and out-of-pocket costs, he said.

“We can embrace our responsibility to deliver high-value, cost-effective care.

That means choosing wisely, and choosing not to deliver lower-value, cost-ineffective care,” he said. n

Disclosure: Dr. Saltz reported no potential conflicts of interest. Dr. Wolchok is a paid consultant and his institution receives research funding from Bristol-Myers Squibb.

Reference 1. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al: Efficacy and safety results from a phase III trial of nivolumab alone or combined with ipilimumab versus ipilimumab alone in treatment-naive patients with advanced melanoma. 2015 ASCO Annual Meeting. Abstract LBA1. Presented May 31, 2015.

continued from page 13

more than 4 mg/d of dexamethasone to control inflammation. They used 7.5 mg/kg of bevacizumab every 3 weeks, which is much lower than the therapeutic dose. n Disclosure: Dr. Desjardins is a co-owner of the intellectual property related to the technology discussed, for which a patent is pending.

Reference 1. Desjardins A, Sampson JH, Peters KB, et al: Oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma: Optimal dose determination. 2015 ASCO Annual Meeting. Abstract 2068. Presented June 1, 2015.

Dose Level (viral load)

Number of Patients

Survival After PVS-RIPO Infusion*

Dose-Limiting Toxicities

1 (1.0 × 10e8 TCID50)

1 (4.2%)

36+ mo

0

2 (3.3 × 10e8 TCID50)

7 (29.2%)

35+, 11+, 8+, 9, 8, 7, 6 mo

0

3 (1.0 × 10e9 TCID50)

1 (4.2%)

6 mo

0

4 (3.3 × 10e9 TCID50)

2 (8.3%)

23+, 20, 15, 12 mo

0

5 (1.0 × 10e10 TCID50)

4 (16.75)

23+, 20, 15, 12 mo

1 (4.2%)

−1 (5.0 × 10e7 TCID50)

9 (37.5%)

7+, 6+, 5+, 4+, 3+, 2+, 1+, 0.4+, 3 mo

0

* Deceased patients in red. TCID50 = median tissue culture infectious dose. Table courtesy of Desjardins A, et al.1

ASCOPost.com | JULY 10, 2015

PAGE 15

American Society of Gene and Cell Therapy Annual Meeting Neuro-oncology

Poliovirus for Glioblastoma Grabs National Attention

By Caroline Helwick

R

esearchers at The Preston Robert Tisch Brain Tumor Center at Duke University are being barraged by patients wishing to enroll in their clinical trial of an engineered poliovirus for recurrent glioblastoma. This comes as a result of a CBS 60 Minutes interview with lead researcher Matthias ­Gromeier, MD, Associate Professor of Surgery, Molecular Genetics and Microbiology, and Medicine at Duke.

The results he shared engendered hope within the glioblastoma community, and understandably so. When glioblastoma recurs, median survival is 6 to 8 months. Using the engineered poliovirus (PVS-RIPO), Dr. Gromeier and his team have extended survival beyond 3 years in some patients.

“What is remarkable is that we get these types of responses with a single administration of virus without further therapy,” said Dr. Gromeier.

Dr. Gromeier recently discussed the approach at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting in New Orleans.1 He also spoke with The ASCO Post.

What Is PVS-RIPO? PVS-RIPO is a live attenuated, oral serotype 1 poliovirus (Sabin) vaccine that contains a heterologous internal ribosomal entry site from human rhinovirus type 2. The vaccine recognizes nectin-like molecule-5 (CD155), the poliovirus receptor and a confirmed tumor antigen that is widely expressed in solid malignancies.

Dr. Gromeier explained the rationale for this therapy, which has been evaluated

so far in 23 patients, with patients continuing to enroll in the phase I trial. He said that researchers are interested in the poliovirus because of its tropism. Simply put, the poliovirus attacks tumor cells, leading to cell lysis (which does not need to be extensive) and then presentation of tumor antigen from these lysed cells.

“Poliovirus induces a form of cell

Details of Treatment PVS-RIPO is delivered intratumorally via a form of convection-enhanced delivery, which takes advantage of the natural flow of the cerebral spinal fluid and delivers drug by a stereotactically placed catheter directly into the tumor.

Once in the brain, the virus triggers the immune response.

What is remarkable is that we get these types of responses with a single administration of virus without further therapy.

—Matthias Gromeier, MD

death that does not resemble any orchestrated form of demise (such as apoptosis, necrosis, or necroptosis). It’s a highly unusual, highly danger-signaling form of death,” he indicated. “At the same time, it elicits antiviral immunity or interferon response, so the combining of the danger signals and pathogen signals helps to recruit cytotoxic T cells to recognize these tumor antigens.…

What you need is activation of innate antiviral response plus cell killing.”

In its very fast-paced life cycle, the poliovirus behaves more like a toxin than a virus, ultimately producing viral polypeptides that exert a toxic effect.

Events conspire, he believes, “to set up a classic immune effector response against the tumor that we believe is protecting some of our patients durably.”

“The true objective of [convectionenhanced delivery] is to cover vast areas of the brain, but in this case, it’s not what we necessarily need,” he explained. “We just want to inject the virus in a way that the tumor is exposed to some degree, so we deliver 3 mL of the virus over about 6 hours.”

At the Society for Neuro-Oncology Annual Scientific Meeting in Miami this past November, Dr. Gromeier’s team reported phase I dose-finding and safety results on 15 patients.2 Median survival was 15.2 months, and the 12-month survival rate was 70%; 18- and 24-month survival rates were 43.8% and 29.2%, respectively. Serious adverse events included hemiparesis, intracranial hemorrhage at catheter removal, lymphopenia, seizure, and hyperglycemia, as well as

lethargy, headache, diarrhea, paresthesia, and hyperbilirubinemia.

Response and Survival At the ASGCT meeting, Dr. Gromeier elaborated on these outcomes. “We have very good survival and complete radiographic responses,” he said, including complete responses in patients whose tumors could not be completely resected.

“The first patient we treated had a very large tumor excised. She got a single PVS-RIPO infusion, and 2 months later the tumor was significantly enlarged. The [magnetic resonance imaging (MRI) scans] looked awful, but the patient was doing fine,” he recalled. “By 6 months, we saw glial scarring. By 11 months, the tumor had significantly shrunk. And by a year or so, the tumor was gone.”

He added, “Three years out, the patient is tumor-free, she’s working, she’s completely fine. She has to take anticonvulsants for the rest of her life, but otherwise you would never know this patient had a brain tumor.”

Another patient’s MRI at 3 years is essentially normal. “He recently delivered a half-hour talk at a fundraiser.

He’s 74 now, and you would not know that this man had a recurrent [glioblastoma],” he reported.

Lessons Learned “So what can we learn from our trial?

We started out really, really positive, and then things got difficult,” he noted.

At the time of the ASGCT meeting, two patients were alive past 3 years and another past 2 years, all of whom were continued on page 16

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The ASCO Post | JULY 10, 2015

PAGE 16

American Society of Gene and Cell Therapy Annual Meeting Poliovirus for Glioblastoma continued from page 15

complete responders to the infusion and not steroid-dependent. On the other hand, patients on high-dose steroids before PVS-RIPO treatment had worse outcomes. This led the researchers to look at the effect of steroids on the treatment.

By observing differences related to prior steroid use and by realizing they created steroid dependency when using the high doses of PVS-RIPO, the researchers concluded that both steroid use and dose of PVS-RIPO were very important to outcomes. They amended their enrollment criteria to exclude patients on high-dose steroids and lowered the treatment dose.

“We can’t leave out steroids entirely because we use a neurosurgical procedure to administer the virus, and the surgeons must give some steroid for that to protect the brain from swelling,” he explained.

“But we try to taper the patient off within a week or so. We believe that high doses of steroids are inappropriate because they are too immunosuppressive.”

The investigators are now treating with “dose level minus 1,” which is 5 × 10e7 (50 million infectious units) and half the initial starting dose. They have been able to successfully taper steroids in eight patients treated with this dose.

Dr. Gromeier emphasized in the interview that it is rare to settle on the lowest dose in a dose-finding study. “In cancer, it’s always ‘more is better.’ But the immune system does not work on dose. The reason the high dose doesn’t work is not just due to toxicity. I believe we get the wrong kind of response.”

On the lower dose, he reported, “patients are doing well on this therapy, so we just keep on watching what’s happening.” He acknowledged that one patient died, “which reminds us this is a terrifying disease.”

aired, he said, “We have received thousands of calls, and we answer all of them.” All patients are considered; however, given that this is a phase I safety study, the eligibility criteria are quite narrow, he indicated.

While the researchers are very encouraged by preliminary data, they ac-

knowledge they need to wait at least another year and a half “to be confident.” n

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

References 1. Gromeier M: Cancer Immunotherapy: Cutting Edge – Clinical. Scientific Sym-

posium. 2015 American Society of Gene and Cell Therapy Annual Meeting. Presented May 14, 2015.

2. Desjardins A, Sampson J, Peters K, et al: Final results of a phase 1 trial of an oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM). 2014 Society for Neuro-Oncology Annual Scientific Meeting. Abstract AT-21.

Possible Mechanism As a virologist, Dr. Gromeier attributes the therapeutic benefit to eliciting an innate human response to polio, setting up a classic effector immune response against the tumor, stemming from a complex interplay of activated macrophages, dendritic cells, cytokines, and “superfast” proinflammatory cell killing.

“I think the most damaging proposal in the oncolytic virus field has been that tumors lack innate immune responses.

I don’t believe that’s true. Plenty of evidence says the opposite. I actually believe the innate response in the tumors themselves plays a very important role in what we’re doing,” he maintained.

Since his interview on 60 Minutes

Learn more about the unmet needs in EGFRm+ NSCLC at targetEGFR.com

ASCOPost.com | JULY 10, 2015

PAGE 17

American Society of Gene and Cell Therapy Annual Meeting Dermatologic Oncology

Oncolytic Immunotherapy in Melanoma: It’s Not All About PD-1

By Caroline Helwick

T

he benefit from immune-directed therapies in patients with advanced melanoma is not limited to the exploding field of checkpoint inhibi-

tors. According to Robert Andtbacka, MD, Associate Professor of Surgical Oncology, at the Huntsman Cancer Institute at the University of Utah, Salt

Lake City, intralesional oncolytic therapy also provides benefit, which can be profound for some patients.

“Oncolytic immunotherapies rep-

We want to change the face of EGFR-targeted therapy Cutaneous toxicities are caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2

resent a new important strategy in the treatment of cancer,” he said at the American Society of Gene and Cell Therapy, where he described several emerging approaches now in phase II and III clinical trials. Dr. Andtbacka has been directly involved in many of these studies.

Oncolytic immunotherapies work not only through a lytic effect but by activating the entire immune system, “not just in lesions we treat, but elsewhere in the body.” He noted that intralesional therapies are tailor-made for local and in-transit cutaneous lesions and the accessible lymph nodes of melanoma.

Intralesional oncolytic immunotherapies aim to achieve a local ablative effect as well as a systemic immune effect, the so-called bystander response. They may also help to prevent the development of visceral metastases, if given early, he predicted. Durable responses with limited toxicity are additional goals.

Types of Intralesional Agents

Inhibition of wild-type and mutant EGFR in non–small cell lung cancer (NSCLC)

Cutaneous toxicities can be dose-limiting

Normal, or wild-type, EGFR is highly expressed on epithelial cells in the skin, liver, and gastrointestinal tract.3-5 Current EGFR tyrosine kinase inhibitors (TKIs) target not only the oncogenic mutant forms of EGFR, but also wild-type EGFR, which may lead to cutaneous toxicities including rash, stomatitis, and paronychia.1,2,6-8

The symptoms and psychosocial impact of cutaneous toxicities can negatively affect both patient quality of life and patient compliance.11,12 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.7,8

90% of patients treated with approved EGFR TKIs experience rash7,8

The future of EGFR inhibition

The skin is dependent on wild-type EGFR signaling for normal growth and differentiation.1,9,10 Druginduced inhibition of wild-type EGFR disrupts its normal function and can cause cutaneous inflammation and injury. This accounts for the high incidence of cutaneous toxicities associated with EGFR TKIs.1,9

Strategies that eliminate inhibition of wild-type EGFR may be most effective at mitigating cutaneous toxicities and maintaining optimal dosing.9 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

Clovis Oncology is leading the fight

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621.

2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist.

2005;10(5):345-356. 3. Harandi A et al. Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. J Clin Oncol. 2009;2009:567486. doi:10.1155/2009/567486. 4. Natarajan A et al. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci U S A. 2007;104(43):17081-17086. 5. Tissue atlas: EGFR. The Human Protein Atlas website. http://www.proteinatlas.org /ENSG00000146648-EGFR/tissue. Accessed February 17, 2015. 6. Antonicelli A et al. EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci. 2013;10(3):320-330. 7. Tarceva [package insert]. Northbrook, IL: Astellas Pharma US Inc; 2014. 8. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014.

9. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803-812. 10. Melosky B et al. Management of common toxicities in metastatic NSCLC related to anti-lung cancer therapies with EGFR–TKIs. Front Oncol. 2014;4:238. doi:10.3389/fonc.2014.00238. 11. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurs. 2011;15(1):88-96. 12. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci .nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed February 2, 2015.

Copyright © 2015 Clovis Oncology. DARO-101(1) 3/15

A dozen or so types of intralesional agents are in development: antibodies, cytokines, glycolipids, microspheres, plasmids, small molecules, radiosensitizers, vaccines, viruses, xeno-antigen cell lines, and combinations of these agents. Most are early in the pipeline, but data from phase II and III trials have become available for some of them.

In his talk, Dr. Andtbacka focused on talimogene laherparepvec (T-VEC; a modified herpes simplex type 1 virus), plasmid interleukin-12 (IL-12) electroporation, PV-10 (rose bengal), and coxsackievirus A21 (CVA21), but they are just a few of the many agents in the pipeline.

T-VEC: A Promising Compound In April 2015, the U.S. Food and Drug Administration’s (FDA’s) Oncologic Drugs Advisory Committee (ODAC) and Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) voted to recommend approval of T-VEC for advanced melanoma. The FDA is expected to make a final decision in October.

When T-VEC is injected into dermal, subcutaneous, and intralymphatic lesions, the virus is replicated in the tumor cell, which is followed by lysis of the cell, exposure of tumor-specific antigen to the immune system, activation of the immune system, and immune activation continued on page 18

The ASCO Post | JULY 10, 2015

PAGE 18

American Society of Gene and Cell Therapy Annual Meeting Immunotherapy in Melanoma continued from page 17

against melanoma at distant sites.

In the phase III OPTiM trial, 436 patients had lesions injected with either T-VEC or granulocyte macrophage colony-stimulating factor (GM-CSF). The primary endpoint, durable response (continuous response for ≥ 6 months), was achieved by 16.3% with T-VEC vs 2.1% with the control, a 14.1% difference (P < .0001).1 “This durable response rate is an unusual endpoint and very stringent,” he noted. “For comparison, if we had used this in trials of BRAF inhibitors, the endpoint would not have been achieved.”

Among the injected lesions, 64% responded, of which 47% were complete responses to T-VEC, as did 34% of noninjected (nonvisceral) lesions. Two-thirds had responses lasting at least 1 year. Patients who responded best were those with earlier stage disease (IIIB/C or IV M1a vs IV M1b/c), for whom median overall survival was 41 months with T-VEC vs 21 months with the control (P < .001).

T-VEC also reduced the development of visceral metastases, boding well for the use of this agent earlier in the disease. Therefore, a phase II neoadjuvant study is evaluating T-VEC in 150 resect-

with the combination compared with what is seen with single agents.

“This study shows we can use these agents in combination, which is ultimately what we need to think about,” said Dr. Andtbacka. “There are a number of treatments moving forward in combination.”

Other Intralesional Immunotherapies Intratumoral electroporation is a means of enhancing cell permeability—via an electrical current delivered into the tumor—which facilitates entry of plasmid IL-12. In a phase II study of 85 lesions, 53% of injected sites responded (with 31% stabilized), as did 59% of uninjected lesions.3 A randomized clinical trial is underway.

PV-10 is a fluorescent compound that accumulates in the lysosome of cancer cells and leads to acute autophagy, lysis of cells, and exposure of antigenic tumor fragments to antigen-presenting cells. In a phase II study of 80 patients, 51% of target lesions responded, as did 33% of nontarget lesions. The median progression-free survival was 11.4 months in responders and 4.1 months in nonresponders.4 CVA21 gains access to cells by binding to the intercellular adhesion molecule 1 (ICAM-1) protein expressed by

Oncolytic immunotherapies represent a new important strategy in the treatment of cancer.

—Robert Andtbacka, MD

able stage IIIB/C/IV M1a patients. In this study, patients will be randomized 1:1 to either surgery (the current standard of care) or T-VEC for 3 months followed by surgery. The primary endpoint is 2-year recurrence-free survival.

A phase Ib study has also evaluated T-VEC in combination with ipilimumab (Yervoy) in previously untreated stage III/IV patients, showing responses in 56% of patients and complete responses in 33%.2 Toxicity was not increased

the cancer cell. Within the cell, the virus replicates, tumor cells are lysed, and the immune system is activated.

In the phase II CALM study,5 in which patients received multiple injections of CVA21 over 48 weeks, more than 38% of patients were progressionfree at 6 months, meeting the study’s primary endpoint. Responses were observed in both localized disease and visceral metastases, and there were no grade 3/4 toxicities.

Fig. 1: CALM Phase II Trial—Local-injected lesion responses in a male with cutaneous melanoma on the chest. Left: Baseline photos; Right: Day 127– histopathologic analysis confirmed complete melanoma regression. Photos courtesy of Andtbacka RH, et al.1

“After multiple injections, cutaneous lesions are flattened out. We see pigmentation but no melanoma left in the lesion,” observed Dr. Andtbacka (see Fig. 1).

Patients often develop neutralizing antibodies to the virus, “but even in the presence of this, we saw responses, which indicates these responses are likely immune-mediated and not just working by a direct lytic effect on the tumor,” he added. Based on the biopsies of lesions before and after injection, he believes CVA21 is capable of “rebooting” the immune system after patients stop responding to other treatments. n

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

References 1. Andtbacka RH, Kaufman HL, Collichio F, et al: Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol.

May 26, 2015 (early release online).

2. Puzanov I, Milhem MM, Andtbacka RHI, et al: Primary analysis of the phase

1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec and ipilimumab in previously untreated, unresected stage IIIB-IV melanoma. 2014 ASCO Annual Meeting. Abstract 9029.

Presented June 2, 2014.

3. Daud A, Algazi AP, Ashworth MT, et al: Systemic antitumor effect and clinical response in a phase 2 trial of intratumoral electroporation of plasmid interleukin-12 in patients with advanced melanoma. 2014 ASCO Annual Meeting. Abstract 9025.

Presented June 2, 2014.

4. Thompson JF, Agarwala SS, Smithers BM, et al: Phase 2 study of intralesional PV10 in refractory metastatic melanoma. Ann Surg Oncol. October 28, 2014 (early release online).

5. Andtbacka RH, Curti B, Kaufman H, et al: CALM study: A phase II study of a novel oncolytic immunotherapeutic agent, CVA21, delivered intratumorally in patients with advanced malignant melanoma.

2015 Society of Surgical Oncology Annual Cancer Symposium. Abstract 2093535.

Presented March 27, 2015.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | JULY 10, 2015

PAGE 19

Announcements

Five Presidential Appointees Named to National Cancer Advisory Board

P

resident Barack Obama recently announced his intent to nominate the following individuals to the National Cancer Advisory Board: ­Peter C. Adamson, MD; Yuan Chang, MD; Timothy J. Ley, MD; Deborah

­ atkins Bruner, RN, PhD, FAAN; W and Max S. Wicha, MD.

the Children’s Hospital of Philadelphia, a position he has held since 1999. Dr. Adamson has been Chair of the Children’s Oncology Group, supported by the National Cancer Insti-

Peter C. Adamson, MD Dr. Adamson is Attending Physician in the Division of Oncology at

GAZYVA® (obinutuzumab)

Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information.

WARNING: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)].

• Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)].

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive.

Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

5.2 Progressive Multifocal Leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations.

Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture.

Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

Premedicate patients with acetaminophen, antihistamine and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

continued on page 20

Peter C. Adamson, MD

For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy.

For patients with Grade 1, 2 or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)].

For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction.

Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication.

The data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy.

Table 3 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1) Adverse Reactions (MedDRAa) System Organ Class

5.4 Tumor Lysis Syndrome Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion.

Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

Injury, poisoning, and procedural complications Infusion 69 21 0 0 reactions

11

8

4

Anemia

12

5

10

4

Leukopenia

7

5

0

0

Infections and infestations Urinary tract 6 2 infection

3

<1

Musculoskeletal and connective tissue disorder Back pain 5 <1 2 0

Table 4 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) Adverse Reactions (MedDRAa) System Organ Class

5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 10% of patients in the trial. In 4% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion.

Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA.

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

All Grades All Grades Grades % 3–4 % Grades % 3–4 %

Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary.

Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

Injury, poisoning and procedural complications Infusion 66 20 38 4 reactions Blood and lymphatic system disordersb Neutropenia 38 33 32

28

Thrombocytopenia 14

10

7

3

Leukopenia

4

2

<1

6

General disorders and administration site conditions Pyrexia 9 <1 7 <1

5.8 Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

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

16

Thrombocytopenia 15

Respiratory, thoracic, and mediastinal disorders Cough 10 0 7 <1

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.

Blood and lymphatic system disordersb Neutropenia 41 35 18

General disorders and administration site conditions Pyrexia 10 <1 7 0

5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)] • Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)]

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 %

5.5 Infections Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy.

Fatal infections have been reported with GAZYVA. Do not administer GAZYVA to patients with an active infection.

Patients with a history of recurring or chronic infections may be at increased risk of infection.

Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

GAZYVA + Chlorambucil n = 241

Gastrointestinal disorders Diarrhea 10 2

8

<1

Constipation

5

0

8

0

Infections and infestations Nasopharyngitis 6 <1 Urinary tract infection

5

1

3

0

2

<1

a

MedDRA coded adverse reactions as reported by investigators.

b

Adverse events reported under “Blood and lymphatic system disorders” reflect those reported by investigator as clinically significant.

The ASCO Post | JULY 10, 2015

PAGE 20

Announcements Presidential Appointees

Yuan Chang, MD

continued from page 19

Dr. Chang is currently Professor of Pathology at the University of Pittsburgh, a position she has held since 2002. Dr. Chang has been a Distinguished Professor of Pathology since 2012 and is the University of Pittsburgh Cancer Institute Chair of Cancer Virolo-

tute, since 2010. He began his pediatric career as a resident at Children’s Hospital from 1984 to 1987. Dr. Adamson received his MD degree from Cornell University.

Yuan Chang, MD

Table 5 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1) GAZYVA + Chlorambucil n = 241

Investigations

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia

78

48

53

27

Lymphopenia

80

40

9

3

Leukopenia

84

37

12

<1

Chemistry Hypocalcemia

38

3

33

2

Hyperkalemia

33

5

18

3

Hyponatremia

30

8

12

3

AST (SGOT increased)

29

1

16

0

Creatinine increased

30

<1

20

2

ALT (SGPT increased)

27

2

16

0

Hypoalbuminemia

23

<1

15

<1

Alkaline phosphatase 18 increased

0

11

0

Hypokalemia

1

5

<1

15

Table 6 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) Investigations

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia

76

46

69

41

Lymphopenia

80

39

50

16

Leukopenia

16

84

35

62

Thrombocytopenia 48

13

40

8

Anemia

39

10

37

10

Chemistry Hypocalcemia

37

3

32

<1

Hyperkalemia

14

1

10

<1

Hyponatremia

26

7

18

2

AST 27 (SGOT increased)

2

21

<1

ALT 28 (SGPT increased)

2

21

1

Hypoalbuminemia 23

<1

16

<1

Infusion Reactions: The incidence of infusion reactions was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 140 patients for whom these mitigation measures were implemented, 74 patients (53%) experienced a reaction with the first 1000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter [see Dosage and Administration (2)].

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 38% in the GAZYVA treated arm and 32% in the rituximab treated arm, with the incidence of serious adverse events being 1% and < 1%, respectively (Table 4). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the rituximab treated arm.

(7%), with the incidence of Grade 3–4 events being 10% and 3%, respectively (Table 4). The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle were 11% in the GAZYVA and 3% in the rituximab treated arms, with Grade 3–4 rates being 8% and 2%, respectively. Four percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion).

The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms, with 3 in the rituximab and 4 in the GAZYVA treated arms. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the rituximab treated arm.

Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders (all events from the System Organ Class), including pain, have been reported in the GAZYVA treated arm with higher incidence than in the rituximab treated arm (18% vs. 15%).

Liver Enzyme Elevations: Hepatic enzyme elevations have occurred in patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT, and ALP). The events occurred most frequently within 24-48 hours of the first infusion. In some patients, elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome. In the pivotal study, there was no clinically meaningful difference in overall hepatotoxicity adverse events between all arms (4% of patients in the GAZYVA treated arm). Medications commonly used to prevent infusion reactions (e.g., acetaminophen) may also be implicated in these events. Monitor liver function tests during treatment, especially during the first cycle. Consider treatment interruption or discontinuation for hepatotoxicity.

6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Of the GAZYVA treated patients, 7% (18/271) tested positive for anti-GAZYVA antibodies at one or more time points. Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known.

6.3 Additional Clinical Trial Experience Worsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Mothers who have been exposed to GAZYVA during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers.

Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on day 28 postpartum, obinutuzumab was detected in offspring, and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Infection: The incidence of infections was similar between GAZYVA and rituximab treated arms. Thirty-eight percent of patients in the GAZYVA treated arm and 37% in the rituximab treated arm experienced an infection, with Grade 3–4 rates being 11% and 13%, respectively. Fatal events were reported in 1% of patients in both arms.

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

Thrombocytopenia: The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm (14%) compared to the rituximab treated arm

8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established.

8.5 Geriatric Use Of 336 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 273 patients (81%) were ≥ 65 years of age and 156 patients (46%) were ≥ 75 years of age. The median age was 74 years. Of the 156 patients ≥ 75 years of age, 72 (46%) experienced serious adverse events and 11 (7%) experienced adverse events leading to death. For 180 patients < 75 years of age, 59 (33%) experienced a serious adverse event and 4 (2%) an adverse event leading to death. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)].

8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) ≥ 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CrCl < 30 mL/min [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment.

10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy.

gy. Dr. Chang received her MD from the University of Utah College of Medicine.

Timothy J. Ley, MD

Timothy J. Ley, MD Dr. Ley is Director of the Stem Cell Biology Section in the Division of Oncology at Washington University School of Medicine, a position he has held since 2000. Dr. Ley has also served as Associate Director for Cancer Genomics at The Genome Institute at Washington University since 2008. Dr. Ley received his MD from Washington University School of Medicine.

17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

• Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

• Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)].

• New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)].

Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6 and 5.7) and Adverse Reactions (6.1)].

• Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)].

• Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

GAZYVA® [obinutuzumab]

Initial US Approval: 2013

Manufactured by: Genentech, Inc.

Code Revision Date: December 2014

A Member of the Roche Group South San Francisco, CA 94080-4990

GAZYVA is a registered trademark of Genentech, Inc.

U.S. License No: 1048

GAZ/011615/0009 1/15

Deborah Watkins Bruner, RN, PhD, FAAN

Deborah Watkins Bruner, RN, PhD, FAAN Dr. Watkins Bruner is the Robert W. Woodruff Professor of Nursing at the Nell Hodgson Woodruff School of Nursing, Professor of Radiation Oncology, and Associate Director for Outcomes Research at the Winship Cancer Institute of Emory University, positions she has held since 2011. Dr. Bruner received her PhD from the University of Pennsylvania.

© 2015 Genentech, Inc.

Max S. Wicha, MD

Max S. Wicha, MD Dr. Wicha is the Madeline and Sidney Forbes Professor of Oncology at the University of Michigan Comprehensive Cancer Center, a position he has held since April 2015. Dr. Wicha received his MD from Stanford University School of Medicine. n

ASCOPost.com | JULY 10, 2015

PAGE 21

National Cancer Policy Forum Breast Cancer

Assessing and Improving Imaging Interpretation in Breast Cancer Screening

By Margot J. Fromer

T

he quality of mammography images has markedly improved over the past few decades. However, the quality of the interpretation of mammograms remains variable. That said, more than 38 million mammograms are performed annually in the United States.

Diana Buist, PhD

So said Diana Buist, PhD, Senior Scientific Investigator, Group Health Breast Cancer Surveillance, as she introduced a workshop hosted by the National Cancer Policy Forum and the American Cancer Society.

What Could Be Improved Congress authorized the Mammography Quality Standards Act (MQSA) in 1992, but image quality and interpretation remain problematic. Both depend on many factors and are difficult to measure. Inconsistency, however, is a constant. Therefore, in preparation for reauthorization of MQSA, Congress commissioned a study from the Institute of Medicine (IOM) in 2005 to determine what could be done to increase accuracy and whether current regulations should be modified.

IOM also was asked to consider access to mammography services and to identify what would ensure safe and effective use of other screening and diagnostic tools.

The Institute made recommendations about medical audits, centers of excellence, continuing medical education, reader volume, double reading, computer-aided detection, state and federal regulations, inspections and enforcement, data analysis, workforce, and accreditation for nonmammography breast imaging methods.

Dr. Buist said that since publication of the 2005 IOM report, Improving Breast Imaging Quality Standards,1 there has been a substantial body of research on factors that influence interpretation, including minimum volume needed for high quality, identification of radiologists who perform below par, and whether live instructors or selfpaced methods are better at improving performance.

Part of the push for improvement is the National Mammography Database, a registry established in 2009 that allows facilities and physicians to monitor and improve quality using standardized measures consistent with the Breast Imaging Reporting and Data System (BIRADS). It currently has 275 registered sites, 162 of which contribute data from more than 9 million exams.

“This provides good representation across the country and across practice types and locations,” said Carl D’Orsi, MD, Director of Breast Imaging Research, Emory Healthcare. The National Mammography Database is automated, and data are sent to it directly. It now collects only mammography data but will expand to include ultrasound and magnetic resonance imaging (MRI) later this year.

Unlike the National Cancer Institute–funded Breast Cancer Surveillance Consortium, the National Mam-

Breast Imaging Reporting and Data System (BI-RADS)

T

he Breast Imaging Reporting and Data System (BI-RADS) is a standardized system to describe mammogram findings and results.

Developed by the American College of Radiology (ACR), results of mammograms are sorted into categories numbered 0 through 6 with interpretation as follows: Category 0: Additional imaging evaluation and/or comparison to prior mammograms is needed.

Category 1: Negative.

Category 2: Benign (noncancerous) finding.

Category 3: Probably benign finding—Follow-up in a short time frame is suggested.

Category 4: Suspicious abnormality—Biopsy should be considered.

Category 5: Highly suggestive of malignancy—Appropriate action should be taken.

Category 6: Known biopsy-proven malignancy—Appropriate action should be taken. n

mography Database does not have information on missed cancers, limiting its ability to effectively evaluate performance and safety.

Medical Audits Etta D. Pisano, MD, Dean Emerita and Distinguished University Professor, Medical University of South Carolina, noted that the required elements of an MQSA medical audit in 2005 included: • All mammograms interpreted as positive, or BI-RADS 4 or 5 • Follow-up of all positive m ­ ammograms • All biopsy results • Correlation of pathology results with final assessment • An interpreting physician for each case • Annual analysis of results and sharing them with the interpreting physician and the entire facility

A positive screening mammogram, he said, has an assessment of BI-RADS 0, 3, 4, or 5, as does a positive ultrasound. “Since the number of images and parameters for either a screening or diagnostic MRI are the same, the definition of a positive screen and diagnostic exam is the same. However, if the screening exam includes additional images [eg, a 90-degree lateral on a screening mammogram or orthogonal images of a cyst on a screening ultrasound], this too is positive.”

Dr. Pisano noted that some changes were made in the revised MQSA audit, but most of IOM’s suggestions were not implemented. Despite the 2005 IOM recommendations, the revised MQSA did not mandate collection of patient characteristics and tumor staging, establishment of a statistical center to analyze data and provide feedback to

Digital mammography makes centralized interpretation of screening mammograms feasible but at the same time less workable for diagnostic evaluation, where a radiologist should be present.

—Barbara Monsees, MD

In addition, said Dr. D’Orsi, a complete audit should include sensitivity (percent of cancers detected by mammography among all cancers that were found in the women receiving screening mammograms), specificity (percent of negative cases interpreted on a mammogram among all cases when women received screening), recall rate (screens given additional imaging), abnormal interpretation rate (positive exams), accuracy (cancer and negative cases identified from all cases), positive predictive value type 1 (screening exams with a positive interpretation and cancer within a year), positive predictive value type 2 (positive exams with a biopsy recommended and cancer within a year), positive predictive value type 3 (biopsies done with a positive interpretation and a known biopsy of cancer in a year), cancer detection rate (number of cancers detected per thousand women), and percent of minimal cancer (less than 1 cm, or ductal carcinoma in situ).

When any of these parameters are unknown, surrogate markers may need to be used for the audit.

interpreting physicians and to report aggregate data to the public, nor development of pay-for-performance incentives for participation in audits and meeting performance criteria—although some payers have implemented pay-for-performance mammography metrics.

Mammography Challenges Barbara Monsees, MD, Emerita Chief, Breast Imaging Section, Washington University School of Medicine, said that it’s not easy to achieve high-quality mammography. She asked, “How do we ensure broad access? What do patients need to understand about new technologies? How does supplemental screening fit in? Finally, how do state laws mandate notification about breast density, and how does this change expectations and outcome tracking?”

Disparities in performance of and access to screening lead to disparities in outcomes, said Tracy O ­ nega, PhD, Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth. For example, 12.6% of white continued on page 22

The ASCO Post | JULY 10, 2015

PAGE 22

National Cancer Policy Forum Breast Cancer Screening continued from page 21

women travel more than 30 minutes to the closest mammography center, 6.4% of black women spend that much time, but 39.6% of Native American women do. In urban areas, only 0.5% of women travel more than a half-hour, but in rural areas, that figure is 27.9%.

The percentages of women over age 40 who have had a mammogram within the past 2 years are 75.4% of whites, 78.6% of blacks, and 63.9% of Native Americans. When white women get breast cancer, 7.6% have stage III or IV at diagnosis, whereas in black women it is 11.2%. Breast cancer mortality had a similar ratio: 22.7% for whites and 30.8% for blacks. Morbidity and mortality rates were not available for Native Americans.

“Geography does not seem to affect access to mammography, but it may limit other breast services,” said Dr. Onega. “Moreover, at facilities that serve vulnerable populations, screening mammography had the same sensitivity as other facilities, but specificity was significantly higher. In diagnostic mammograms, the false-positive rates were much higher at facilities that serve vulnerable women.”

MQSA audit requirements and the way BI-RADS addresses them will have an effect on outcome. For example, what tools should be used, what are appropriate audit measures, and how often should data be reviewed? What are reasonable goals for recall rates, detection rates, and tumor size and stage? Are there reasonable tradeoffs for sensitivity and specificity, and if so, what are they?

These challenges are complicated by the fact that breast imaging includes both screening and diagnostic mammography, ultrasound, MRI, imageguided needle biopsy, and other modalities. “Expectations are high,” said Dr. Monsees, “and medicolegal implications can be an issue. Variability in interpretation is a problem, but double reading is not feasible even though it is often used in other countries. More modalities and procedures can help with patient management, but they are time consuming and expensive.”

Overall, however, mammography has improved. Technologists have learned how to produce better images

with good compression and positioning. Digital mammography means that technique is less of a factor because of wider recording latitude and elimination of film processors. Quality control is easier and more streamlined, and there are fewer lost exams.

More and more radiologists do only breast imaging, although some general radiologists interpret screening mammograms or perform diagnostic workups, including breast ultrasound. “Digital mammography makes centralized interpretation of screening mammograms feasible but at the same time less workable for diagnostic evaluation, where a radiologist should be present,” said Dr. Monsees.

Training, Experience, and Performance Dr. Buist said that interpretation variability is due to patient factors, practice and facility characteristics, and radiologist training, years of experience, and volume. “Volume requirements differ greatly across countries, as do quality standards,” she said. “In the United States, we have demonstrated poorer performance for radiologists with low interpretive volume, leading to higher false-positive rates, lower cancer detection, and lower sensitivity.”

The most important finding in the United States is improved screening and diagnostic interpretive performance for

Geography does not seem to affect access to mammography, but it may limit other breast services.

—Tracy Onega, PhD

Dr. Onega added that access to mammography is generally good, but the mammography workforce (radiologists and technologists) is not standardized, and quality varies with practices.

Dr. Monsees said that use of computer-aided detection during screening mammography among Medicare beneficiaries is a good news–bad news story, leading to an increased incidence of ductal carcinoma in situ, diagnosis of invasive breast cancer at earlier stages, and increased diagnostic testing among women without breast cancer.

Teleradiology, now 67% of the telemedicine market, also is inconsistent, said Dr. Onega. Whereas local access emphasizes machines and technicians, teleradiology separates interpretation from physical location. Mammography readers could increase volume, but it remains to be seen to what extent volume has a relationship with outcome.

She added that mammography misses about 20% of breast cancers, but digital breast tomosynthesis seems to increase detection and reduce recall.

radiologists who interpret some proportion of diagnostic examinations and also for radiologists who interpret some of their own recalled screening exams.

Diana Miglioretti, PhD, Dean’s Professor in Biostatistics, Department of Public Health Sciences, University of California Davis, said that 18% of radiologists fall into the low-performance range in sensitivity, 48% in specificity, 49% in recall rate, and 38% in positive predictive value type 1 (ie, with abnormal findings at screening). She added that most radiologists are in the low range for at least one measure of competence, and many interpret few mammograms associated with a cancer diagnosis.

Patricia A. Carney, PhD, Professor of Family Medicine and of Public Health & Preventive Medicine, Oregon Health & Science University, concurred. “There is significant variability in the interpretive acumen of practicing radiologists: 75% to 95% for sensitivity and 83% to 98.5% for specificity.”

Dr. Buist suggested that consideration should be given to increasing mini-

Patricia A. Carney, PhD

mum interpretation volumes, including diagnostic exams, which should be a proportion of total volume. She also thinks radiologists should be required to perform a minimum number of diagnostic workups resulting from their own recalls.

Radiology Technologists Louise M. Henderson, PhD, Assistant Professor, Department of Radiology, University of North Carolina, Chapel Hill, said, “Mammograms are interpreted by radiologists but performed by technologists who are responsible for image quality.”

The American Registry of Radiologic Technologists (ARRT) tests, certifies, and registers the more than 250,000 technologists and awards the Registered Technologist designation. Even though ARRT provides continuing education and reregisters technologists every year, certification is voluntary and is not the same as state licensure.

“Technologists have a significant impact on mammography performance, specifically recall rate, sensitivity, specificity, [positive predictive value], and cancer detection rate,” said Dr. Henderson. They also can serve as double readers, although this is more common in Europe than in the United States. Where they do serve as such for screening mammograms, cancer detection rates increase without significantly increasing recall or falsepositive rates. n

Disclosure: Drs. Buist, D’Orsi, Pisano, Monsees, Onega, Miglioretti, Carney, and Henderson reported no potential conflicts of interest.

Reference 1. Institute of Medicine: Improving Breast Imaging Quality Standards. May 23, 2005. Available at http://www.iom.edu/Reports/2005/Improving-Breast-Imaging-Quality-Standards.aspx. Accessed June 22, 2015.

Visit The ASCO Post website at ASCOPost.com

Pediatric Oncology Research –

Funding Available!

Introduction

The Pediatric Oncology community has invested a major effort over many years to collect and analyze long-term data in the pediatric population. Bristol-Myers Squibb seeks to fund research for Pediatric Oncology investigators to further the surveillance of pediatric/ adolescent/young adult patients treated with targeted agents and Immunotherapy to assess for short- and long-term adverse events.

Program Goals

Application Process

In 2015, the Pediatric Oncology Research Program seeks to:

» To submit an application, visit: www.bms.com/israpplications

» Support research to further strengthen the science and knowledge of Pediatric Oncology

• Click on Pediatric Oncology Research Funding

» Support the development of future clinical researchers

• Set up an ISR login

• Select Apply • Complete application

» M.D. pediatric oncology fellows or investigators

» To be considered, completed application must be submitted through the website by 5 P.M. EST on July 31st, 2015

» Desire to enhance knowledge within the field of Pediatric Oncology

» For questions regarding this program, contact Michael Trigg at Michael.Trigg@bms.com

Eligibility Criteria

» Faculty member identified to serve as project mentor at the applicant’s institution

Enrollment and Funding » $50,000 per year will be funded to prioritized proposals for up to 3 years. No indirect costs will be provided.

© 2015 Bristol-Myers Squibb

All support for Fellows Research Training Program Grants is awarded at the sole discretion of Bristol-Myers Squibb based on the above and other criteria that Bristol-Myers Squibb considers applicable to research grants.

ONCUS15UB00500-01-01 05/15

The ASCO Post | JULY 10, 2015

PAGE 24

Journal Spotlight Genitourinary Oncology

16-Gene Assay Recurrence Score Predicts Recurrence After Surgery for Localized Renal Cell Carcinoma

By Matthew Stenger

I

n a study reported in The Lancet Oncology, Brian Rini, MD, of the Cleveland Clinic Taussig Cancer Institute, and colleagues developed a 16gene assay and recurrence score that predicted postoperative outcome in patients with stage I to III clear cell renal cell carcinoma.1

Development Phase In the development phase, examination of the association between expression of 732 genes measured by reverse transcription–polymerase chain reaction and clinical outcome in 942 patients with stage I to III clear cell renal cell carcinoma who had undergone nephrectomy at the Cleveland Clinic yielded 516 genes that were associated with a recurrence-free interval.

In this population, 63% of patients were male; the median age was 62 years (26% ≥ 70 years); 58% had radical surgery; 49% had a tumor size ≤ 4 cm; stage was I in 68%, II in 10%, and III in 22%; necrosis was present in 17%; Fuhrman grade was 1 in 0.4%, 2 in 56%, 3 in 35%, and 4 in 9%; 0.5% had positive nodes; and 23% had recurrence.

Of the 516 genes, 11 were selected by additional statistical analyses and were combined with 5 reference genes, with a recurrence score (0–100) algorithm being developed. The genes included in the assay consisted of those involved in vascular processes (APOLD1, EDNRB, NOS3, PPAP2B), cell growth/division (EIF4EBP1, TUBB2A, LMNB1), immune response (CEACAM1, CX3CL1, CCL5), and inflammation (IL-6) as well as the reference genes (AAMP, ARF1, ATP5E, GPX1, RPLP1).

Validation Phase In the validation phase, the recurrence score was investigated in a French cohort

of 626 patients. In this population, 71% of patients were male (P = .002 vs development cohort); the median age was 61 years (29% ≥ 70 years); 64% had radical surgery (P = .01); 46% had a tumor size ≤ 4 cm; stage was I in 64%, II in 9%, and III in 28% (P = .03); necrosis was present in 33% (P < .0001); Fuhrman grade was 1 in 4%, 2 in 30%, 3 in 46%, and 4 in 20% (P < .0001); 0.6% had positive nodes; and 16% had recurrence.

Risk Prediction On univariate analysis, the continuous recurrence score (median = 37) was associated with a recurrence-free interval, with a hazard ratio (HR) of 3.91 (P < .0001) for each 25-unit increase in the score. Other significant predictors on univariate analysis were tumor size

Predicting Recurrence Risk in Renal Cell Carcinoma ■■ The 16-gene assay recurrence score was significantly associated with the risk of recurrence in patients with stage I to III clear cell renal cell carcinoma.

■■ The recurrence score identified high-risk stage I patients and low-risk stage II to III patients.

currence score with any of the covariates for recurrence-free interval was observed (all P > .10).

In multivariate analysis including the Leibovich score, the recurrence score remained a significant predictor of recurrence, with a hazard ratio of 4.20 (P < .0001) per 25-unit increase, and the Leibovich score was no longer a significant predictor (P = .06). Tumor size remained a significant predictor on multi-

Our findings validate the recurrence score as a predictor of clinical outcome in patients with stage I to III clear cell renal cell carcinoma, providing a more accurate and individualized risk assessment beyond existing clinical and pathological parameters.

—Brian Rini, MD, and colleagues

(HR = 2.63, P = .002, for ≤ 4 vs > 4 cm), Fuhrman grade (HR = 2.84, P < .0001, for 3–4 vs 1–2), and Leibovich score (HRs = 4.31 for high vs low and 3.08 for intermediate vs low, P = .01).

On multivariate analysis, the recurrence score was a significant predictor of recurrence, with a hazard ratio of 3.37 (P < .0001) for each 25-unit increase after stratification by stage and adjustment for tumor size and Fuhrman grade. No significant interaction of re-

variate analysis (HR = 2.09, P = .02). The C statistic for recurrence with recurrence score alone was 0.79; the addition of recurrence score to the Leibovich score improved the C statistic to 0.81 from 0.74 with the Leibovich score alone.

Change in Risk Grouping The recurrence score identified patients with stage I disease at high risk and patients with stage II to III disease at low risk. The recurrence score thresh-

olds of 32 and 44 were identified post hoc as distinguishing risk levels, with scores < 32 indicating low risk, scores 32–44 indicating intermediate risk, and scores > 44 indicating high risk.

On this basis, 39% of 398 stage I patients were at low risk, with a mean 5-year recurrence risk of 2%, and 15% were at high risk, with a mean 5-year recurrence risk of 23%. Among patients with stage II to III disease, 19% of 224 were at low risk, with a mean 5-year recurrence risk of 2%, and 44% were at high risk, with a mean 5-year recurrence risk of 39%. The recurrence score risk groupings distinguished 5-year overall survival and renal cancer–specific survival rates in patients with stage I disease and in those with stage II to III disease.

The investigators concluded: “Our findings validate the recurrence score as a predictor of clinical outcome in patients with stage I to III clear cell renal cell carcinoma, providing a more accurate and individualized risk assessment beyond existing clinical and pathological parameters.” n

Disclosure: The study was funded by Genomic Health Inc and Pfizer Inc. For full disclosures of the study authors, visit www. thelancet.com.

Reference 1. Rini B, Goddard A, Knezevic D, et al: A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: Development and validation studies. Lancet Oncol 16:676-685, 2015.

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PAGE 25

Perspective

Predicting Recurrence After Surgery in Renal Cell Carcinoma: 16-Gene Assay Recurrence Score Ushers in New Era

By Derek Raghavan, MD, PhD

I

n a study reported in The Lancet Oncology and reviewed in this issue of The ASCO Post, Brian Rini, MD, of the Cleveland Clinic Taussig Cancer Institute, and colleagues showed that a 16-gene assay recurrence score could predict postoperative outcome in patients with stage I to III clear cell renal cell carcinoma.1 The work reported by Dr. Rini and colleagues represents a forecast of the future.

The team at the Taussig Cancer Institute was an early adopter of the services offered from Genomic Health, during my watch as Head of the Institute, and I was delighted at the productive collaboration that emerged. Several hallmark studies have been published on gene expression in colorectal cancer, prostate cancer, and now renal carcinoma by the Genomic Health and Taussig Cancer Institute teams. In each case, important signatures that allow molecular prediction and prognosticaDr. Raghavan is President, Levine Cancer Institute, Carolinas HealthCare System, and Professor, University of North Carolina School of Medicine, Chapel Hill.

tion with a pretty strong degree of reliability have been identified.

We are seeing an elegant interplay of careful clinical investigation with hypothesis-driven molecular science.

Efforts such as this one will lead to a new era in prediction of outcomes that will refine our approaches to treatment.

Algorithm Stands the Test of Time The Cleveland Clinic genitourinary oncology team, formerly headed by Ron Bukowski, MD, Eric Klein, MD, and Rob Dreicer, MD, took leadership roles in identifying important clinical prognosticators for the management of advanced renal cell carcinoma and created an important algorithm that has stood the test of time. Now Rini et al have extended these clinical observations to the molecular level, leveraging the Cleveland Clinic tissue resources, augmented by an international collaboration.

There are two aspects that particularly appeal to me about this work. First, this is intelligent, hypothesis-driven translational science, as one would expect from Dr. Rini and his partners—focused on known gene expression, mechanisms of invasion, metastasis, tumor vascularization, inflammatory response, and tumor growth. This is so much better than the soft science that we constantly encounter focused on molecular fishing expedi-

—Derek Raghavan, MD, PhD

tions in which “investigators” perform batteries of random gene tests and hope to find “something.”

Second, as I recall it, Genomic Health actually funded these studies, rather than simply charging the system for unproven technology. I have always been puzzled by the tendency of molecular diagnostic groups to provide unproven and sometimes unvalidated services to the oncology community while happily charging somebody (health funds, Medicare, patients) for their services. By contrast, most of the ethical pharmaceutical industry tends to bankroll its early-phase studies, choosing to make profits once

specific efficacy has been identified.

Perhaps the most important issue here is that we are seeing an elegant interplay of careful clinical investigation with hypothesis-driven molecular science. Efforts such as this one will lead to a new era in prediction of outcomes that will refine our approaches to treatment. n

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

Reference 1. Rini B, Goddard A, Knezevic D, et al: A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma. Lancet Oncol 16:676-685, 2015.

Don’t Miss These Important Reports in This Issue of The ASCO Post Amir Qaseem, MD, PhD, MHA, FACP, on High-Value Screening see page 66

Clara D. Bloomfield, MD, FASCO, Reflects on Her Career see page 50

Patrick Conway, MD, on Medicare and Translating Science Into Government Policy see page 47

Robin Hardbattle, MS, LAc, on Fitness Programs for Children With Cancer see page 40

Edward B. Garon, MD, on Pembrolizumab in NSCLC see page 30

Brian Rini, MD, on a 16-Gene Assay Predictive of Recurrence of Localized Renal Cell Carcinoma see page 24

Robert Andtbacka, MD, on Oncolytic Immunotherapy see page 17

Matthias Gromeier, MD, on the Poliovirus in Glioblastoma Treatment see page 15

Leonard Saltz, MD, on Costs of Immunotherapy see page 14

Visit The ASCO Post online at ASCOPost.com

2 FDA APPROVALS For use both as monotherapy and in combination with paclitaxel

CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal (GE) junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinumcontaining chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions

Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs) • Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/ tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.

Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforations was also increased in patients who received CYRAMZA plus paclitaxel (1.2%) as compared to patients who received placebo plus paclitaxel (0.3%). Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing • Impaired wound healing can occur with antibodies inhibiting the VEGF pathway.

CYRAMZA has not been studied in patients with serious or nonhealing wounds.

CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome • Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy.

Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction • Monitor thyroid function during treatment with CYRAMZA. Embryofetal Toxicity • Based on its mechanism of action, CYRAMZA can cause fetal harm when

CYRAMZA® (ramucirumab) PLUS PACLITAXEL SIGNIFICANTLY EXTENDED OVERALL SURVIVAL (OS)1 RAINBOW OS: MEDIAN - MONTHS (95% CI)*1 1.0

CYRAMZA + paclitaxel (8.5, 10.8)

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

9.6

MONTHS

30% INCREASE IN MEDIAN OS

0.6

Hazard Ratio=0.81 (0.68, 0.96); P=0.017

0.4

7.4

0.2

MONTHS

CYRAMZA + paclitaxel Placebo + paclitaxel (6.3, 8.4)

Placebo + paclitaxel

0.0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

TIME FROM RANDOMIZATION (MONTHS) Number at Risk

CYRAMZA 330 + paclitaxel Placebo 335 + paclitaxel

308

267

228

185

148

116

78

60

41

24

13

6

1

0

294

241

180

143

109

81

64

47

30

22

13

5

2

0

• The percentage of deaths at the time of analysis was 78% (256 patients) and 78% (260 patients) in the CYRAMZA plus paclitaxel and placebo plus paclitaxel treatment arms, respectively1 The phase III RAINBOW trial evaluated the efficacy and safety of CYRAMZA plus paclitaxel vs placebo plus paclitaxel in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- and platinum-containing chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). All patients were Eastern Cooperative Oncology Group performance status 0 or 1. Prior to enrollment, 97% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease. Twenty-five percent of patients had received anthracycline in combination with platinum/ fluoropyrimidine therapy, while 75% did not. Patients were randomized 1:1 to CYRAMZA 8 mg/kg (n=330) or placebo (n=335) every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle.1,3 CI=confidence interval. *Intent-to-treat (ITT) population. † ITT population.

ORR was defined as complete plus partial response. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.2

CYRAMZA PLUS PACLITAXEL ALSO SIGNIFICANTLY DELAYED DISEASE PROGRESSION AND PROVIDED SIGNIFICANTLY GREATER ORR VS PLACEBO PLUS PACLITAXEL (SUPPORTIVE EFFICACY OUTCOME MEASURES)*1 • Median PFS with CYRAMZA plus paclitaxel was 4.4 months (95% CI: 4.2, 5.3) vs 2.9 months (95% CI: 2.8, 3.0) with placebo plus paclitaxel (hazard ratio 0.64 [95% CI: 0.54, 0.75]; P<0.001)1 - The percentage of events at the time of analysis was 85% (279 patients) and 88% (296 patients), respectively • Significantly more patients responded to CYRAMZA combined with paclitaxel (28%; 95% CI: 23, 33) than to placebo plus paclitaxel (16%; 95% CI: 13, 20) (P<0.001)†1,2

VISIT WWW.CYRAMZAHCP.COM FOR MORE INFORMATION, INCLUDING CYRAMZA MONOTHERAPY TRIAL DATA administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions—Single Agent • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZAtreated patients in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusionrelated reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusionrelated reactions was 0.4%.

Most Common Adverse Reactions—Combination with Paclitaxel • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).

• The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.

• Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).

• Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).

Drug Interactions • No pharmacokinetic interactions were observed between ramucirumab (CYRAMZA) and paclitaxel.

Use in Specific Populations • Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm.

Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development.

Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. • Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page.

RB HCP ISI 24APR2015 References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 2. Wilke H, Muro K, Van Cutsem E, et al; for the RAINBOW Study Group.

Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. 3. Data on file, Eli Lilly and Company. ONC09302014b.

RB97116

05/2015 PRINTED IN USA

© Lilly USA, LLC 2015. All rights reserved.

CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

INDICATIONS AND USAGE Gastric Cancer CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy.

Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients. ®

CYRAMZA (ramucirumab) injection

RB-G HCP BS 29APR2015

Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women.

Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks.

Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal.

CYRAMZA Administered as a Single Agent Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months.

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo N=236 N=115 Adverse Reactions (MedDRA)a System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a

MedDRA Version 15.0.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

CYRAMZA Administered in Combination with Paclitaxel Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 60 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months.

In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%).

Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA plus Paclitaxel in Study 2 CYRAMZA plus Paclitaxel Placebo plus Paclitaxel (N=327) (N=329) Adverse Reactions (MedDRA) System Organ Class All Grades Grade ≥3 All Grades Grade ≥3 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Neutropenia Thrombocytopenia Gastrointestinal Disorders Diarrhea Gastrointestinal hemorrhage events

54 13

41 2

31 6

19 2

32 10

4 4

23 6

2 2

1

7

1

12 2

44 14

6 1

1

5

1

1

6

0

0

7

0

15

6

3

Stomatitis 20 General Disorders and Administration Site Disorders Fatigue/Asthenia 57 Peripheral edema 25 Metabolism and Nutrition Disorders Hypoalbuminemia 11 Renal and Urinary Disorders Proteinuria 17 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 31 Vascular Disorder Hypertension 25 ®

CYRAMZA (ramucirumab) injection

RB-G HCP BS 29APR2015

Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel treated patients in Study 2 were sepsis (3.1% CYRAMZA plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% CYRAMZA plus paclitaxel versus 0.3% for placebo plus paclitaxel).

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No pharmacokinetic interactions were observed between ramucirumab and paclitaxel.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.

Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.

PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness].

• Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event.

• Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment.

• Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA Additional information can be found at www.CYRAMZAHCP.com.

DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to paclitaxel, refer to the current prescribing information.

CYRAMZA® (ramucirumab) injection

RB-G HCP BS 29APR2015

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2015, Eli Lilly and Company. All rights reserved.

RB-G HCP BS 29APR2015 CYRAMZA® (ramucirumab) injection

RB-G HCP BS 29APR2015

The ASCO Post | JULY 10, 2015

PAGE 30

Journal Spotlight Thoracic Oncology

PD-1 Inhibitor Pembrolizumab Active in Advanced NSCLC: Outcomes Better With Higher PD-L1 Expression

By Matthew Stenger

I

n the phase I KEYNOTE-001 trial reported in The New England Journal of Medicine,1 Edward B. Garon, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, and colleagues found that the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab (Keytruda) produced durable responses in patients with advanced non–small cell lung cancer (NSCLC). Response rate and progression-free survival were increased in patients with higher levels of PD-1 ligand 1 (PD-L1).

Study Details In the study, 495 patients received at least one dose of pembrolizumab between May 2012 and February 2014. Patients were assigned to a dose of 2 mg (n = 6) or 10 mg/kg (n = 287) every 3 weeks or 10 mg/kg every 2 weeks (n = 202) in either a training group (n = 182) or a validation group (n = 313).

PD-L1 expression was measured in tumor samples using immunohistochemical analysis; a proportion score was generated using the percentage of neoplastic cells with staining for membranous PD-L1. Response was assessed by central review every 9 weeks.

Among all patients: median age was 64 years; 53% were male; 82% were white; 35% and 64% had Eastern Cooperative Oncology Group performance status of 0 and 1; EGFR mutation was present in 15%, KRAS mutation in 26%, and ALK alteration in 2%; histology was nonsquamous in 81%; 24%, 21%, and 21% had received two, three, and at least four prior systemic therapies; 10% had a history of brain metastases; and 25% were neversmokers.

Outcome in All Patients At the time of data cutoff, median duration of follow-up was 10.9 months (range = 5.2–27.5 months), and 115 patients (23%) continued to receive treatment. Among all patients, the objective response rate was 19.4% (95% confidence interval [CI] = 16.0%–23.2%), including 18.0% (95% CI = 14.4%– 22.2%) in 394 previously treated patients and 24.8% (95% CI = 16.7%– 34.3%) in 101 previously untreated patients. Stable disease was observed in 21.8% of patients.

Response rate was similar irrespective of dose, schedule, or histology. Current or former smokers had a higher response rate than never-smokers (22.5% vs 10.3%).

months (95% CI = 4.1–8.6 months) in previously untreated patients. Median overall survival was 12.0 months (95% CI = 9.3–14.7 months) among all the patients, including 9.3 months (95% CI = 8.4–12.4 months) in previously treated patients and 16.2 months (95% CI = 16.2 months to not reached) in previously untreated patients.

Patients With High PD-L1 Expression PD-L1 expression in ≥ 50% of tumor cells was selected as the proportion score cutoff for high expression in analysis of the training group. Among 824 samples from the total of 1,143 patients screened for the trial, PD-L1 proportion scores were ≥ 50% in 23.2%, 1%

Prospective testing of PD-L1 expression is feasible and retrospectively identified patients with an enhanced likelihood of having a clinical benefit from treatment with pembrolizumab.

—Edward B. Garon, MD, and colleagues

At the time of analysis, 84.4% of patients with a response had no disease progression. Median duration of response was 12.5 months (range = 1.0– 23.3 months) in all patients, including 10.4 months (range = 1.0–10.4 months) in previously treated patients and 23.3 months (range = 1.0–23.3 months) in previously untreated patients.

Median progression-free survival was 3.7 months (95% CI = 2.9–4.1 months) among all patients, including 3.0 months (95% CI = 2.2–4.0 months) in previously treated patients and 6.0

Pembrolizumab in Advanced Lung Cancer ■■ Objective response was observed in 19% of patients, including 18% of previously treated patients and 25% of previously untreated patients.

■■ Response rate, progression-free survival, and overall survival were greater in patients with higher PD-L1 expression.

to 49% in 37.6%, and < 1% in 39.2%, with proportion scores ≥ 50% in 24.9% of previously untreated patients and 22.7% of previously treated patients.

In the validation group, PD-L1 status could not be assessed in 83 patients. In the remainder, the objective response rate was 45.2% (95% CI = 33.5%– 57.3%) in 73 patients with a proportion score ≥ 50%, including rates of 43.9% (95% CI = 30.7%–57.6%) in previously treated patients and 50.0% (95% CI = 24.7%–75.3%) in previously untreated patients. No marked difference in response rate was observed according to dose, schedule, or smoking status in patients with a proportion score ≥ 50%.

Among 356 evaluable patients in the training and validation groups, PDL1 expression proportion scores were ≥ 50% in 119, 1% to 49% in 161, and < 1% in 76. Median progression-free

survival among patients with a proportion score ≥ 50% was 6.3 months (95% CI = 2.9–12.5 months) among all patients, including 6.1 months (95% CI = 2.1–12.5 months) in 294 previously treated patients and 12.5 months (95% CI = 2.4–12.5 months) in 62 previously untreated patients. Median overall survival among patients with a proportion score ≥ 50% was not reached in all patients (95% CI = 13.7 months to not reached), in previously treated patients (95% CI = 9.3 months to not reached), or in previously untreated patients (95% CI = not reached to not reached).

Adverse Events The most common treatment-related adverse events of any grade were fatigue (19%), pruritus (11%), and decreased appetite (11%), with no clear difference according to dose or schedule. Treatment-related grade ≥ 3 adverse events occurred in 9.5% of patients, with the most common being dyspnea (3.8%) and pneumonitis (1.8%). Treatmentrelated inflammatory or immune-mediated adverse events occurring in > 2% of patients consisted of infusion-related reactions (3.0%), hypothyroidism (6.9%), and pneumonitis (3.6%).

Treatment discontinuation due to an infusion-related reaction occurred in one patient. One patient died from treatment-related pneumonitis.

The investigators concluded: “[W]e have shown the efficacy and safety of pembrolizumab for previously treated and previously untreated patients with non–smallcell lung cancer. Prospective testing of PD-L1 expression is feasible and retrospectively identified patients with an enhanced likelihood of having a clinical benefit from treatment with pembrolizumab.” n

Disclosure: The study was funded by Merck.

For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.

Pembrolizumab in Advanced NSCLC: The Promise of Immune Checkpoint Inhibitors See discussion by Vamsidhar Velcheti, MD, and Roy Herbst, MD, PhD, on page 31.

ASCOPost.com | JULY 10, 2015

PAGE 31

Perspective Thoracic Cancer

Pembrolizumab in Advanced NSCLC: The Promise of Immune Checkpoint Inhibitors

By Vamsidhar Velcheti, MD, and Roy Herbst, MD, PhD

D

rugs targeting the immunecheckpoint pathways have shown promising activity in non– small cell lung cancer (NSCLC). In a recent article in The New England Journal of Medicine, Garon and colleagues reported the results of the KEYNOTE-001 clinical trial evaluating single-agent pembrolizumab (Keytruda) in patients with advanced NSCLC1; the study is reviewed in this issue of The ASCO Post.

Pembrolizumab is a humanized monoclonal IgG4 antibody directed against programmed cell death protein 1 (PD-1). PD-1 is a co-inhibitory receptor on activated T cells that can promote T-cell exhaustion on binding to its ligand PD-L1, thus inhibiting the cytotoxic T-cell response.2 PD-L1 expression is a common mechanism of immune evasion in NSCLC.3

A Closer Look at KEYNOTE-001 KEYNOTE-001 is a large international multicenter phase I trial evaluating the safety and efficacy of pembrolizumab in patients with advanced melanoma and NSCLC. The lung cohort of the trial enrolled a total of 495 patients with advanced NSCLC; among these patients, 384 had received prior therapies, and 101 patients were treatment-naive.

The adverse effect profile of pembrolizumab in the trial was favorable, with less than 10% of patients experiencing grade 3 or higher toxicities.

The most common immune-related adverse event was hypothyroidism (6.9%, any grade), which was reported to be easily managed with thyroid supplementation. Pneumonitis was reported in 18 of the 495 patients (3.6%), and half of them were reported to be grade 3 or higher (including one death, 0.2%).

The overall response rate for the study was 19.4% in the total of 495 Dr. Velcheti is Assistant Professor, Department of Hematology and Oncology, Cleveland Clinic. Dr. Herbst is Ensign Professor of Medicine, Professor of Pharmacology, Chief of Medical Oncology, Director, Thoracic Oncology Research Program, Associate Director for Translational Research, Yale Comprehensive Cancer Center, Yale School of Medicine.

patients evaluated (18% in 394 previously treated patients and 24.8% in 101 untreated patients). The median duration of response was 12.5 months in the overall population and nearly 2 years in previously untreated patients.

The trial evaluated the role and the optimal cut point of PD-L1 expression in predicting response to pembrolizumab. Of the 495 patients, 182 patients were enrolled in the training cohort, and 313 patients were enrolled in the validation cohort. The PD-L1 diagnostic assay employed was Dako EnVision FLEX+/HRP polymer kit, using the antibody clone 22C3 to detect PD-L1.

Using receiver-operating-characteristic curve analysis in the training cohort of 182 patients, the PD-L1 cutoff was determined to be membranous PD-L1 expression in at least 50% of tumor cells. Using this cut point, nearly one-quarter of the patients evaluated tested positive for PD-L1 expression.

The objective response rate in PDL1–positive patients was 45.2%, and the median overall survival was not reached. Response rates were 16.5% in patients who had low expression of PD-L1 (1%–49%) and 10.7% in those who were PD-L1–negative (< 1%).

The results of the KEYNOTE-001 trial further our understanding of and enthusiasm for this exciting class of drugs for the treatment of lung cancer. The most consistent finding with these agents is the durability of responses. This was again demonstrated in this trial, with the median duration of response being over a year in patients responding to pembrolizumab (84.4% of the responders had no disease progression at the time of the data cutoff for the ­publication).

Potential Predictive Biomarker Early clinical studies with PD-1/ PD-L1 inhibitors suggested PD-L1 expression by immunohistochemistry may predict response to these agents.4-7 However, clinical trials have measured tumor PD-L1 expression using immunohistochemistry with different antibodies, including Dako clone 28-8 (nivolumab [Opdivo]), Spring Bioscience clone SP142 (MP-

The results of the KEYNOTE-001 trial further our understanding of and enthusiasm for this exciting class of drugs for the treatment of lung cancer. The most consistent finding with these agents is the durability of responses.

—Vamsidhar Velcheti, MD (top), and Roy Herbst, MD, PhD (bottom)

DL3280A), Spring Bioscience clone SP262 (MEDI4736), and, in the current study with pembrolizumab, Dako clone 22C3.

In addition, trials reported thus far had variable definitions of positivity for PD-L1; some assays use tumor expression, whereas others use PD-L1 staining in the stromal immune infiltrates. The percentages of positive cells required to consider the case as positive or negative are also dissimilar.

Moreover, there also appears to be inherent spatial and temporal heterogeneity of PD-L1 expression as a function of interaction and adaptation to the dynamic tumor immune microenvironment. Hence, the reproducibility of PD-L1 assays and their potential as a predictive biomarker have been questioned.

The biomarker evaluation in KEYNOTE-001 trial was well ­ planned and had comprehensive validation in an independent cohort. The findings from this trial suggest the predictive value of PD-L1 expression, with nearly 50% response rates in PDL1–positive (> 50% tumor cells) patients. However, in patients who were defined as PD-L1–low or –negative (< 50% tumor cells), the responses rates were still higher than expected with cytotoxic chemotherapy (15.2% in the validation cohort overall).

These results will be further explored in an ongoing prospective randomized phase III trial of docetaxel vs pembrolizumab ­(KEYNOTE-10).

Closing Comments The KEYNOTE-001 trial provides valuable information regarding the role of PD-L1 expression and the efficacy of pembrolizumab in both refractory and treatment-naive patients with NSCLC. The PD-L1 assay used in the trial appears to enrich for patients who could potentially respond to pembrolizumab. However, the drug also has activity in low–PD-L1 patients and is comparable (and perhaps superior) to cytotoxic chemotherapy in NSCLC, especially in the refractory setting.

Thus, the utility of the PD-L1 assay in NSCLC patients, particularly in the second line and beyond, remains uncertain. However, PD-L1 expression in the future could potentially be used to stratify patients in clinical trials and inform decisions regarding combinatorial strategies with other immunotherapies, chemotherapy, or radiation therapy. n

Disclosure: Dr. Velcheti reported no potential conflicts of interest. Dr. Herbst has been a consultant for Merck.

References 1. Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.

2. Schalper KA, Venur VA, Velcheti V: Programmed death-1/programmed death-1 ligand axis as a therapeutic target in oncology: Current insights. J Receptor Ligand Channel Res 8:1-7, 2015. continued on page 32

The ASCO Post | JULY 10, 2015

PAGE 32

Perspective

Pembrolizumab in NSCLC continued from page 31

3. Velcheti V, Schalper KA, Carvajal DE, et al: Programmed death ligand-1 expression in non-small cell lung cancer.

Lab Invest 94:107-116, 2014.

4. Taube JM, Klein A, Brahmer JR,

et al: Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to antiPD-1 therapy. Clin Cancer Res 20:50645074, 2014.

5. Topalian SL, Sznol M, McDermott DF, et al: Survival, durable tumor remis-

sion, and long-term safety in patients with advanced melanoma receiving nivolumab.

J Clin Oncol 32:1020-1030, 2014.

6. Herbst RS, Gordon MS, Fine GD, et al: A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors.

2013 ASCO Annual Meeting. Abstract 3000.

7. Herbst RS, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563-567, 2014.

Don't Miss These Important Reports in this issue of The ASCO Post

Gregory T. Armstrong, MD, on Survivors of Childhood Cancer Living Longer and Better Lives see page 1

Richard J. Boxer, MD, FACS, on Biosimilars see page 1

Richard G. Margolese, MD, on Anastrozole and Tamoxifen for Ductal Carcinoma in Situ see page 4

For more on prostate cancer, visit ASCOPost.com

© 2015 Genentech USA, Inc. All rights reserved. COB/092414/0002(1) Printed in USA.

ASCOPost.com | JULY 10, 2015

PAGE 33

Announcements

Bert Vogelstein, MD, Receives 2015 Dr. Paul Janssen Award for Biomedical Research

J

ohnson & Johnson named Bert Vogelstein, MD, of Johns Hopkins University, Johns Hopkins Kimmel Cancer Center, and the Howard

Hughes Medical Institute, the winner of the 2015 Dr. Paul Janssen Award for Biomedical Research for his breakthroughs in oncology research, which

have spanned more than 2 decades and have formed the basis of modern cancer research.

Dr. Vogelstein was honored June 16

IN ONCOLOGY, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis. Studies have shown that the MAPK pathway plays an important role in some cancers.1 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

during a reception at the 2015 BIO International Convention in Philadelphia.

The award is named for Dr. Paul Janssen, one of the 20th century’s most gifted and passionate researchers. He helped save millions of lives through his contribution to the discovery and development of more than 80 medicines, four of which remain on the World Health Organization’s list of essential medicines.

I set out to determine what molecular changes drive malignancy, in the hope that this would lead to improved approaches to diagnosis and therapy.

—Bert Vogelstein, MD

“Dr. Vogelstein’s work forms the paradigm for understanding how nearly all forms of human tumors arise and progress,” said Paul Stoffels, MD, Chief Scientific Officer and Worldwide Chairman, Pharmaceuticals, Johnson & Johnson. “His discoveries triggered a new wave of innovation in the field, resulting in transformational solutions for patients.”

Discoveries in Genetics and Biomarkers

REFERENCE: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119.

Beginning in the 1980s, Dr. Vogelstein and his colleagues designed novel approaches to study the molecular basis of colorectal tumors and found that they result from the sequential accumulation of alterations in oncogenes and tumor suppressor genes. His group went on to discover many of the most important of these genes, such as TP53, the gene encoding the p53 protein, altered more often than any other gene across tumor types. Dr. Vogelstein’s work throughout the past 2 decades has continued to illuminate cancer genes and the pathways continued on page 38

The ASCO Post | JULY 10, 2015

PAGE 34

Direct From ASCO

2015 Breast Cancer Symposium to Encourage Collaboration in Patient Care, Education, and Research

A

SCO’s educational symposia have historically provided attendees with a forum for learning and discussion, demonstrating ASCO’s commitment to promoting a network of global oncology expertise. The 2015 Breast Cancer Symposium, to be held in San Francisco, California, from Friday, September 25, to Sunday, September 27, will be no exception. It will bring together attendees from all disciplines of oncology practice and research to exchange ideas and learn from each other, with the ultimate goal of improving patient care.

The theme for this year’s Symposium—Enhancing Clinical Care Through Collaboration—highlights the importance of cross-disciplinary interaction and cooperation in making progress against breast cancer.

ASCO will cosponsor the Symposium with the American Society of Breast Surgeons, the American Society of Radiation Oncology, and the Society of Surgical Oncology.

Truly Multidisciplinary The Breast Cancer Symposium is open to all members of the oncology community interested in the prevention, screening, evaluation, and management of breast cancer, resulting in a diverse group of attendees and a vibrant setting for discussion. Medical oncologists, radiation oncologists, surgeons, and other members of the cancer care team will find ample opportunities to make connections with other breast cancer specialists and expand their professional networks.

With an educational program designed to be as multifaceted as its attendees, the Symposium will highlight progress in the field of breast cancer management and examine promising directions for future research. Sessions on topics ranging from risk assessment to survivorship care will feature presentations from a variety of perspectives, ensuring that all attendees are able to expand their breast cancer knowledge in every session.

Featured Sessions This year’s Symposium will feature multidisciplinary sessions to encourage collaboration in patient care, education, and research advancements, as exemplified in the Featured Sessions here.

The most up-to-date program information, including session times, speakers, and presentation topics, is available on breastcasym.org.

General Session 1: State-of-theArt Breast Cancer Care–Past, Present, and Future In this session, Eric P. Winer, MD, FASCO, of the Dana-Farber Cancer Institute, Eleftherios P. Mamounas, MD, of the UF Health Cancer Center at Orlando Health, and Timothy J. Whelan, BM, BCh, MSc, of Cancer Care Ontario, will discuss where we are and where we are going in medical, surgical, and radiation oncology and correlate science with current clinical issues. The presentations will include lessons learned from past practice and how they apply to outstanding issues in the management of breast cancer. To continue the conversation, this session will be followed by a session on the future of therapy, including ongoing trials and where the field is headed next.

Eric P. Winer, MD, FASCO

Eleftherios P. Mamounas, MD

Timothy J. Whelan, BM, BCh, MSc

Otis W. Brawley, MD, FASCO

Jafi Alyssa Lipson, MD

Suparna B. Wedam, MD

Daniel F. Hayes, MD, FASCO

Nancy E. Davidson, MD, FASCO

Matthew Ellis, MD, PhD

General Session 5: Health Policy and Drug Approvals The legislative and regulatory environment strongly affects the management of breast cancer, and this session will focus on key issues of the day, including breast density legislation, how the Affordable Care Act is changing oncology practice, and the process for U.S. Food and Drug Administration drug approvals, including ways of getting drugs to patients sooner. Session faculty includes Otis W. Brawley, MD, ­FASCO, of the American Cancer Society, Jafi Alyssa Lipson, MD, of Stanford University School of Medicine, and Suparna B. Wedam, MD, of the National Cancer Institute at the National Institutes of Health.

General Session 7: Genomics and Personalized/Precision Medicine Personalized precision medicine is gaining prevalence in current clinical practice, with multiple omics technologies already in use and in development.

In this session, Daniel F. Hayes, MD, FASCO, of the University of Michigan Comprehensive Cancer Center, and Nancy E. Davidson, MD, FASCO, of the University of Pittsburgh Cancer Institute, will discuss omics as they

are applicable in the clinic and how they may be used in clinical trials. The session will cover the use of wholegenome sequencing in the prediction, detection, and management of disease.

After the didactic presentations, the speakers will participate in a case discussion, highlighting real-world issues in the context of the session.

Gianni Bonadonna Breast Cancer Award The ASCO Gianni Bonadonna Breast Cancer Award and Lecture will also be presented at the Symposium.

First given in 2007, it recognizes an active clinical and/or translational researcher with a distinguished record of accomplishments in advancing the field of breast cancer. The award also provides $50,000 to a fellow in the institution of the award recipient.

This year’s recipient is Matthew ­Ellis, MD, PhD, Director of the Lester and Sue Smith Breast Center and Professor of Medicine and Cellular and Molecular Biology at Baylor College of

Medicine. A renowned clinician scientist in the area of genomics and molecular profiling of breast cancer, Dr. Ellis has been instrumental in developing a Genome Atlas and Therapeutic Road Map for estrogen receptor­ –positive breast cancer. He also pioneered research into the clinical relevance of activating mutations in HER2 and in the deployment of patient-derived xenografts for the pharmacological annotation of breast cancer genomes. He is co-leader for The Cancer Genome Atlas (TCGA) Breast Project and Co-Principal Investigator for the Clinical Proteomic Tumor Analysis Consortium, which endeavors to translate TCGA genomic discoveries into protein-based biomarkers with clinical utility.

The 2015 Breast Cancer Symposium hotel reservation and early registration deadline is August 19, 2015. For more information and to register, please visit breastcasym.org. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | JULY 10, 2015

PAGE 35

Direct From ASCO

For reliability and quality,

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At Amgen, we pour commitment, passion, and a drive for perfection into every biologic medicine we make.

From innovative biotechnology to extensive experience in biologic manufacturing, see how Amgen strives to deliver on its commitment to your patients.

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The ASCO Post | JULY 10, 2015

PAGE 36

Direct From ASCO

ASCO QOPI® Certification Program Benefits Oncology Practices and Patients

C

hrista Braun-Inglis, MS, NP, has seen her last three practices certified through ASCO’s Quality Oncology Practice Initiative (QOPI®). Ms. BraunInglis, a nurse practitioner with Kaiser Hawaii Region, was not solely responsible for the designations, although she helped some of the practices become certified. She does, however, take pride in knowing her current and former practices are committed to delivering the highest form of cancer care.

“When patients come to you, they want to know ‘Why should I come to you for my oncology care?’,” Ms. BraunInglis said. “[With QOPI], you can show you’ve actually met this certain standard. It gives patients and third-party payers more faith in you to provide quality care.”

Volume 7, Issue 3

May 2011

Journal of oncology Practice

The QOPI Certification Program is a 3-year certification for outpatient hematology-oncology practices that helps medical providers facilitate better care for patients through a series of

performance measures and standards measured through data submitted by individual practices.

There are 261 QOPI-Certified Practices in the United States, ranging from small practices to large practices, such as the Dana-Farber Cancer Institute, the H. Lee Moffitt Cancer Center and Research Insti-

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

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting

By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity?

By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists

By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials

By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice

By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

What’s Hot in

JOP

JOP.ascopubs.org Use of Adjuvant Cisplatin-Based Versus Carboplatin-Based Chemotherapy in Non–Small-Cell Lung Cancer: Findings From the Florida Initiative for Quality Cancer Care

by Tawee Tanvetyanon, et al Hepatitis B Virus Screening for Patients With Cancer Before Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update

by Jessica P. Hwang, et al

Redesigning Advanced Cancer Care Delivery: Three Ways to Create Higher Value Cancer Care

by Manali I. Patel, et al

Choosing Treatments on the Basis of Cost: Can Clinicians Opt for Less Expensive Treatments?

by Prabashni Reddy, et al

Projected Clinical, Resource Use, and Fiscal Impacts of Implementing Low-Dose Computed Tomography Lung Cancer Screening in Medicare

by Joshua A. Roth, et al

tute, the University of Pittsburgh Medical Center, and Tennessee Oncology. One of the larger institutions participating in the QOPI Certification Program is the University of Arkansas for Medical Sciences (UAMS). Issam Makhoul, MD, helped the institution receive its certification, a process, he admitted, that was larger than he initially anticipated.

QOPI Certification did not solely involve the university’s hematologyoncology division, but rather the whole institution, requiring significant buy-in from staff, Dr. Makhoul said. The end result, however, not only improved the patient care at UAMS, but also raised expectations for the smaller practices in Arkansas, he said. “As a leading institution, you lead by example. In that sense, in my opinion, you are setting the stage here for other institutions to follow suit.”

W. Charles Penley, MD, FASCO, a partner with QOPI-Certified Tennessee Oncology, said the quality certification allowed his practice to identify areas for improvement and improved communication between physicians and nurses.

ASCO understands the specific needs of oncologic practices, he said.

“It is a program designed by oncologists, for oncology practices,” said Dr. Penley, Chair of the Conquer Cancer Foundation of the American Society of Clinical Oncology Board of Directors. “The program exists solely to promote quality, with no hidden agenda. It is not a quality program that has been developed by a third-party payer, which could have inherent bias.”

The QOPI Certification Program provides performance measures and standards applicable to multiple aspects

of a patient’s care. If a patient is prescribed oral chemotherapy, for example, certification requires the monitoring of toxicities the patient may be experiencing and the monitoring of treatment regimen adherence. These guidelines ensure patient access to the medication, as well as a comprehensive understanding of the treatment plan and the overall ramifications of treatment compliance.

The outlined scenario also requires input from all team members on the physician treatment plan, including physicians, nurses, financial advisors, pharmacologists, and social workers.

The measures and practices applied as part of QOPI Certification are the true benefit of the program, according to Dr. Makhoul. “It’s not about the certificate,” he said. “It’s about the measures that are geared toward a healthy practice focusing on patient-centered care.”

The next qualifying QOPI round opens in September 2015, and all practices that achieve a threshold quality score can then apply for certification after the round closes in November.

Practices can learn more about the application process at qopi.asco.org. Certification is open to U.S. and U.S.-territory practices. Practices are encouraged to apply as a whole entity, as long as they demonstrate that all of their office sites are functionally integrated. n Originally printed in ASCO Daily News. © American Society of Clinical Oncology. “ ASCO QOPI® Certification Program Benefits Practices, Patients.” https://am.asco. org/asco-qopi%C2%AE-certification-program-benefits-practices-patients. All rights reserved.

ASCO Recommends Palliative Care as Part of Cancer Treatment

A

SCO recommends that doctors, patients, and caregivers talk about palliative care soon after diagnosis for any patient with metastatic cancer and for patients with many and/or severe symptoms. ASCO has developed a resource to help patients understand the importance of palliative care from diagnosis through treatment and beyond. Order ASCO Answers Palliative Care booklets for your practice at www.cancer.net/estore,

and help your patients better understand the goals of treatment and maintain their quality of life.

Free shipping, and members save 20%. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | JULY 10, 2015

PAGE 37

Direct From ASCO

ASCO Releases Payment Reform Proposal to Support Higher Quality, More Affordable Cancer Care

A

SCO has released a proposal to significantly improve the quality and affordability of care for cancer patients. Expanding on a payment model circulated last year, the ASCO proposal would fundamentally restructure the way oncologists are paid for cancer care in the United States, by providing sufficient payment to support the full range of services that cancer patients need and removing the barriers created by the current payment system to delivering highquality, affordable care.

ASCO’s Patient-Centered Oncology Payment: Payment Reform to Support Higher Quality, More Affordable Cancer Care (PCOP) proposal is designed

to simultaneously improve services to patients and reduce spending for Medicare and other payers.

ASCO’s proposal addresses one of the major problems in today’s fee-forservice system: inadequate payment for the wide range of services critical to supporting patients with cancer and managing a complex illness that often changes from day to day. They include: • Education and support to help patients make the best choices about their cancer treatment, • Rapid response for patients experiencing problems during treatment to help avoid emergency department visits or hospitalizations, • Care coordination with other health-

care providers, and • Continued support to patients after active treatment ends.

Under PCOP, oncology practices would commit to delivering evidence-based care ensuring patients are receiving the most appropriate tests and treatments, while avoiding unnecessary expenses.

The PCOP proposal was developed by an ASCO volunteer work group of leading medical oncologists from diverse practice settings, seasoned practice administrators, and experts in physician payment and business analysis.

The PCOP proposal incorporates extensive input that the Society received on an earlier draft proposal,

Consolidated Payments for Oncology Care (CPOC), released in May 2014. Over the past year, many ASCO members and other stakeholders have endorsed the need for payment reform in oncology and provided suggestions on ways to improve the CPOC model. That input was used to develop the PCOP proposal.

ASCO is soliciting comments on its payment reform model through July 20.

For more information, and the complete text version of the ASCO payment reform model, please visit www.asco. org/paymentreform. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCO Members, Public Working Together to ‘Take Down’ Cancer

F

rom Wrigley Field to McCormick Place, Chicago residents and visitors felt the energy surrounding the launch of The Campaign to Conquer Cancer during the ASCO 2015 Annual Meeting.

The Conquer Cancer Foundation of the American Society of Clinical Oncology (CCF) threw out the ceremonial first pitch at a Chicago Cubs game on May 29 before the Annual Meeting to help kick off fundraising for The Campaign to Conquer Cancer.

Today, CCF is encouraging all ASCO members to lend their support to the Campaign—a multiyear effort to raise $150 million to support the mission of ASCO and CCF—by sharing information about CCF and the Campaign in

their communities and practices.

“The CCF Campaign is addressing key elements of ASCO’s mission of research, patient education, and quality of oncology practice,” said Campaign CoChair Robert J. Mayer, MD, FASCO, Faculty Vice President for Academic Affairs and Institute Physician at the DanaFarber Cancer Institute and Stephen B. Kay Family Professor of Medicine at Harvard Medical School. “To achieve those goals and ensure that we can continue to be leaders in the field, fund the best research, and serve the needs of our members, we need to broaden the circle of supporters who have gotten us this far, and invite new donors to be a part of the collective effort to conquer cancer.”

Together, we’re taking it down.

While nearly 1 in 2 people will get cancer in their lifetime, 2 in 3 will survive it.* And that’s a profound testament to the progress you’ve helped forge as we work collectively to make it harder for cancer to survive.

Join The Campaign to Conquer Cancer at conquer.org/progress. #ConquerCancer * CancerProgress.Net. Progress & Timeline. Timeline. Major Milestones Against Cancer. Available at: http://cancerprogress.net/timeline/major-milestones-against-cancer. Accessed April 7, 2015.

Robert J. Mayer, MD, FASCO

Dr. Mayer is Co-Chairing the Campaign with Thomas G. Roberts Jr, MD, Managing Member of Farallon Capital Management, LLC. Desirée Rogers, CEO of Johnson Publishing Company and long-time Chicago civic leader, is the Honorary Co-Chair.

Members’ participation in the Campaign through advocacy and building awareness is perhaps even more important to Dr. Mayer and Dr. Roberts than financial contributions.

“With this campaign we hope to see participation of a sizable percentage of the ASCO membership,” Dr. Mayer said. “It is not how much one gives, but how many people participate in the effort, indicating the broad support that the oncology community has for the Foundation and its work.”

The Campaign to Conquer Cancer provides a meaningful opportunity for patients, families, caregivers, and community members to support cancer research and the cancer community. Since the Cam-

paign officially began in a silent phase in November 2011, donors have contributed more than $95 million in support of ASCO and CCF initiatives, including cancer research, quality of cancer care and CancerLinQ™, physician and patient education, and global oncology.

The “jewel in the crown” of CCF is its ability to provide funding opportunities for oncology professionals at various stages of their career, Dr. Mayer said. Funding opportunities available through the CCF include Research Professorships, Merit Awards, Advanced Clinical Research Awards, Career Development Awards, and Young Investigator Awards.

ASCO’s achievements—coupled with CCF’s support—have cemented its place among the world’s top cancer organizations. The Campaign to Conquer Cancer promises to build on this success and accelerate the field of cancer research and care for all patients.

To find out more about The Campaign to Conquer Cancer and lend your support, visit conquer.org. n Selected portions reprinted from ASCO Daily News. © American Society of Clinical Oncology. “The Campaign to Conquer Cancer Launched at Chicago Cubs Game.” https://am.asco.org/campaign-conquer-cancer-launched-chicagocubs-game. All rights reserved.

The ASCO Post | JULY 10, 2015

PAGE 38

Announcements Bert Vogelstein, MD continued from page 33

they control, guiding the current scientific revolution in genome-wide studies of tumors.

“Dr. Vogelstein’s groundbreaking research has transformed our understanding of cancer biology and holds the promise for new treatments based on cancer genetics,” said Craig Mello, PhD, Professor of Molecular Medicine at the University of Massachusetts Medical School, Investigator at the Howard Hughes Medical Institute, and Chair of the Dr. Paul Janssen Award Independent Selection Committee. “His work, including examining genetic and biochemical events that initiate solid tumors, is widely applicable to the diagnosis, treatment, and management of cancer and provides broad practical implications for patients with both hereditary and sporadic forms of cancer.”

Dr. Vogelstein is the Director of the Ludwig Center for Cancer Genetics & Therapeutics at the Johns Hopkins Kimmel Cancer Center, Clayton Pro-

fessor of Oncology and Pathology at Johns Hopkins University, and an Investigator of the Howard Hughes Medical Institute.

“For me, this journey began with one of my first patients, a 4 year old with leukemia—a disease we knew very little about at the time. I set out to determine

what molecular changes drive malignancy, in the hope that this would lead to improved approaches to diagnosis and therapy,” said Dr. Vogelstein. “I am honored to have my laboratory’s work recognized and to join the list of exceptional past winners of the Dr. Paul Janssen Award for Biomedical Research.”

ADVERTORIAL

CANCER STEM CELLS

For interviews with experts conducted live at the ASCO Annual Meeting on this study and others, visit http://video.ascopost.com/

The winners of the Dr. Paul Janssen Award for Biomedical Research are chosen by an independent selection committee of the world’s most renowned scientists. The Award, which includes a $200,000 prize, will be presented to Dr. Vogelstein at ceremonies in the United States and Belgium in September. n

SIGNALING PATHWAYS

Cancer Stem Cells and Their Role Despite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 Cancer stem cells are a subset of the total cancer cell population that is highly tumorigenic.2,3 Chemotherapy and radiation have been shown to affect the primary tumor, but not the cancer stem cell.4 Many patients with cancer, even though diagnosed early, succumb to the disease because of recurrence and metastasis.5,6 Cancer stem cells are thought to contribute to this recurrence and metastasis.7 Another characteristic of cancer stem cells is that they possess stemness. Stemness distinguishes cancer stem cells from ordinary cancer cells by their ability to continually self-renew, differentiate into cancer cells, migrate, and regrow the tumor.7,8

Most chemotherapeutic strategies target actively proliferating cancer cells, resulting in bulk tumor shrinkage. Cancer stem cells, however, may be highly resistant to these therapies and may not be eradicated during treatment, resulting in recurrence and metastasis. 4,7 Moreover, chemotherapy and radiation have the potential to induce stemness properties in non-stem cancer cells.2,9 Several signaling pathways are involved in the induction and maintenance of stemness in cancer stem cells, including JAK/STAT, Wnt/ β-catenin, Hedgehog, Notch, and Nanog.10-12 Targeting these aberrant signaling pathways may result in cancer stem cell apoptosis, while reducing the toxicity to normal tissues that is associated with chemotherapy.4

ASCOPost.com | JULY 10, 2015

PAGE 39

Announcements

Roberto Pili, MD, Expert in Prostate, Renal, and Bladder Cancers, Joins Indiana University Simon Cancer Center

R

oberto Pili, MD, a nationally recognized expert in prostate, renal, and bladder cancers, has joined the Indiana University (IU) Melvin and

Bren Simon Cancer Center.

Dr. Pili is the Robert Wallace Miller Professor of Oncology at the Indiana University School of Medicine and

Researcher at the IU Simon Cancer Center. In his new position, Dr. Pili will also be Director of the Genitourinary Research Program at the Cancer Cen-

ter. In addition, Dr. Pili will serve as the Medical Director of the Genitourinary Clinical Program at the IU Health Simon Cancer Center. The genitourinary program supports treatment for prostate, bladder, kidney, testicular, and penile cancers.

Roberto Pili, MD

REGROWTH

APOPTOSIS

in Recurrence and Metastasis Boston Biomedical is developing the next generation of cancer therapeutics with drugs designed to inhibit cancer stem cell pathways.

Clinical trials are underway with the goal of reducing recurrence and metastasis.

Learn more at www.bostonbiomedical.com

References: 1. Li Y, Rogoff HA, Keates S, et al. Supression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci. 2015;112(6):18391844. 2. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 3. Clarke MF. Self-renewal and solid-tumor stem cells. Biol Blood Marrow Transplant. 2005:11(2 suppl 2):14-16. 4. Boman BM, Huang E. Human colon cancer stem cells: A new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838. 5. Ahmad A. Pathways for breast cancer recurrence. ISRN Oncol. 2013;2013:290568. doi: 10.1155/2013/290568. 6. Hung JH, Wu YC. Stage I non-small cell lung cancer: recurrence patterns, prognostic factors and survival. In: Cardoso P, ed.

Topics inThoracic Surgery. Shanghai, China: InTech; 2012:285-292. http://www.intechopen.com/books/topics-in-thoracic-surgery/stage-i-non-smallcell-lungcancer-recurrence-patterns-prognostic-factors-and-survival. Accessed May 8, 2015. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 9. Ghisolfi L, Keates AC, Hu X, Lee D, Li CJ. Ionizing radiation induces stemness in cancer cells. PLOS ONE. 2012;7(8):1-11. 10. Hoffmeyer K, Raggioli A, Rudloff S, et al. Wnt/βcatenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336(6088):1549-1554. 11. Bourguignon LYW, Earle C, Wong G, Spevak CC, Krueger K. Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene. 2012;31(2):149-160. 12. Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther. 2013;6:1249-1259.

EDU-NPS-0027

5/2015

©2015 Boston Biomedical

The Genitourinary Research Program’s scientists will collaborate with researchers at the Purdue University Center for Cancer Research. The developing program will be co-led by Timothy Ratliff, PhD, the Robert Wallace Miller Director of the Purdue Cancer Center.

On the clinical side, Dr. Pili said his goal is to focus on drug resistance in those genitourinary cancers, providing new options for those patients.

Prior Appointments Most recently, Dr. Pili was Professor of Oncology, Chief of the Genitourinary Section, and Leader of the Genitourinary Program at the Roswell Park Cancer Institute.

Dr. Pili earned his medical degree from the Catholic University School of Medicine, in Rome, Italy.

He did his residency training in internal medicine at Montefiore Medical Center, completed a clinical research fellowship in medical oncology at Johns Hopkins University, and a second fellowship at the National Institute on Aging, National Institutes of Health. His laboratory research focuses on the development of novel therapeutic agents, including epigenetic agents such as histone deacetylase inhibitors and understanding their immunomodulatory effects. He also conducts phase I/II clinical trials of novel agents for the treatment of genitourinary malignancies.

Dr. Pili is a member of ASCO and the American Association for Cancer Research. He serves as a reviewer for study sections of the National Cancer Institute and the Department of ­Defense. n

The ASCO Post | JULY 10, 2015

PAGE 40

Integrative Oncology The Pediatric Fitness Program: A Mind-Body Approach

By Robin Hardbattle, MS, LAc

T

he fundamental challenge in treating children with cancer centers on how to help relieve their suffering while they undergo difficult care. Typically, they do not yet have adult coping skills, and even if they had some ability to cope, many of the issues they face during treatment are overwhelming.

During the span of their treatment, pediatric patients with cancer face a range of physical and emotional issues, including pain, nausea, fatigue, and physical weakness, along with the similarly common emotional challenges of anxiety, fear, and depression.

Within the unlikely field of martial arts, we have applied a tailored approach to each individual that greatly relieves these common challenges. At a brief glance, using martial arts in a hospital setting as an integrative modality may seem incompatible to the restrictions inherent in treating cancer. On closer examination and with appropriate application, however, it becomes evident that it has much to offer.

Although commonly seen as simply a way to fight, the field of martial arts is a rich, multilayered body of knowledge on dealing with physical, psychological, emotional, and spiritual adversities.

With appropriate adaption to the pediatric environment and solid understanding of pediatric oncology, the martial arts are well suited to soothe the physical and emotional needs of children in pain.

The MSKCC Program

Since 2012, Memorial Sloan Kettering Cancer Center (MSKCC) has provided a martial arts program

Robin Hardbattle, MS, LAc, engages a pediatric patient in martial arts as an integrative modality suited to soothe the physical and emotional needs of children in pain. Photo by Rick DeWitt. Courtesy of Memorial Sloan Kettering Cancer Center.

that serves all pediatric patients with cancer. Combining the mind-body practices of physical fitness, breath awareness, guided imagery, and meditation, this program introduces a range of appropriate coping mechanisms that improve mood, reduce anxiety, and alleviate pain.

Each session is tailored to the individual needs of the patients, working in small groups or individually in the Pediatric Day Hospital or at the bedside. Sessions are provided also for patients in isolation for extended periods, such as those undergoing

GUEST EDITOR

I

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.

The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the close to 300 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.

In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices.

hematopoietic stem cell transplantation. Throughout the duration of their treatment, from the first visit to the end of care, the program provides support in close collaboration with nurses, physical therapists, occupational therapists, social workers, and child life specialists.

The program aims to help patients at the time and place of their choosing and when a mind-body intervention would be most effective. This often requires accompanying patients while they undergo painful or frightening procedures.

Reinforcing the exercises taught earlier while providing emotional support significantly improves the patients’ experience. Ideally, as children integrate the coping skills taught from the outset, they become more confident and self-sufficient, to the point that the therapist is no longer needed.

Benefits of Physical Exercise

With more than 200 studies demonstrating the benefits of physical fitness in patients with cancer, physical activity is increasingly acknowledged as a legitimate medical therapy.1 Data increasingly show that physical activity increases survival.2,3 Evidence also indicates that activity can decrease both physical and emotional symptoms during treatment, with improvement in muscle strength,

aerobic capacity, quality of life, fatigue, and overall emotional status.4,5

Adaptability of Martial Arts Practices

Fitness activities are adapted from a variety of martial arts styles. A suitable activity can be introduced regardless of one’s physical limitations and given a willingness to participate. Specific appropriate techniques can be adapted and applied to each circumstance, whether the children are standing, sitting, or supine.

In addition to developing strength, balance, and coordination, these techniques can help to reduce anxiety and pain, improve sleep, and serve as an emotional release. The activity offers a healthy physical outlet for the children’s fear when they need it most. Such a release can help with behavioral and compliance issues, particularly in younger patients who have few established coping mechanisms in place.

These activities also empower pediatric patients, providing a sense of strength when they are physically weak and struggling with fear. That sense of physical strength can translate to a sense of determination to persevere.

Within the context of martial arts, the child’s situation is reframed from that of a victim of circumstance to a fighter in the battle against disease.

By working with physical and occu-

ASCOPost.com | JULY 10, 2015

PAGE 41

Integrative Oncology pational therapy, the children’s specific needs can be addressed from multiple angles that they may perceive as fun.

They follow the appropriate path to rehabilitation without knowing it. Enthusiasm for these activities often inspires children to maintain physical activity throughout their treatment. This often continues following discharge and be-

martial arts is more scant. The most notable studies to date address Tai Chi and Qigong, practices that include both physical and meditative components.

Early results indicate clear benefits, both physical and cognitive.9-11 Breath regulation and focus, both adapted from the martial arts, are central to mind-body practices. By becoming

With appropriate adaption to the pediatric environment and solid understanding of pediatric oncology, the martial arts are well suited to soothe the physical and emotional needs of children in pain.

—Robin Hardbattle, MS, LAc

comes a regular pursuit. The most common question parents ask at that point is “My kid wants to do martial arts at home. What do you recommend?”

The foundation of meditative practice is integral to many martial arts activities. Therefore, physical training and practice are used as a bridge to mindbody activities. Introducing simple breathing exercises in the context of learning correct punching, for example, is an ideal way to introduce the concept of mindful breathing to children.

Mind-Body Practice

There is now ample evidence indicating the value of breathing, mindfulness, and meditative practices as effective treatments for a wide range of symptoms, including pain, anxiety, depression, fatigue, and sleep disturbance.6-8 Research pertaining specifically to

mindful of their breathing, patients take the first step in controlling their bodies. This activates the parasympathetic nervous system and subsequently their reaction to stress. Moreover, this exercise becomes the foundation for more sophisticated visualization practices.

Guided imagery is an ideal way to introduce children to the practice of meditation. A successful guided meditation is possible with patients as young as 3 years of age. Even in the busy environment of a pediatric hospital, pediatric and adult patients can achieve a deep state of physical and emotional relaxation. Long-term patients, trapped in an environment with little privacy or comfort, often struggle with anxiety and depression. Through the practice of meditation, and especially guided imagery, children can reclaim a sense of control in an environment where they have

The Mind-Body Program in Action

H

ere are several real-life examples of the positive effects of the mindbody program, shared by Robin Hardbattle, MS, LAc, and the parents of children who benefited from it.

• Breathing Practices and Guided Imagery: Prior to learning breathing practices and guided meditation, Matt, a 12-year-old boy, was experiencing pain and high levels of anxiety every week when it was necessary to have a line inserted. Later, when applying the breathing practices and guided meditation he had learned, he was able to deal with the procedure with little if any pain and without panic. After I guided him through this several times, he told me that he was okay and didn’t need me there anymore. His sense of control in place, Matt knew that he could confidently get through the procedure without fear.

• Meditation and Guided Imagery: One parent explained how this approach helped her daughter and shared her gratitude. “I’ll never forget how you calmed my fearful daughter by teaching her to focus on her breath—her anchor—and how you transported her…. Your voice lulled her out of our tiny, loud, beeping machine-filled space to a space of tranquility, where the ocean waves gently crashed on the shore and the sun was beaming on her back. Thank you: Her body and spirit were so relaxed. You taught her to use her breath and mind to literally remove the noise of the hospital and distract her from her fears.”

• Breathing Exercises, Guided Imagery, and Music Therapy: Another comment by a parent illustrates the benefit of such approaches. “Robin works with my son during very difficult 3F8 monoclonal antibody treatments. He has taught him how to meditate and focus. Both Robin and my son amaze me.” n

little if any control. They can close their eyes and “go home.”

In the short term, these skills help with the immediate issues of anxiety, fear, and pain by promoting self-control, inner peace, and tranquility. In the long term, these skills become tools throughout life.

Challenges in Pediatrics

An especially difficult challenge in pediatric oncology is administration of a painful therapy or procedure to an uncooperative child. From delaying tactics

to outright rebellion, children struggle to prevent it, but inevitably they must undergo the procedure. By arming children with appropriate mind-body skills, we can reframe the procedure from a traumatic experience to an unpleasant but necessary event.

An especially difficult treatment at Memorial Sloan Kettering’s Pediatric Day Hospital is the monoclonal antibody therapy for neuroblastoma. This treatment causes extreme pain for 20 to 30 minutes, and children routinely

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The ASCO Post | JULY 10, 2015

Integrative Oncology Pediatric Fitness Program continued from page 41

scream in pain. This is traumatic for the patient and difficult for all participants, including parents and medical staff.

In collaboration with other integrative medicine therapists and the pediatric staff, we are able to guide children through this treatment in relative comfort. Using breathing exercises, guided imagery, and music, we place them into a deep meditative state. This can profoundly relieve pain and fear and improves the overall experience, as early data corroborate.12 The most notable organization to have worked successfully in hospitals is the nonprofit “Kids Kicking Cancer.”

It was with the committed martial arts instructors at this organization that we were first introduced to the potential of this modality. To our knowledge, Memorial Sloan Kettering’s martial arts program may be the first dedicated hospital program of its kind.

Closing Thoughts

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As an integrative therapy, martial arts are in their infancy yet have substantial promise. They have substantial potential as a mind-body modality to help not only children with cancer but also to manage other severe medical challenges. It is our hope that, as the benefits of this discipline become increasingly well recognized, additional institutions will look toward the combination of martial arts and meditation as an important addition to patient care. For children facing pain and adversity, this modality may very well be of help. n Disclosure: Mr. Hardbattle reported no potential conflicts of interest.

References 1. Steindorf K, Leitzmann M, Friedenreich C: Physical activity and primary cancer prevention, in Ulrich CM, Steindorf K, Berger NA (eds): Exercise, Energy Balance, and Cancer, pp 83-106. New York, Springer, 2013.

2. Meyerhardt JA, Giovannucci EL, Holmes MD, et al: Physical activity and survival after colorectal cancer diagnosis. J Clin

The ASCO Post Wants to Hear From You

Oncol 24:3527-3534, 2006.

3. Meyerhardt JA, Giovannucci EL, Ogino S, et al: Physical activity and male colorectal cancer survival. Arch Intern Med 169:2102-2108, 2009.

4. Mishra SI, Scherer RW, Geigle PM, et al: Exercise interventions on health-related quality of life for cancer survivors. Cochrane Database Syst Rev 8:CD007566, 2012.

5. Cramer H, Lange S, Klose P, et al: Yoga for breast cancer patients and survivors: A systematic review and meta-analysis. BMC Cancer 12:412, 2012.

6. Deng G, Cassileth BR: Integrative oncology: Complementary therapies for pain, anxiety, and mood disturbance. CA Cancer J Clin 55:109-116, 2005.

7. Birnie K, Garland SN, Carlson LE: Psychological benefits for cancer patients and their partners participating in mindfulness-based stress reduction (MBSR). Psychooncology 19:1004-1009, 2010.

8. Syrjala KL Jensen MP, Mendoza ME, et al: Psychological and behavioral approaches to cancer pain management. J Clin Oncol 32:1703-1711, 2014.

9. Oh B, Butow P, Mullan B, et al: Impact of medical Qigong on quality of life, fatigue, mood and inflammation in cancer patients: A randomized controlled trial. Ann Oncol 21:608-614, 2010.

10. Oh B, Butow PN, Mullan BA, et al: Effect of medical Qigong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: A randomized controlled trial. Support Care Cancer 20:1235-1242, 2012.

11. Chen Z, Meng Z, Milbury K, et al: Qigong improves quality of life in women undergoing radiotherapy for breast cancer: Results of a randomized controlled trial.

Cancer 119:1690-1698, 2013.

12. Ahmed M, Modak S, Sequeira S: Acute pain relief after Mantram meditation in children with neuroblastoma undergoing anti-GD2 monoclonal antibody therapy. J Pediatr Hematol Oncol 36:152-155, 2014.

Mr. Hardbattle, a third-degree black belt with more than 25 years of experience in teaching and practicing martial arts, leads the Memorial Sloan Kettering Cancer Center inpatient program in Pediatric MindBody Fitness.

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

ASCOPost.com | JULY 10, 2015

PAGE 47

Health-Care Policy Screening

Translating Study Recommendations Into Medicare Coverage A Conversation With Patrick Conway, MD

By Ronald Piana

L

ung cancer doggedly remains the leading cause of cancer-related death in the United States. This grim mortality figure is due, in part, to a lack of early detection methods; more than half of all lung cancers have metastasized at the time of diagnosis. For decades, lung cancer advocates lobbied

I am a pediatrician by training and, before joining CMS, served as Director of Hospital Medicine and Associate Professor at Cincinnati Children’s Hospital.

In that role, I was also Assistant Vice President for Outcomes Performance, responsible for leading measurement, including the electronic health record

CMS established evidence-based coverage criteria, including data collection and standardized lung nodule identification, classification and reporting system to facilitate continuous improvement in screening techniques, and protocols to help reduce false-positive results.

—Patrick Conway, MD

for low-dose computed tomography (CT) screening programs that would help promote early detection and reduce mortality. In 2011, the National Lung Screening Trial, sponsored by the National Cancer Institute, demonstrated that screening with low-dose CT reduces lung cancer mortality.

Based on this large trial, the U.S. Preventive Services Task Force issued a report giving low-dose CT in lung cancer a grade B recommendation, which garnered coverage by the Centers for Medicare & Medicaid Services (CMS). However, translating science into policy is difficult. To shed light on the challenge, The ASCO Post spoke with a principal administrator at CMS, Patrick Conway, MD.

Background and Current Role Please describe your medical background and a bit about your position at CMS. I am currently the acting principal Deputy Administrator of CMS, and I also serve as its Chief Medical Officer.

I lead the Center for Clinical Standards and Quality and the Center for Medicare and Medicaid Innovation.

measures, and facilitating improvement of health outcomes across the healthcare system. I attended Baylor College of Medicine and completed my pediatrics residency at Harvard Medical School’s Children’s Hospital Boston.

Age Cutoff for Screening Please talk about the difference in age cutoffs for low-dose CT screening coverage between the U.S. Preventive Services Task Force (80 years) and CMS (77 years).

Certain advocacy groups were critical of the CMS decision.

The age range of 55 to 77 years for Medicare coverage is based on data from the National Lung Screening Trial and is within the age range of the [U.S. Preventive Services Task Force’s] grade B recommendation.

The [U.S. Preventive Services Task Force] used modeling with potentially unrealistic assumptions to extend the age range. However, we found no empirical data to support screening in adults aged 78 to 80 years, as the [National Lung Screening Trial] did not enroll or have follow-up data on these individuals. Therefore, we have not included these ages.

Other Eligibility Criteria Is CMS confident that eligibility criteria such as a patient’s smoking history can be assessed with accuracy?

We recognize the importance of accurate ascertainment of smoking history and have created a specific shared decision-making visit to allow a careful calculation of pack-years, in addition to an interactive discussion of the potential risks and benefits of screening. If calculated carefully and systematically, we believe smoking history can be assessed as well as it was in the [National Lung Screening Trial].

High-Quality Screening Availability The National Lung Screening Trial was conducted in large facilities with the resources to execute standardized low-dose CT testing and data collection. Is CMS confident that widespread low-dose CT screening can be done in controlled highquality settings across the nation?

In 2014, the Medicare Evidence Development & Coverage Advisory Committee also expressed concerns about the implementation of this service outside a controlled trial. CMS established specific evidence-based criteria such as beneficiary eligibility, radiologist training, imaging center requirements, and data collection to increase the likelihood of obtaining true positive results and to ensure that the benefits of screening outweigh harms for the Medicare population.

Benefits vs Harms Is CMS comfortable that the harms associated with true false-positive results will be kept to a minimum, so that they are outweighed by the benefits of low-dose CT? CMS established evidence-based coverage criteria, including data collection and standardized lung nodule identification, classification and reporting system to facilitate continuous improvement in screening techniques, and protocols to help reduce false-positive results. With these criteria, we believe the number of false-

Key Challenges to CMS Coverage for Low-Dose CT Screening ■■ Patients must be accurately identified for screening to be successful. Although age is typically straightforward to measure, incongruity between the National Lung Screening Trial (which provided data for patients up to 77 years of age) and screening recommendations may potentially compound implementation problems.

■■ A patient’s smoking history— usually self-reported and subject to recall bias—is particularly challenging yet critical to determine, since screening trials in patients with a less-extensive smoking history have not shown improved health outcomes.

■■ Lung cancer screening must be performed as part of a cohesive screening program to enhance its likelihood of success.

Radiologists should not only properly furnish and interpret the low-dose CT but also reinforce the importance of adherence to evidence-based screening, smoking cessation, and follow-up evaluations.

■■ During the course of screening, a patient may encounter physicians from a number of different specialties. Each physician has a unique role and responsibility, but effective communication and coordination will be needed.

positives will be minimized and show recognized benefits over harms of screening.

We also included a shared decisionmaking visit between the clinician and beneficiary to discuss the potential risks and benefits. Finally, in the future, screening programs will improve as appropriate data are collected. n

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | JULY 10, 2015

PAGE 48

Expert’s Corner Health Information Technology

CancerLinQ™ Can Benefit continued from page 1

CancerLinQ will also provide an individual oncologist seated in a local exam room access to outcome data from hundreds or thousands of patients similar to the one sitting in front of him.

A Brief History of CancerLinQ ASCO has been discussing and refining this exciting concept since 2010, and its Board of Directors formally voted to go forward with the project in 2012. A proofof-concept prototype was completed in 2013, with more than 170,000 de-identified medical records of breast cancer patients from four large cancer centers around the country and one oncology data analysis organization. The prototype showed that a full CancerLinQ system encompassing all cancers was feasible.

CancerLinQ was first presented to the cancer community in 2013 during a briefing at the National Press Club in Washington, DC, and a demonstration of the full system was presented to both oncologists and patient advocates at this year’s ASCO Annual Meeting. Both sessions received an enthusiastic response.

As news continues to spread regarding this huge venture, it is important that patients with cancer and the general public know about the great promise of CancerLinQ. It is also important to understand that CancerLinQ is an ongoing work in progress and to keep expectations in line with reality.

ASCO is now beginning to develop CancerLinQ with 15 vanguard oncology practices that are expected to contribute at least 500,000 patient records for research on treatment outcomes.

The practices are diverse in geography, size, governing structure, and electronic health record systems.

While easy to explain, making the technology actually work is daunting. SAP, a global software company, is supporting ASCO staff in this monumental job. Both ASCO and SAP are working to meet the needs of patients at every juncture of care and are focused on protecting the privacy and security of patient information. I am among six patient advocates serving on CancerLinQ’s Patient Advisory Committee to help guide these efforts.

Establishing Patient Trust CancerLinQ is for and about better care for patients with cancer. MaintainDr. Omel is a patient advocate, multiple myeloma survivor, and full-time caregiver for his wife, who has multiple sclerosis. He was diagnosed with myeloma in 1997 and retired from active medical practice in 2000.

ing patients’ trust is vital to the success of this big data learning system.

Without full support from patients and agreement to use their data, CancerLinQ (and all technologies that capture patient outcomes) will fail.

Approximately 1.3 million patients will be told they have cancer this year.

Consider how our collective knowledge would soar if oncologists could access the aggregated treatment and outcome information contained in CancerLinQ for the benefit of those patients and the 1.3 million new patients who will follow them next year, and each successive year.

Currently, the vast bulk of the clinical data contained in electronic health records is known only to the patient, the patient’s physician and hospital

ble to practicing oncologists in an exam room with their patient.

How Patient Diversity Impacts Care As mentioned earlier, CancerLinQ allows physicians to obtain information not just from the 3% of patients accrued into clinical trials each year, but from other patients as well and might allow researchers to see how patient diversity, including race, health status, and age, may impact patient care and outcome.

For example, 90% of patients enrolled into National Cancer Institute trials are white, but 23% of the U.S. population is nonwhite; 40% of patients with kidney cancer are not healthy enough to qualify for trials that support

Although completion of the full development of CancerLinQ is several years away, with each progress report, we can take comfort in the promise that this exciting health information technology platform offers to guide personalized cancer treatment decisions, inform research, and improve quality of life for millions of patients with cancer.

—Jim Omel, MD

point of care, and the patient’s family.

By making these data accessible to clinicians and researchers everywhere, CancerLinQ offers the promise of learning about the benefits and harms of specific treatment, improving quality of care, and quickening the development of new therapies.

Patients think this is all being accomplished right now, but it isn’t. They think their doctors know how most patients being treated with the treatment regimen they are being offered will fare, but they don’t. Oncologists know the results of randomized clinical trials, which guide and slowly change cancer therapy, but they only have outcome information many years after completion of those trials.

Moreover, oncologists are flooded with a tidal wave of information overload. If we assume only 1% of that new literature is relevant to an individual oncologist’s practice and that the oncologist reads two articles every night, that oncologist would still be more than 10 years behind in the current ­literature.

Indeed, keeping up with the mass amounts of cancer data generated is humanly impossible. CancerLinQ will quantify and populate millions of data points, making the information accessi-

the approval of their treatments; and only 25% of patients enrolled in clinical trials are over age 65, whereas 61% of patients with cancer are over age 65.

Comorbidities and preexisting conditions exclude many cancer patients from clinical trials, but the reality is that these patients will be prescribed treatments tested in just a small percentage of patients. Oncologists need outcome data for their many diverse patients deserving of the best treatment but who may not be well represented in clinical studies or who are ineligible to receive a specific therapy in clinical trials.

ASCO must manage expectations and be careful not to overpromise or underdeliver the benefits of this technology. As stated earlier, patient advocates have been consulted and are involved in the development of CancerLinQ. We’ve received assurance of data safety and privacy and discussed how information will be gathered and used. An easy “opt out” policy will be in place for patients who are treated at clinics and institutions using CancerLinQ but who choose not to contribute their data. The outcome data provided by CancerLinQ will help patients better understand their treatment options during conversations with their physicians, and we are hopeful that these conversations will lead to better outcomes.

Patients Helping Patients A detailed description of CancerLinQ’s vision and how it works can be found at CancerLinQ.org. There you will see examples of case histories and how CancerLinQ can improve patient care.

One example is a rural Wyoming patient with a rare throat cancer. His local physician has very little data to support a treatment plan. By accessing CancerLinQ, the physician can find treatment and outcome data on many aggregated de-identified patients with the same rare throat cancer across the United States and consider the best treatment course for his patient. The patient’s information then becomes part of CancerLinQ’s database to help inform the care of other patients for years to come.

There are other exciting aspects of CancerLinQ being developed—which confidentiality precludes me from revealing at this time—that will directly benefit individual cancer patients. In general terms, they include the promise of genomic matching, clinical trial eligibility and suitability matching, and biomarker identification.

In addition to providing clinicians and researchers with usable, real-world cancer information, CancerLinQ also allows patients, through their data, to help other patients with the disease. Once patients receive information generated by CancerLinQ to guide their own treatment decisions, their data will then be added to the database to help those following them.

One of the greatest comforts patients treated for cancer can have is the ability to use their ordeal to strike out against their disease and to help other patients. CancerLinQ provides that comfort.

Keeping Patients Informed As the development and rollout of CancerLinQ attract more and more attention, it is important for patient advocates and cancer support group leaders to know its capabilities, so they can pass the information to patients. Soon, Twitter, Facebook, and other social media outlets will be discussing this new technology, and it is quite probable that patients will be asking their oncologists if they are part of the CancerLinQ network or if they intend to be.

Although completion of the full development of CancerLinQ is several years away, with each progress report, we can take comfort in the promise that this exciting health information technology platform offers to guide personalized cancer treatment decisions, inform research, and improve quality of life for millions of patients with cancer. n Disclosure: Dr. Omel reported no potential conflicts of interest.

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PAGE 49

Announcements

First Winners of Tri-Institutional Breakout Awards Announced

S

ix young scientists at Memorial Sloan Kettering Cancer Center, Rockefeller University, and Weill Cornell Medical College have been named the inaugural winners of a new prize established to recognize postdoctoral investigators in the life sciences. The Tri-Institutional Breakout Awards for Junior Investigators, which include a $25,000 prize for each recipient, were established by three Tri-Institutional winners of the 2013 Breakthrough Prize in Life Science — one from each of the three institutions — with additional financial support from the institutions themselves.

Hani Goodarzi, PhD

the likelihood of their future success as independent investigators. The contributing Breakthrough Prize winners were not involved in the selection of the winning postdocs.

2015 Breakout Recipients (Oncology-Focused)

Pfizer is proud to announce the Advancing Science through Pfizer – Investigator Research Exchange (ASPIRE) Breast Cancer Research Awards, a competitive, peerreviewed grants program sponsored by Pfizer for investigators in the United States

Hani Goodarzi, PhD, Rockefeller University Dr. Goodarzi is using an algorithm he developed during his doctoral research at Princeton University to scan both the sequence and shape of RNA molecules in breast cancer cells, leading to the discovery of a post-transcriptional network that regulates metastasis.

Julian Lange, PhD

The seed money for the Breakout Awards came from three investigators— Charles L. Sawyers, MD, of Memorial Sloan Kettering; Cornelia I. Bargmann, PhD, of Rockefeller; and Lewis C. Cantley, PhD, of Weill Cornell—who each received a $3 million award from the 2013 Breakthrough Prize, which was established by a group of well-known Silicon Valley entrepreneurs.

Beginning this year, Breakout Awards will be given annually to between three and six outstanding postdoctoral trainees, with one prize given to an applicant from each of the three founding institutions and additional awards made to the best candidates, regardless of affiliation. A committee containing faculty members from each of the institutions selects awardees on the basis of their past research accomplishments, the impact of their science, and

2015 ASPIRE Breast Cancer Research Awards Program

Costas Lyssiotis, PhD

Julian Lange, PhD, Memorial Sloan Kettering Cancer Center Dr. Lange has pioneered novel methods for studying recombination in the creation of egg and sperm cells in mice. In his recent work, he has uncovered how meiotic cells regulate the distribution of DNA damage.

Costas Lyssiotis, PhD, Weill Cornell Medical College Dr. Lyssiotis investigates the biochemical pathways and metabolic requirements that enable pancreatic tumor growth, and is translating discoveries into the development of targeted therapies.

The other three recipients are Ziv Shulman, PhD (Rockefeller); Jing Yang, PhD (Rockefeller); and Dilek Colak, PhD (Weill Cornell).

For more information about the Tri-Institutional Breakout Awards, visit https:// breakthroughprize.org/Prize/2. n

Call for Research Proposals For complete information on the scope of research, please visit ASPIRE website at www.aspireresearch.org Mission The mission of the ASPIRE Awards is to support clinical research of a Pfizer compound in advanced breast cancer through a competitive grants program to advance knowledge in the treatment and disease management of advanced breast cancer.

Awards 2015 ASPIRE Breast Cancer Research Awards program intends to fund three to six clinical studies within scope, for a total of approximately 3 million US dollars.

It is open to US investigators. Selection of research proposals will be performed by an independent external review panel of breast cancer experts.

Submissions are due September 8, 2015

Cornelia I. Bargmann, PhD

Lewis C. Cantley, PhD

Charles L. Sawyers, MD

www.aspireresearch.org

The ASCO Post | JULY 10, 2015

PAGE 50

Women in Oncology Clara D. Bloomfield, MD, FASCO: Never One to Back Down From a Challenge

By Ronald Piana

Clara D. Bloomfield, MD, FASCO

C

lara D. Bloomfield, MD, FASCO, always sat in the front row at school.

She grew up during a rigidly paternalist period in American society, and her early feminist leanings were brushed aside as grade-school adventures. The medical school lecture room of the 1960s was a male-dominated culture, and when Dr. Bloomfield sat front-row center, it raised eyebrows. “The dean called me into his office and rather curtly explained that sitting in the front row that way was unladylike. I said, ‘When you become a lady you can tell me how to act like one,’ and walked out,” Dr. Bloomfield told The ASCO Post.

Academic Childhood Dr. Bloomfield was born in New York, New York, during World War II. Both parents were academics, and the household brimmed with a bookish environment: comic books and even TV, once available, were not allowed.

With her trademark frankness, Dr. Bloomfield told The ASCO Post that she was conceived to spare her father from combat in the war. Early on, a man with a dependent was deferred.

Dr. Bloomfield’s father was an expert in labor and industrial relations, which was needed on the War Labor Board, so he uprooted the family and moved to Washington DC. “When the war ended, my father took a position at the University of Illinois in Champaign-Urbana. Many of his trainees and visitors were foreign, and we’d often have dinner guests from South America or subSaharan Africa. It was an exciting time, full of possibilities,” said Dr. Bloomfield.

Mother as Mentor Although her father filled the household with worldly intellectuals, Dr. Bloomfield regards her mother as her

mentor, the spark that set her career path toward medicine. She had an early interest in science, and one day, when she was in second grade, she told her mother that she wanted to be a nurse when she grew up. “My mother, not one to disparage nursing, said, ‘If you want to go into medicine, why not become a doctor!’ So that’s when I made my decision to become a doctor, and I never swayed,” said Dr. Bloomfield.

Her mother, a feminist in her own right, was one of the first women to attend the law school at the University of Illinois. Having an independent and selfmotivated mother also helped mold Dr. Bloomfield’s mettle and career drive.

“My mother began law school when I was in first grade, and she received her law degree when I graduated high

University of Illinois Laboratory High School, Dr. Bloomfield entered the University of Wisconsin and while doing her premed, she became very interested in genetics, which would inform much of her later research. She married a chemist during her junior year who wanted to do his postdoctoral work in a renowned research institute in La Jolla, California, so off they went to the West Coast.

“Since the University of California at San Diego did not exist at the time, I finished my last year of college at San Diego State College and then was faced with the challenge many women in academia face: how to coordinate two academic careers,” said Dr. Bloomfield.

Coordinating careers resulted in a longdistance commuter marriage: Her hus-

Don’t be afraid to challenge authority…. Look at what’s in front of you and trust your own analysis.

That’s the way breakthroughs happen.

—Clara D. Bloomfield, MD, FASCO

school,” said Dr. Bloomfield, adding, “When I was 9, my mother announced that she wasn’t spending enough time with the family, so she decided to quit law school. My younger brother and I started crying and screaming that we couldn’t have a mother who wasn’t going to law school,” said Dr. Bloomfield.

She commented that the state had to pass a law allowing her mother to obtain her law degree since her lengthy schooling had passed the statute of limitations governing the time it takes to complete law school.

Interest in Oncology and Genetics While attending grade school, Dr. Bloomfield had classmates who developed leukemia. Because of the limited options in the early 1950s, they were sent to the National Cancer Institute for treatment.

“Then they’d return with steroid-bloated faces and soon die,” she said.

“I remember thinking to myself, how cool it would be to develop a medicine that could save kids from dying of childhood leukemia. I’d already decided to become a doctor, so seeing the real-life effects of cancer certainly helped shape my early desire to become an oncologist.”

In 1959, after graduating from the

band accepted a chemistry professorship offer at the University of Illinois in Champaign-Urbana, and she decided to go to medical school at the University of Chicago.

In the year prior to entering medical school, Dr. Bloomfield worked in a biochemistry lab at the prestigious Scripps Research Institute, which was at the cutting edge of scientific exploration.

“At that time, a prominent faculty member working where my husband was had Hodgkin disease, and he was traveling back and forth to Stanford to see renowned Hodgkin specialist Henry Kaplan, MD, a radiotherapist who was largely responsible for the transformation of Hodgkin disease from a hopeless to highly curable disease.”

She continued, “My mindset, from my grade school days seeing classmates die of leukemia, was that cancer was a death sentence—I was amazed by how well my husband’s professor colleague was responding. That experience had a significant effect on my decision to study hematologic malignancies,” said Dr. Bloomfield.

At the University of Chicago, Dr. Bloomfield worked with Henry ­R appaport, MD, best known for his “Rappaport Classification” in lympho-

ma. “The structure at the University was geared toward an academic career, which fit in to how I’d been brought up,” said Dr. Bloomfield.

Grand Rounds With Dr. Kaplan Between her junior and senior years, Dr. Bloomfield did a subinternship at the University of California at San Francisco (UCSF). “After a month or so, I saw a patient with Hodgkin disease who was not being treated with curative intent. I said, this is terrible, you’re not giving this patient modern therapy,” said Dr. Bloomfield. Her attending replied, “Well, if you’re so smart, we’ll have you do grand rounds on how to treat Hodgkin disease.”

Not one to back down from a challenge, but also wanting support, Dr. Bloomfield called Stanford and asked the famous Dr. Kaplan for advice.

“Henry was really nice; he said he’d be thrilled to come and help me do grand rounds,” said Dr. Bloomfield. To the surprise of the attending at UCSF, Dr. Bloomfield, a medical student, conducted grand rounds with her associate from Stanford, Dr. Henry Kaplan.

Confronted Pay Discrimination In 1971, Dr. Bloomfield began her medical oncology fellowship at the University of Minnesota, where she became one of the institution’s first female Chief Residents and was awarded an American Cancer Society Junior Clinical Faculty Fellowship.

“Throughout my career in academia, I’ve confronted issues of pay discrimination for women,” said Dr. Bloomfield.

While at the university, she moved from Assistant Professor to Associate Professor in just 3 years and later became the university’s first female full Professor of Medicine.

Dr. Bloomfield recalled how her promotion unfolded. “My husband also worked at the university. When the head of medicine called me into his office, he said, ‘Congratulations on the promotion, Clara, but because your husband makes such a good salary, we’ve decided not to give you a raise.’ And he said it with a straight face!

When I got home, I told my husband.

He was a bit of a heavyweight there, so he called his dean who called the University president, and my pay issue was immediately solved. That was my first,

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PAGE 51

Women in Oncology but certainly not my last, exposure to the pay bias women face in the academic setting,” Dr. Bloomfield said.

Leukemia Research As a beginning assistant professor, she created and ran the Medical Oncology Division’s newly formed Leukemia and Lymphoma Service at the University of Minnesota, initially seeing every patient herself. It proved to be an invaluable career move.

As a fellow, she conducted a seminal study looking at all adult patients with acute leukemia seen at her institution over the past 10 years. “The majority had acute myeloid leukemia (AML).

Our longest survivor was 17 years old and lived for 33 months. Given the success we were beginning to see in childhood leukemia, I saw an opportunity in adult disease. We stratified the patients by age, and as a result, I found that the older adult patients could do just as well as the younger ones,” said Dr. Bloomfield.

Dr. Bloomfield and coauthor ­Athanasios Theologides, MD, PhD, published their results in 1973 in JAMA, showing that older adult patients could respond just as well to treatment as their younger counterparts. “At the time, all of the major hematologists contended that treating AML patients over 50 years of age was tantamount to malpractice. So you can imagine the stir I caused,” said Dr. Bloomfield.

“It was an important lesson,” she continued, “one that resulted in my telling my fellows, don’t be afraid to challenge authority, even if it’s the biggest name in the field. Look at what’s in front of you

and trust your own analysis. That’s the way breakthroughs happen.”

Dr. Bloomfield’s subsequent research further helped reshape the clinical approach to hematologic malignancies. “We conducted one of the first prospective studies on bone marrow chromosomes and their clinical significance. We learned that leukemia and lymphoma belong to a heterogeneous group of genetic diseases.” Subsequently, she and her team were the first to identify the Philadelphia chromosome in acute lymphoblastic leukemia as well as the biologic and genetic markers important in the diagnosis and treatment of AML—more controversial, groundbreaking work from the young, indomitable researcher.

“Many prominent cytogeneticists did not believe my data on the Philadelphia chromosome. However, one of them, Dr. Avery Sandberg, while surprised by the discovery said, ‘She may be right. Sometimes these youngsters get things that we’ve missed,’” said Dr. Bloomfield.

Dr. Bloomfield left Minnesota in 1989, taking a position at Roswell Park Cancer Institute, serving as Roswell’s Chair of the Department of Medicine.

In 1997, a career turn took her to The Ohio State University (OSU), where she served as Director of the Division of Hematology and Oncology and Director of the OSU Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Solove Research Institute (OSUCCC–James) until 2003. She is currently a Distinguished University Professor, William G. Pace III Professor of Cancer Research and Senior Advisor

Clara D. Bloomfield, MD, FASCO, is the Distinguished University Professor & William G. Pace III Professor of Cancer Research at The Ohio State University.

at the OSUCCC–James.

On the global scale, her work has also translated into internationally accepted classification systems for blood disorders, including that of the World Health Organization, which incorporated genetics into its classification of AML. “We now cure 40% of adult patients between the ages of 16 and 60 with primary (de novo) acute leukemia,” Dr. Bloomfield pointed out.

Baroness Bloomfield After Dr. Bloomfield’s first marriage ended, she married Albert de la ­Chapelle, MD, PhD, a geneticist and Professor in the Department of Molecular Virology, Immunology, and Medical Genetics at Ohio State University. “We’ve been married for 31 years,

but as we have different names and are prominent in separate fields, lots of people don’t know we’re a couple,” said Dr. Bloomfield.

Dr. de la Chapelle is of Finnish nobility, a landed baron whose family owns a vast estate by the sea in his homeland. So, among Dr. Bloomfield’s other notable designations, she has added baroness.

Asked what she and her husband do besides work, Dr. Bloomfield said, “That’s about it. Although we have a tandem bicycle that we have enjoyed riding. But last year, my husband was unable to ride in the 180-mile cancer fundraiser at the OSUCCC, so now I ride with one of my fellows on the tandem bike. He’s a bull.” n Disclosure: Dr. Bloomfield reported no potential conflicts of interest.

Save the Date Best of ASCO® Boston

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July 31­–August 1, 2015

August 7–8, 2015

August 28–29, 2015

Renaissance Boston Waterfront Hotel

San Francisco Marriott Marquis

Swissotel Chicago

Boston, Massachusetts

San Francisco, California

Chicago, Illinois

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

ssion e r g o r p e s t disea r your patients a I D N A T Start X static CRPC fo1 to meta therapy* on GnRH

*Or af

ter

.1 ctomy ie h c r al o bilater

Important Safety Information Contraindications XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In Study 1, conducted in patients

with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure.

Study 1 excluded the use of concomitant medications that may lower threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Adverse Reactions The most common adverse reactions

(≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

Other Adverse Reactions include: • Laboratory Abnormalities: In the two studies, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

• Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Significantly extended radiographic progression-free survival†1

Significantly improved overall survival†1 • 29% reduction in risk of death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.71 [95% CI, 0.60-0.84]; P < 0.0001)

• 83% reduction in risk of radiographic disease progression or death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.17 [95% CI, 0.14-0.21]; P < 0.0001)

• Estimated median overall survival was 32.4 months (95% CI, 30.1-not reached) for XTANDI + GnRH therapy* and 30.2 months (95% CI, 28.0-not reached) for placebo + GnRH therapy*1

• Estimated median radiographic progression-free survival was not reached (95% CI, 13.8-not reached) for XTANDI + GnRH therapy* and was 3.7 months (95% CI, 3.6-4.6) for placebo + GnRH therapy*1

Oral, once-daily dosing with no required steroid coadministration1

Significantly delayed time to chemotherapy initiation†1 • Delayed time to chemotherapy initiation by a median of 28.0 months with XTANDI + GnRH therapy* vs 10.8 months with placebo + GnRH therapy* (HR = 0.35 [95% CI, 0.30-0.40]; P < 0.0001)

• Dosage: XTANDI 160 mg (four 40 mg capsules) is administered orally, once daily • Steroids were allowed but not required‡

94% §

of insured patient lives are covered for XTANDI§3

As of February 2015. A product’s placement on a plan formulary involves a variety of factors known only to the plan and is subject to eligibility.

To learn more, please visit XtandiHCP.com

• Falls: In the two studies, falls including fall-related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo.

Falls were not associated with loss of consciousness or seizure.

Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas.

• Hypertension: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis.

Medical history of hypertension was balanced between arms.

Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients.

Drug Interactions • Effect of Other Drugs on XTANDI - Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible.

© 2015 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 076-0800-PM 3/15 XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma Inc.

• Effect of XTANDI on Other Drugs - XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information. †As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC that progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,2 ‡In the PREVAIL trial, 27% of patients in the XTANDI arm and 30% of patients in the placebo arm received glucocorticoids for varying reasons. In the AFFIRM trial (Study 1), 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids. AFFIRM was a phase 3, multicenter, placebo-controlled, randomized trial that enrolled 1199 patients with metastatic CRPC who had previously received docetaxel.1 References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433. 3. Data on file, Medivation, Inc.

The ASCO Post | JULY 10, 2015

PAGE 54

In Memoriam

Noted Pediatric Oncologist, Robert J. Arceci, MD, PhD, Dies

By Ronald Piana

O

ver the past 50 years, great strides have been made in diagnosis, treatment, and survival of childhood cancer. In the 1960s, the probability

of survival for a child with cancer was less than 25%, whereas today it may exceed 80%. This incredible cancer success story has been made possible

by the work of researcher-physicians such as Robert J. Arceci, MD, PhD, who co-directed the Ronald A. Matricaria Institute of Molecular Medicine

at Phoenix Children’s Hospital, in Arizona. Dr. Arceci was killed in a motorcycle accident on June 8, 2015. He was 65 years old.

Table 1. Adverse Reactions in Study 1 (cont.)

Respiratory Disorders

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information.

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in Study 1

Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDItreated patients and 37% of placebo-treated patients.

Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

INDICATIONS AND USAGE

XTANDI N = 800

XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Grade 1-4a (%)

CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].

WARNINGS AND PRECAUTIONS Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience readministering XTANDI to patients who experienced seizure.

Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

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

Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.

The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

General Disorders Asthenic Conditionsb Peripheral Edema

Placebo N = 399

Grade Grade Grade 3-4 1-4 3-4 (%) (%) (%)

50.6

9.0

44.4

9.3

15.4

1.0

13.3

0.8

Musculoskeletal And Connective Tissue Disorders Back Pain

26.4

5.3

24.3

4.0

Arthralgia 20.5 Musculoskeletal 15.0 Pain Muscular 9.8 Weakness Musculoskeletal 2.6 Stiffness Gastrointestinal Disorders

2.5

17.3

1.8

1.3

11.5

0.3

1.5

6.8

1.8

0.3

0.3

0.0

21.8

1.1

17.5

0.3

Hot Flush

20.3

0.0

10.3

0.0

Hypertension

6.4

2.1

2.8

1.3

Diarrhea Vascular Disorders

Nervous System Disorders Headache

12.1

0.9

5.5

0.0

Dizzinessc Spinal Cord Compression and Cauda Equina Syndrome Paresthesia Mental Impairment Disordersd Hypoesthesia

9.5

0.5

7.5

0.5

Epistaxis

3.3

0.1

1.3

0.3

a CTCAE v4 b Includes asthenia and fatigue. c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Table 2. Adverse Reactions in Study 2 XTANDI N = 871 Grade 1-4a (%)

Grade 3-4 (%)

Placebo N = 844 Grade 1-4 (%)

Grade 3-4 (%)

General Disorders Asthenic 46.9 3.4 33.0 2.8 Conditionsb Peripheral 11.5 0.2 8.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders Back Pain

28.6

2.5

22.4

3.0

Arthralgia

21.4

1.6

16.1

1.1

Gastrointestinal Disorders 7.4

6.6

4.5

3.8

6.6

0.0

4.5

0.0

4.3

0.3

1.8

0.0

4.0

Infections And Infestations Upper Respiratory Tract 10.9 Infectione Lower Respiratory 8.5 Tract And Lung Infectionf Psychiatric Disorders

0.3

0.0

1.8

6.5

0.0

0.3

2.4

4.8

1.3

Insomnia

8.8

0.0

6.0

0.5

Anxiety

6.5

0.3

4.0

0.0

Renal And Urinary Disorders Hematuria

6.9

1.8

4.5

1.0

Pollakiuria

4.8

0.0

2.5

0.0

Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 Non-pathologic 4.0 1.4 0.8 Fractures Skin And Subcutaneous Tissue Disorders

0.0 0.3

Pruritus

3.8

0.0

1.3

0.0

Dry Skin

3.5

0.0

1.3

0.0

Constipation

23.2

0.7

17.3

0.4

Diarrhea

16.8

0.3

14.3

0.4

Vascular Disorders Hot Flush

18.0

0.1

7.8

0.0

Hypertension

14.2

7.2

4.1

2.3

Nervous System Disorders Dizzinessc

11.3

0.3

7.1

0.0

Headache

11.0

0.2

7.0

0.4

Dysgeusia

7.6

0.1

3.7

0.0

5.7

0.0

1.3

0.1

2.1

0.1

0.4

0.0

0.6

8.5

0.6

0.0

10.5

0.0

1.5

4.7

1.1

0.1

5.7

0.0

Mental Impairment Disordersd Restless Legs Syndrome

Respiratory Disorders Dyspneae

11.0

Infections And Infestations Upper Respiratory 16.4 Tract Infectionf Lower Respiratory Tract And 7.9 Lung Infectiong Psychiatric Disorders Insomnia

8.2

ASCOPost.com | JULY 10, 2015

PAGE 55

In Memoriam

Dr. Arceci completed his undergraduate studies at Trinity College, Hartford, and received his PhD and MD degrees from the University of Rochester. He then completed his residency in pediatrics and fellowship in pediatric hematology/oncology at The Children’s Hospital, Bos-

ton, and at Harvard Medical School.

Following faculty appointments at Harvard Medical School, the DanaFarber Cancer Institute, and Boston Children’s Hospital, Dr. Arceci became Director of Pediatric Hematology/Oncology at Children’s Hospital Medical Center in Cincinnati.

In 2000, Dr. Arceci became Director and King Fahd Professor of Pediatric Oncology and Professor of Oncology and Pediatrics at the Johns Hopkins University School of Medicine. In 2012, Dr. Arceci was teaching at the Johns Hopkins University School of Medicine when he moved Robert J. Arceci, MD, PhD

Table 2. Adverse Reactions in Study 2 (cont.)

Renal And Urinary Disorders Hematuria

8.8

1.3

5.8

1.3

Injury, Poisoning And Procedural Complications Fall

12.7

1.6

NonPathological 8.8 2.1 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 Appetite

5.3

0.7

3.0

1.1

16.4

0.7

8.5

0.2

Investigations Weight Decreased

12.4

0.8

Reproductive System and Breast Disorders Gynecomastia

3.4

0.0

1.4

0.0

a b c d

CTCAE v4 Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4).

The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.

Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible.

Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)].

Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl

enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)].

The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.

Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible.

Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)].

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category X [see Contraindications (4)].

Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryofetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).

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

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical

experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted.

Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)].

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function.

The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)].

OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: September 2014 14B006-XTA-BRFS Rx Only © 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

076-0472-PM

to Arizona, after being recruited to be part of Phoenix Children’s Hospital’s Institute of Molecular Medicine.

An International Authority He was considered an international authority in many challenging areas of clinical pediatric oncology, including the diagnosis and treatment of leukemia and Langerhans cell histiocytosis.

He has served on a variety of committees in the Pediatric Oncology Group; the Children’s Cancer Group; and the Children’s Oncology Group, including Chairperson for the Myeloid Leukemia Committee and Vice-Chair of the Biology and Therapeutics Translational Committee.

As an avid motorcyclist, Dr. Arceci married two of his passions by exploring the desert landscape of Arizona and participating in charitable motorcycle rides to benefit pediatric medicine. “I love motorcycles because really, everything else is just transportation,” he was fond of saying.

About his life’s work in pediatric cancers, Dr. Arceci said, “Children are going to be the people who help the adults. They are going to save us. I think it is truly phenomenal.”

Dr. Arceci is survived by his wife and two children. n

 In Memoriam Robert J. Arceci, MD, PhD

1950 – 2015 

The ASCO Post | JULY 10, 2015

PAGE 56

2015

2015 Oncology Meetings June ASCO Review 2015 June 26 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/ courses/2015/ASCO15/default.asp 2nd EACR Special Conference on Cancer Genomics June 28-July 1 • Cambridge, United Kingdom For more information: www.eacr.org

Palliative Medicine and Supportive Oncology 2015 July 23-25 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/ courses/pallmed15/overview.asp APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28-August 1 • Washington, DC For more information: www.apos-society.org 16th Annual International Lung Cancer Congress® July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/ meetings/16th-International-LungCancer-Congress

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July

August

7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp

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Best of ASCO - San Francisco August 7-8 • San Francisco, California For more information: http://www.keck.usc.edu/events/6thannual-pain-management-symposiumfrom-evidence-to-clinical-practice/

ASCO Multidisciplinary Cancer Management Course (MCMC) August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/

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September 2015 World Molecular Imaging Congress September 2-5 • Honolulu, Hawaii For more information: www.wmis.org/meetings/ International Palliative Care Workshop September 3-5 • Fez, Morocco For more information: www.asco.org/international-programs/ international-palliative-care-workshops 25th World Congress of the International Association of Surgeons, Gastroenterologists, and Oncologists September 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org

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18th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO) September 16-20 • Xiamen, China For more information: www.csco.ac.cn American Society of Hematology (ASH) Meeting on Hematologic Malignancies September 17-19 • Chicago, Illinois For more information: www.hematology.org/Malignancies/ ISEH 44th Annual Scientific Meeting September 17-19 • Kyoto, Japan For more information: www.iseh.org/?page=Meeting HPV 2015–30th International Papillomavirus Conference September 17-21 • Lisbon, Portugal For more information: www.hpv2015.org 3rd Annual Hematology/Oncology Pharmacy Association (HOPA) Oncology Pharmacy Practice Management Program September 18-19 • Chicago, Illinois For more information: www.hoparx.org/education/2015Practice-Management-Program/2015practice-management-programwelcome.html 2nd International Symposium of the Cancer Research Center of Lyon (CRCL) September 21-23 • Lyon, France For more information: www.crclsymposium2015.fr continued on page 65

The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2

AGENTS.

1

THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1-3

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

150 mg twice daily

as a single agent

overall response rate1,2 overall response rate1,2

76 54%

% (95% CI: 62, 87)

median duration of response1,2

(95% CI: 40, 67)

median duration of response1,2

10.5 months 5.6

months

(95% CI: 7, 15)

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.

Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.

Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAPkinase signaling and increased cell proliferation in BRAF wildtype cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST.

To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Novartis recently acquired these products from GSK. To ensure a seamless transition, GSK is continuing to provide support for these products and related programs on behalf of Novartis at this time.

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1,2 Major efficacy outcome: Investigator-assessed overall response rate1,2 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

60

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1,2

50 40 30 20 10 0

9%

4

%

Complete Response

Partial Response

TAFINLAR as a single agent 150 mg twice daily

(N=54)

Complete Response

TAFINLAR

150 mg twice daily

+

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with

MEKINIST and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55).

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances.

Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent.

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1,2 Efficacy outcome: Investigator-assessed median duration of response1,2

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months TAFINLAR as a single agent 150 mg twice daily (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1,2 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1,2 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1,2

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment.

RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level.

Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1.

If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent.

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202).

Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection.

Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.

Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent,

respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%).

The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%).

Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib.

Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

Effects of the Combination of Dabrafenib with Trametinib.

Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions.

To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. MEKINIST [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 3. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703.

Novartis recently acquired these products from GSK. To ensure a seamless transition, GSK is continuing to provide support for these products and related programs on behalf of Novartis at this time.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2015 Novartis

4/15

MAF-1111266

BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent.

The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.

Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55).

Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749).

RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose.

Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.

In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202).

Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/ iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days).

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations.

Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).

Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity.

TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman.

Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.

Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.

In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades a a 3 and 4 Grades Grades Adverse Reactions General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders Rashc 45 0 43 Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

0

8

2

0

2

0

0

9

2

0

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.

Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute.

Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness.

Gastrointestinal Disorders: Stomatitis, pancreatitis.

General Disorders and Administration Site Conditions: Asthenia.

Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.

Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

b

Tests Hematology Leukopenia Lymphopenia Neutropenia Anemia Thrombocytopenia Liver Function Tests Increased AST Increased alkaline phosphatase Increased ALT Hyperbilirubinemia Chemistry Hyperglycemia Increased GGT Hyponatremia Hypoalbuminemia Hypophosphatemia Hypokalemia Increased creatinine Hypomagnesemia Hyperkalemia Hypercalcemia Hypocalcemia

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4a

62 55 55 55 31

5 22 13 4 4

46 59 37 46 31

4 19 2 7 2

21 40 9 28 8

0 6 2 0 0

60

5

54

0

15

0

60

2

67

6

26

2

42 15

4 0

35 7

4 4

11 0

0 0

58 56 55 53 47 29 24 18 18 15 13

5 11 11 0 5 2 5 2 0 0 0

67 54 48 43 41 15 20 2 22 19 20

6 17 15 2 11 2 2 0 0 2 0

49 38 36 23 40 23 9 6 15 4 9

2 2 2 0 0 6 0 0 4 0 0

No Grade 4 events were reported in patients receiving TAFINLAR as a single agent.

ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.

QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. a

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)].

Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)].

Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.

In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals.

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

8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].

Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.

Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].

Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].

Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].

MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].

The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated.

• TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)].

• TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)].

• TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)].

• TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)].

• TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)].

• MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)].

• TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)].

• TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)].

• TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)].

• TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)].

• MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness.

• MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment.

• TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

• Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)].

• Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)].

• TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.

MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved.

Revised: 01/2014 TFR: 4BRS Novartis recently acquired these products from GSK. To ensure a seamless transition, GSK is continuing to provide support for these products and related programs on behalf of Novartis at this time.

ASCOPost.com | JULY 10, 2015

PAGE 65

2015

2015 Oncology Meetings continued from page 56

4th Annual Conference on Immunotherapy in Pediatric Oncology (CIPO2015) September 25-26 • Seattle, WA For more information: www.seattlechildrens.org/research/ childhood-cancer/CIPO-2015/ 2015 Breast Cancer Symposium September 25-27 • San Francisco, CA For more information: http://breastcasym.org

B:14.25 in

T:14 in

S:13 in

European Cancer Congress (ECC 2015) September 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/ European-Cancer-Congress-2015 17th Annual International Meeting of the Institute of Human Virology September 27-30 • Baltimore, MD For more information: http://medschool.umaryland.edu/ ihvmeeting/default.html 5th World Congress on Cancer Therapy September 28-30 • Atlanta, Georgia For more information: http://cancer. global-summit.com/america/

October Advances in Cancer ImmunotherapyTM October 2 • Nashville, Tennessee For more information: www.sitcancer. org/sitc-meetings/aci2015/tn 5th International Breast Cancer Prevention Symposium October 2-3 • Le Gosier, Guadeloupe, French West Indies For more information: www.purdue.edu/breastcancer/ CAP ’15-The Pathologists’ MeetingTM (College of American Pathologists) October 4-7 • Nashville, Tennessee For more information: www.thepathologistsmeeting.org

American College of Surgeons Clinical Congress October 4-8 • Chicago, Illinois For more information: www.facs.org/meetings_events/ future_congress/future 30th Annual Harvard “Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis, and Immunology” October 5-8 • Boston, Massachusetts For more information: http://steele.mgh.harvard.edu/ tumorcourse 20th World Congress on Advances in Oncology and 18th International Symposium on Molecular Medicine October 8-10 • Athens, Greece For more information: www.spandidos-publications.com/ pages/conference Congress of the International Society of Pediatric Oncology October 8-11 • Cape Town, South Africa For more information: http://siop2015.kenes.com Palliative Care in Oncology Symposium October 9-10 • Boston, Massachusetts For more information: http://pallonc.org National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies™ October 16-17 • San Francisco, California For more information: www.nccn.org/professionals/ meetings/hematological/default.aspx

2015 International Cancer Education Conference October 21-23 • Tucson, Arizona For more information: http://2015.attendicec.org ACCC 32nd National Oncology Conference October 21-24 • Portland, Oregon For more information: www.accc-cancer.org/meetings/ calendar.asp 53rd Annual Meeting of the Japan Society of Clinical Oncology (JSCO) October 24-26 • Kyoto, Japan For more information: www.jsco.or.jp/english/index/page/ id/73 ESGO 2015-International Meeting of the European Society of Gynaecological Oncology October 24-27 • Nice, France For more information: http://esgo2015.esgo.org Lynn Sage Breast Cancer Symposium October 29-November 1 • Chicago, Illinois For more information: www.lynnsagebreastcancer.org

November NRCI Cancer Conference November 1-4 • Liverpool, UK For more information: http:// conference.ncri.org.uk Chemotherapy Foundation Symposium November 4-6 • New York, New York For more information: www.chemotherapyfoundationsymposium.org Society for Immunotherapy of Cancer 30th Anniversary Annual Meeting November 4-8 • National Harbor, MD For more information: www.ncer.org/sitc-meetings/sitc2015

ASTRO’s 57th Annual Meeting October 18-21 • San Antonio, Texas For more information: www.astro.org/Meetings-andEvents/2015-Annual-Meeting/Index. aspx

Advanced Breast Cancer Third International Consensus Conference November 5-7 • Lisbon, Portugal For more information: www.abc-lisbon.org

14th International Kidney Cancer Symposium November 6-7 • Miami, Florida For more information: http://registeruo.niu.edu/ iebms/wbe/wbe_p1_main. aspx?oc=40&cc=WBE4014167 ESMO Summit Americas 2015– Oncology Updates: From Evidence to Practice November 6-8 • Miami, Florida For more information: www.esmo.org/Conferences/ESMOSummit-Americas-2015 Best of ASTRO November 13-14 • San Diego, California For more information: www.astro.org/Meetings-andEvents/2015-Best-of-ASTRO/Index. aspx Society for Integrative Oncology 12th International Conference November 14-16 • Boston, Massachusetts For more information: http://www.integrativeonc.org/ conference 12th International Conference of the Society for Integrative Oncology November 15-16 • Boston, MA For more information: www.integrativeonc.org/index.php/ events Advances in Cancer ImmunotherapyTM November 18 • San Francisco, CA For more information: www.sitcancer.org/sitc-meetings/ aci2015/casf 20th Annual Scientific Meeting of the Society for Neuro-Oncology November 19-22 • San Antonio, Texas For more information: www.soc-neuro-onc.org ESMO Symposium on Immuno-Oncology November 20-21 • Lausanne, Switzerland For more information: www.esmo.org/Conferences/ Immuno-Oncology-2015

The ASCO Post | JULY 10, 2015

PAGE 66

In the News Screening

Agreement on High-Value Screening for Five Common Cancers

By Charlotte Bath

F

inding agreement on high-value cancer screening among organizations publishing screening guidelines, the American College of Physicians (ACP) issued advice listing the least-intensive screening strategies that all the organizations recommend—as well as strategies not recommended—for five common cancers: breast, colorectal, ovarian, cervical, and prostate. Publishing the advice in the Annals of Internal Medicine, the ACP High Value Care Task Force stressed that the advice applied to asymptomatic adults at average risk for the five cancers.1 The report has received national media attention, including CBS News, the Los Angeles Times, AP, and Reuters, and generated interest among its target audience of clinicians. “It has only recently been published, but generally we have received very positive feedback,” one of the paper’s lead authors, Amir Qaseem, MD, PhD, MHA, FACP, told The ASCO Post. “All these recommendations that we have summarized in this paper are evidence-based clinical recommendations from reputable guideline groups. So it is not a surprise that everyone is in agreement,” added Dr. Qaseem, Director of Clinical Policy of the ACP and President Emeritus of Guidelines International Network.

“There is no doubt that screening is one of the strategies to reduce cancer deaths. No one is arguing that. The issue that people have started to come to

realize is that more intensive screening does not result in any additional reduction in cancer deaths but increases the harm. As intensity increases beyond a certain level, the increase in benefits is not really there, but the harms keep on going up, and, hence, the value of any kind of screening test starts going

can Urological Association, and American Gastroenterological Association.

Strictly defined, a guideline is “a systematic review of evidence,” Dr. ­Qaseem noted. The ACP Task Force did not review primary literature or evidence because that had already been done by those organizations.

Yes, cancer screening is one of the strategies that has saved lives, but maybe the pendulum swung too far on the other end, where we start realizing that there are harms of each and every one of these tests.

—Amir Qaseem, MD, PhD, MHA, FACP

down,” Dr. Qaseem stated. “We wanted to focus on appropriate screening, to do the high-value screening and avoid the low-value screening. That is what we tried to clarify in this paper.”

“What we tried to do was essentially look at the guidelines that are already out there and identify areas of agreement, and there are plenty of areas of agreement, across most of these organizations,” Dr. Qaseem said.

Review of Guidelines and Evidence

Areas of Common Agreement

The ACP High Value Care Task Force based its advice on a review of clinical guidelines and evidence synthesis from the ACP, U.S. Preventive Services Task Force, American Cancer Society, American Academy of Family Physicians, American Congress of Obstetricians and Gynecologists, Ameri-

Breast Cancer: The review of guidelines from all the organizations cited previously found that “all groups recommend mammography screening, or discussions about screening, at least every 2 years for women aged 40 to 74 years,” the ACP Task Force noted. “No group recommends regular systematic

magnetic resonance imaging (MRI) or tomosynthesis screening for averagerisk women.”

Colorectal Cancer: “All organizations recommend screening persons aged 50 to 75 years with one of four strategies,” the ACP Task Force noted.

These strategies are high-sensitivity fecal occult blood test or fecal immunochemical test every year, sigmoidoscopy every 5 years; combined high-sensitivity fecal occult blood test or fecal immunochemical test every 3 years plus sigmoidoscopy every 5 years; or optical colonoscopy every 10 years.

Ovarian Cancer: “All organizations recommend against pelvic examinations, cancer antigen 125 blood tests, and transvaginal ultrasonography for ovarian cancer screening.”

Cervical Cancer: “All organizations recommend starting screening with cytology without human papillomavirus (HPV) tests every 3 years at age 21 years, regardless of sexual history. At age 30 years, women have the choice of continuing cytology screening every 3 years or cotesting with cytology plus HPV testing every 5 years. Do not screen in women who had a hysterectomy and the cervix was removed.”

Prostate Cancer: “No organization recommends prostate-specific antigen (PSA) testing for prostate cancer screening without a discussion of the benefits and harms and a patient’s expressed, clear preference for screening.”

Expect and Encourage Questions About the Benefits and Harms of Cancer Screening

I

ssuing advice for high-value care in screening for five common cancers, the High Value Care Task Force of the American College of Physicians (ACP) stated: “The target audience for this paper is all clinicians. The target patient population is average-risk, asymptomatic patients.”

“What we tried to do is simplify the message, not only just for physicians and clinicians, but also for patients. So if any patient picks up this document, they will be able to see that as well,” ACP task force member Amir Qaseem, MD, PhD, MHA, FACP, said in an interview with The ASCO Post. Dr. Qaseem is

Director of Clinical Policy, ACP, and President Emeritus, Guidelines International Network. The screening advice was published in the Annals of Internal Medicine. The article and a summary for patients are available at acponline.org.

Team-Based Approach “It is a team-based approach. We have to work together,” Dr. Qaseem said. “As a patient, I need to know what is happening. But as a physician, I am also responsible to educate the patient: Here are the benefits, but here are the harms. Every test is associated with false positives. Some tests may have more or

less, but every test has some harms.”

The screening advice is based on guidelines from “reputable guideline groups” for breast, colorectal, ovarian, cervical, and prostate cancers, Dr. Qaseem noted, but “these are guidelines only. They are population-based, and, of course, physicians have to use their own judgment.”

“It is important for patients to become educated consumers as well. Patients should be empowered anyway,” he added, and encouraged to ask questions.

What if the Patient Persists?

What if a patient acknowledges screening may not be high value, but still wants it, to feel safer or not

to break well-established routine, or for whatever reason?

“That really comes down to a physician’s responsibility to do no harm,” Dr. Qaseem said. “You need to sit down and talk to your patients, to hear them out and find out why they feel like that.

There might be some reason. Maybe they have a family history” not previously disclosed. “Maybe they have heard something from their neighbor, who might have been getting screened.

In that case, you would need to explain that maybe the neighbor had a family history or some other risk factor. Most patients are reasonable.” n Disclosure: Dr. Qaseem reported no potential conflicts of interest.

ASCOPost.com | JULY 10, 2015

PAGE 67

In the News It’s Not Just About the Money As defined by ACP, “value is determined by an intervention’s health benefits vs its harms and costs,” the Task Force wrote. “High-value strategies return large health benefits for the harms and costs incurred; low-value strategies return disproportionately small benefits for the harms and costs. Although highintensity strategies aim to maximize cancer detection, value is optimized by finding the level of intensity that best balances benefits with harms and costs.”

The authors searched databases, models of screening effectiveness, and national studies for information on costs, but that was just one factor and not a major focus in formulating the screening advice. “We need to differentiate between this value and costs,” Dr. Qaseem said, so that the screening advice is not misinterpreted merely as a means to save money. “A cheap test can actually still be a low-value test. And an expensive test actually can still be of high value.”

The ACP Task Force found “20% of women aged 30 to 39 years received a physician recommendation for mammography, and 23% to 35% in this age group had mammography. Most women having mammography receive it annually. One-third of surveyed primary care physicians screen with ul-

trasonography and MRI, in addition to mammography, in women not at increased risk for breast cancer.” Not only is cervical cancer screening “commonly done earlier and more frequently than recommended,” but it continues to be done in 38% of women aged 80 years or older.”

‘Perfect Storm of Overuse’ In a companion article4 outlining a framework for thinking about the value of varying intensities of cancer screening, the ACP Task Force noted: “Physicians and patients are under great pressure from many sources to use the continued on page 68

® ®

makes all the difference makes all the difference

‘A Classic Example’ “Screening average-risk adults aged 50 to 75 for colorectal cancer with a high-sensitivity fecal occult blood test every year is an example of high-value care. Screening women without a cervix for cervical cancer is an example of lowvalue care,” according to an ACP press release announcing the publication of the screening advice.2 And according to the published article, “Nearly 70% of women without a cervix received a Pap test for cervical cancer screening in 2002.”3 Really? “Yes, it still happens. Dr. Qaseem confirmed. “The Pap test is one of those tests that is being overused for sure. It’s a classic example. Just a simple Pap test is actually a low-cost test. But it still is of low value if you are going to do it on an annual basis.”

Screening Is Popular “Regardless of value, cancer screening is popular among the U.S. public and is done more frequently than in other countries,” the article pointed out.

Among adults receiving colonoscopies, 60% had them more frequently than guidelines recommend, “and screening often occurs in adults with life expectancies of 5 years or less,” the authors reported. “Most persons having PSA testing received annual cancer screening, and one-half of men aged 75 to 79 years had recent screening,” the authors added. Overall, more than 50% of men and women older than 75 years report that their physicians continue to recommend screening, according to the article.

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PAGE 68

In the News Cancer Screening continued from page 66

‘maximal cancer detection’ framework rather than the value framework.”

Factors that could contribute to this pressure include a lack of knowledge or understanding of the harms of screening, fear of cancer, belief that earlier detection is always better, media messages about screening, stories of survivors, belief that action is better than inaction, and intolerance of uncertainty. “The relative importance of these factors in stimulating the use of overly intensive low-value screening strategies is underinvestigated and largely unknown,” the authors acknowledged. “However, many factors seem to encourage this practice, creating what has been described as a ‘perfect storm’ of overuse.”

‘Cascade of Events’ “Screening is a cascade of events rather than a single test,” the ACP Task Force members noted in the companion article.

“Absolutely,” Dr. Qaseem resolutely concurred. “Because once you do the test and you find something, it always leads to the next test. You never just leave it at that. It just does not happen.

Once you find something, it is going to

lead to more tests, more biopsies. Once you are in that cycle, it gets very difficult to get out.”

Freeing Up Time and Money Reducing the intensity of screening would not only reduce the harms associated with it, but “the other benefit is that you are going to spend time talking about other services that might provide higher value,” Dr. Qaseem said. “So in the 10 to 15 minutes you have to sit down and to talk to patients, rather than talking about something that might not provide much benefit, you can spend time discussing things that actually might have much added value. It could be about exercise. It could be about their cholesterol. It could be about their hypertension.”

Moving to the value approach to screening could redirect funds to increase screening among disadvantaged groups, people for whom screening is not popular because they haven’t been able to afford health care. If funds were so redirected, Dr. Qaseem said that he hoped it would be for screening based on the ACP advice and not past practices.

“Hopefully, funds will be directed to the right place, where we need the money, to the uninsured, or the folks who may

not have enough, the underserved population.” He cited the example of colorectal cancer, for which high-value screening is available, but it currently is not being used in many average-risk, asymptomatic adults. “We are not even screening the people who should be screened, and on the other hand, we are actually overscreening people who are already in the system,” Dr. Qaseem said.

Understanding of Concepts Increasing At the conclusion of the value framework article, the authors noted, “There is reason to believe that understanding of these concepts is increasing.” They credit campaigns to increase professional and public awareness of overly intensive low-value screening, as well as articles and books about screening harms and costs.

In addition to publishing and publicizing the high-value screening advice, ACP is sponsoring education programs in several formats for physicians. A summary of the screening advice for patients also is available at acponline.org.

“Slowly, definitely, things are changing,” Dr. Qaseem said. “It comes back to how the message is being conveyed.

Yes, cancer screening is one of the strat-

Visit ASCOPost.com for Interviews Filmed During the 2015 ASCO Annual Meeting The ASCO Post presents these and other important discussions: ■■

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egies that has saved lives, but maybe the pendulum swung too far on the other end, where we start realizing that there are harms of each and every one of these tests.” n

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

References 1. Wilt TJ, Harris RP, Qaseem A, for the High Value Care Task Force of the American College of Physicians: Screening for cancer: Advice for high-value care from the American College of Physicians. Ann Intern Med 162:718-725, 2015.

2. American College of Physicians: American College of Physicians releases high value care screening advice for five common cancers. May 18, 2015. Available at http://www.eurekalert.org/pub_releases/2015-05/acop-arh051215.php. Accessed June 11, 2015.

3. Sirovich BE, Welch HG: Cervical cancer screening among women without a cervix. JAMA 291:2990-2993, 2004.

4. Harris RP, Wilt TJ, Qaseem A, for the High Value Care Task Force of the American College of Physicians: A value framework for cancer screening: Advice for highvalue care from the American College of Physicians. Ann Intern Med 162:712-717, 2015.

ASCOPost.com | JULY 10, 2015

PAGE 69

Patient’s Corner

Building and Adjusting to My Life After Cancer

By Jennifer Titche, as told to Jo Cavallo

I

had been watching a lump in my left breast for signs of cancer for 10 years, from around the time I was 21. Screening tests had failed to find any tissue abnormality, and my doctor said I was too young to have cancer, so I wasn’t overly concerned. But when I noticed the lump getting bigger in 2010, I went back to my doctor, and she performed a biopsy of the tumor, which showed that I had invasive ductal carcinoma. At just 31, I thought I still had time to meet someone, get married, and start a family, but now I was facing treatment that would irrevocably alter those plans.

Financial and Physical Burdens The fertility treatment and insurance copays for my cancer treatment have left me $28,000 in debt, which will take

me a long time to repay. But even more difficult to cope with than the financial burden cancer has left in its wake is its physical destruction. Because a substan-

tial amount of tissue had to be removed to capture all the cancer cells, I opted to have breast reconstruction surgery, but continued on page 70

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Once you are through with cancer and its treatment, it is impossible to reconstruct the exact life you had prior to your diagnosis. So, my challenge now is building a life with new goals that will make me happy and fulfilled.

Join ASCO’s Leadership Development Program

SHAPE YOUR FUTURE & OURS Participants in this year-long leadership program will learn valuable leadership skills as well as gain extensive exposure to the mission of ASCO. This program requires a time commitment for travel and training.

—Jennifer Titche

Applicants must have completed their final subspecialty training between 2006 and 2011.

My oncologist was recommending trastuzumab (Herceptin) to shrink the tumor, then a lumpectomy, then adjuvant radiation, followed by 5 years— which has since changed to 10 years—of tamoxifen. Because I was still hoping to have a family one day, before my treatment began, I met with a fertility specialist who counseled me on harvesting my eggs, then fertilizing the eggs through a sperm donor, and cryopreserving them until after my cancer treatment was over and I was once again cancer-free.

We were successful at harvesting eight eggs, but four failed to become fertilized, so four eggs are cryopreserved for possible future use, but the idea of going through this process again after I’m finished with tamoxifen, when I’m in my 40s, is daunting, and it’s difficult for me to plan that far into the future.

THROUGH THE LEADERSHIP DEVELOPMENT PROGRAM, PARTICIPANTS WILL: • Participate in a diverse class of oncologists from different practice settings • Enhance your leadership skills through interactive sessions • Network and receive mentorship from ASCO leadership

• Gain exposure to ASCO committees • Receive first-hand advocacy experience on Capitol Hill • Be assigned an ASCO strategic issue to research and deliver recommendations to the Board of Directors

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The ASCO Leadership Development Program strives to teach its participants how to build a team and then lead that team to greatness. As participants in this program, we have been challenged to define a strategic issue and work together to reach a desired outcome. I see this program as a springboard for future leadership opportunities in my clinic and oncology.

”

— Melissa Dillmon, MD, FACP, HARBIN CLINIC

The ASCO Post | JULY 10, 2015

PAGE 70

Patient’s Corner Life After Cancer continued from page 69

the result was not good, and I’m selfconscious about how I look. In addition to the scars on my chest and my back from the muscle flap and skin graft used to rebuild my breast, tamoxifen has left me 60 pounds heavier and in full-blown

menopause, so the thought of meeting someone and becoming intimate is unimaginable to me right now.

The Patient/Doctor Partnership After my breast cancer diagnosis, I was plagued by the thought of a recurrence. I still worry the cancer will

come back, but the possibility doesn’t consume me, and I’m getting on with my life. I see my oncologist every 6 months for checkups, and he has been a lifeline for me. From the beginning, he made sure I was his partner in all our treatment discussions. He would give me his opinion and educate me

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about my options and never pressured me into a decision I wasn’t comfortable with. Most of all, he is a compassionate person and a good listener, and I can’t imagine going through this experience without him.

Facing the Future Cancer has taught me that it is a family disease. Although there is no history of cancer in our family, the fact that I’ve had breast cancer at such a young age means that my sister and her daughter will have to be extra vigilant about performing breast selfexams and getting cancer screenings, and I regret that they now have that burden.

I’m still sorting through all that has happened over the past 5 years and adjusting to a life I never expected to have. Once you are through with cancer and its treatment, it is impossible to reconstruct the exact life you had prior to your diagnosis. So, my challenge now is building a life with new goals that will make me happy and fulfilled. The pace has been slow, but I’m finding my way. n Jennifer Titche lives in Lafayette, Indiana.

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PAGE 71

In the Literature

Emerging Clinical Data on Cancer Management HEALTH-CARE DISPARITIES Significant Differences in Age at Diagnosis Between Blacks and Whites for Six Types of Cancer Although blacks were diagnosed at a younger age than whites for nearly every cancer type, after adjustments for population structure shifted the comparisons toward older ages among blacks, only six statistically significant differences of 3 or more years remained, according to a study in the Journal of the National Cancer Institute. Blacks were 10.2 years younger than whites at diagnosis for Kaposi sarcoma, 5.6 years younger for male soft-tissue cancer, 5.5 years younger for male anal cancer, and 3.7 years younger for non-Hodgkin lymphoma. Blacks were 4.7 years older than whites at diagnosis for cervical cancer and 3.3 years older for female thyroid cancer.

“Smaller differences (< 3 years) were present for female breast, female colon, lung, pancreas, prostate, and uterine corpus cancers (all P ≤ .001),” reported researchers from the National Cancer Institute and Johns Hopkins Bloomberg School of Public Health.

Using Surveillance, Epidemiology, and End Results (SEER) data for non-Hispanic blacks and whites from 18 regions for the year 2010, the investigators “calculated crude mean ages at diagnosis among cases of 29 cancer types for whites and blacks.

Separately, we calculated adjusted means that corrected for differences in population structure, which we obtained by fitting linear regression models to the ages at diagnosis with statistical weights specific to age and sex,” the authors explained.

The population distribution in the

SEER data was older for whites than blacks. “Individuals older than age 50 years made up 23.2% and 34.7% of the population for blacks and whites, respectively, and individuals older than age 70 years made up 4.2% and 8.1%, respectively. The mean age among blacks was 33 years, compared with 39 years for whites,” the authors reported.

Among 29 cancer types included in the analysis, “a statistically significant (P < .10) interaction between gender and race was present for esophageal, colon, anal, softtissue, and thyroid cancers,” the researchers stated, and analyses for these cancers were stratified by gender. This resulted in 34 comparisons, and in 32 of them, the crude mean age at cancer diagnosis was younger in blacks than in whites, with differences ranging from 13.3 years younger for blacks diagnosed with Kaposi sarcoma to 1.3 years older for cervical cancer.

“After adjusting for differences in population structure between blacks and whites, the apparently younger mean age for blacks was greatly diminished for most cancers, and for a few cancers, adjustment for population structure revealed older ages in blacks that were previously masked,” the researchers stated. Adjusted mean differences ranged from 10.2 years younger for blacks with Kaposi sarcoma to 4.7 years older for cervical cancer.

“Most differences between blacks and whites in the age at cancer diagnosis are small,” the investigators concluded. “Large differences for a few cancer types may be driven by etiologic and subtype heterogeneity as well as disparities in access to care.”

Robbins HA, et al: J Natl Cancer Inst 107:dju489, 2015.

LUNG CANCER Date of Last Chemotherapy Is Not a Proxy for Deciding When to Stop Treating Metastatic NSCLC “Patients, their families, and oncologists recognize the administration of chemotherapy near death as aggressive and poor-quality care,” William F. Pirl, MD, MPH, and colleagues from Massachusetts General Hospital, Boston, wrote in the Journal of Oncology Practice. “However, rates have been slowly rising over the last decade, and 5% to 22% of all patients with advanced cancer receive chemotherapy within 2 weeks of death.”

To identify the processes leading to discontinuation of chemotherapy for patients with metastatic non–small cell lung cancer (NSCLC) at the end of life, the researchers reviewed health records of a prospective cohort of 151 patients with newly diagnosed metastatic NSCLC from a trial of early palliative care. The mean age of patients was 64, and the median number of lines of chemotherapy was 2 to 2.5.

Of 144 patients who died, 81 had received intravenous chemotherapy and 48 had received oral chemotherapies as their final regimen, but 40 of those 48 patients (83.3%) switched from intravenous to oral delivery as their final regimen, the investigators noted. The median time between transitioning from intravenous to oral chemotherapy was 134.5 days. Nine patients did not receive chemotherapy, and six were excluded due to transfer of care or lack of end-of-life data.

The median time between the last intravenous chemotherapy infusion and death was 55 days. “However, almost onequarter of patients in the sample had no documented decision to discontinue [intravenous] chemotherapy altogether,” the researchers wrote. For patients with documented final decisions, the median time from the decision to the patient’s death was only 20 days.

Five Processes

©Michael Crawford/The New Yorker Collection/www.cartoonbank.com

The authors identified five processes for stopping intravenous chemotherapy: definitive decisions (19.7%), deferred decisions or breaks (22.2%), disruptions for radiation therapy (22.2%), disruptions resulting from hospitalization (27.2%), and no decisions (8.6%). Notes for patients in the no-decision category “suggest that they were unexpected, with some oncologists indicating that patients died a “sudden death.” Nonetheless, several notes

raise the possibility that oncologists may not have recognized that patients were close to death,” the authors wrote.

“The five processes occurred at significantly different times before death and, except for definitive decisions, ultimate decisions for no further chemotherapy and referral to hospice were often made months later,” the researchers reported.

The processes “seemed to vary based on how confident the oncologist might be in his or her assessment of the time course of a patient’s disease,” the authors added.

“Oncologists have been shown to overestimate the survival of their terminally ill patients, which could lead to overconfidence in administering chemotherapy to a patient close to death.”

Study Implications The “study demonstrates that the date of last chemotherapy treatment is not a proxy for when a decision to stop cancer treatment is made,” the investigators observed. “In this sample of patients with metastatic NSCLC, < 20% had evidence of a definitive decision to stop chemotherapy at the time their chemotherapy was discontinued. For the majority of patients, a substantial amount of time followed the last [intravenous] chemotherapy treatment before a final decision to stop chemotherapy was made.”

Although ASCO “recommends stopping chemotherapy when evidence-based therapies show no benefit and the clinical value of further treatment lacks supporting evidence,” in this study “discontinuation of chemotherapy seemed to occur more often in response to failures rather than futility or lack of benefit,” the authors noted.

The authors concluded that “chemotherapy discontinuation should not just be considered a date before death; it is a process. Differentiating the processes of discontinuing chemotherapy seems to be meaningful, because these processes occur at significantly different time points before death and may affect subsequent end-of-life care, such as hospice referral, days in hospice, and death in the hospital. Understanding these processes has the potential to reduce the administration of chemotherapy at end of life by identifying not only practices with better outcomes but also factors that trigger earlier discontinuation.”

Pirl WF, et al: J Oncol Pract 11:e405e412, 2015.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

The ASCO Post | JULY 10, 2015

PAGE 72

Perspective Biosimilars continued from page 1

Laws and Definitions According to the FDA,1 a biologic product may be demonstrated to be biosimilar if data show that, among other things, the product is “highly similar” to an already-approved biologic product.

The biosimilar also must show it has no clinically meaningful differences from the innovator product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable in biosimilar products.

The Affordable Care Act amended the Public Health Service Act to create an abbreviated licensure pathway for biologic products that are demonstrated to be “biosimilar to” or “interchangeable with” an FDA-licensed biologic product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act. A phrase used to describe the biosimilar creation—“the process is the product”—illustrates that it is critical to understand the biosimilar development process.2 Biosimilars are derived from many sources, including humans, animals, microorganisms, or yeast. Some, such as blood cells or stem cells, are extracted from living beings. Others are produced using advanced genetic technology. If the host cells, cell culture process, or purification methods are different, there may be clinically significant alterations in the safety and effectiveness of the drug.

Regulatory Guidance Recently, the FDA clarified its views through regulatory guidance. The FDA suggested that manufacturers of bio-

similar drug products would be allowed to extrapolate innovator data to support the approval of all indications the branded product is approved for. While they may reduce the overall resources required in bringing a biosimilar to market, other aspects of the guidance were not as favorable to these stakeholders. The guidance also suggested that the FDA does not believe the current technology is evolved enough to truly establish the interchangeability of a biosimilar with a branded product.3 The World Health Organization has

not as easy to produce as generics, which are copies of brand-name drugs.”5 Thus, uncertainties about interchangeability and their implications for biosimilar development remain to be resolved. In the meantime, federal regulators are charged to determine whether a biosimilar product is sufficiently similar clinically to an innovator biologic drug to merit the same approval for use.

Cost Considerations Questions about interchangeability aside, it is predicted that biosimilars will

There must be a balance between encouraging the development of new, lifesaving, or life-improving drugs, and their cost. Whether biosimilars will help in achieving such balance remains to be seen.

—Richard J. Boxer, MD, FACS

stated, “The approach established for generic medicines is not suitable for development, evaluation, and licensing of similar biotherapeutic products since biotherapeutics consist of relatively large and complex proteins that are difficult to characterize.”4 Indeed, biosimilars are not generics.

“It is important to note that a biosimilar is not just like a generic drug,” according to Leah Christl, PhD, Associate Director for Therapeutic Biologics in the FDA’s Office of New Drugs. “Because of the differences in complexity of the structure of the biologic and the process used to make a biologic, biosimilars are

Summer 2015

save patients money. Biosimilars are expected to save $13 billion over the next 10 years, according to the Congres­ sional Budget Office. The initial promise of biosimilars was that they would save patients 30% to 40%. (As a point of reference, generic drugs, which have 85% of the U.S. pharmaceutical market, cost about 80% to 85% less than their corresponding brand-name products, according to the FDA.3) Unfortunately, bringing biosimilars to market is proving far more complex than anticipated, and therefore, 10% to 20% less than the cost of the branded medication is a more reasonable expectation. In Europe, biosimilars have often been associated with only a 10% discount from the brand-name product.3 Express Scripts, a pharmacy benefits manager, has stated that biosimilars will provide $250 billion in U.S. health-care savings over the next decade if 11 biologics gain biosimilar competition,6 but the RAND Corporation projects much lower savings—about $44 billion— from the introduction of biologics.7 Another class of new biologic drugs is called “biobetter drugs.” A biosimilar drug is a mere structural imitation; a biobetter drug possesses some molecular modification that constitutes an im-

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provement over the original innovator drug. Such improvements may range from a longer half-life (allowing for less frequent dosing) to more potency with less toxicity. Biosimilar drugs and biobetter drugs offer the very real possibility of quality alternatives and even enhanced treatments at better prices.

More Key Issues Another important question is, will biosimilar drugs stymie innovation in research and development? Clearly, there must be a return on investment for original biologic medication, and it can take hundreds of millions of dollars to prove a drug’s efficacy and bring it to market. The cost of discovery is staggering, but the cost of copying, even though biosimilars are not chemically exact copies, is significantly less.

There must be a balance between encouraging the development of new, lifesaving, or life-improving drugs and their cost. Whether biosimilars will help in achieving such balance remains to be seen. n

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

References 1. U.S. Food and Drug Administration: Biosimilars. Available at www.fda.gov. Accessed June 23, 2015.

2. Thelwell C, Longstaff C: Biosimilars: The process is the product. The example of recombinant streptokinase. J Thromb Haemost 12:1229-1233, 2014.

3. Howell P: How much cheaper will biosimilars be? March 2, 2012. Available at www.fiercepharma.com. Accessed June 23, 2015.

4. Expert Committee on Biological Standardization: Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs).

Geneva, Switzerland, World Health Organization, 2009. Available at www.who.int.

Accessed June 23, 2015.

5. U.S. Food and Drug Administration: Biosimilars: More treatment options are on the way. March 6, 2015. Available at www. fda.gov. Accessed June 23, 2015.

6. Milman J: The cheaper cancer drug that could pave the way for much more affordable medicine. The Washington Post.

January 5, 2015.

7. RAND Corporation: Biosimilar medications could create billions in health care savings. November 3, 2014. Available at rand.org. Accessed June 23, 2015.

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

ASCO Meetings Best of ASCO速

boa.asco.org

Boston July 31-August 1, 2015 | Boston, Massachusetts

San Francisco August 7-8, 2015 | San Francisco, California

Chicago August 28-29, 2015 | Chicago, Illinois

Breast Cancer Symposium

breastcasym.org

September 25-27, 2015 | San Francisco, California Cosponsored with: American Society of Breast Surgeons, American Society for Radiation Oncology, and Society of Surgical Oncology

pallonc.org

Palliative Care in Oncology Symposium October 9-10, 2015 | Boston, Massachusetts Cosponsored with: American Academy of Hospice and Palliative Medicine, American Society for Radiation Oncology, and Multinational Association of Supportive Care in Cancer

gucasym.org

Genitourinary Cancers Symposium January 7-9, 2016 | San Francisco, California Cosponsored with: American Society for Radiation Oncology and Society of Urologic Oncology

Cancer Survivorship Symposium: Advancing Care and Research A Primary Care and Oncology Collaboration

survivorsym.org

January 15-16, 2016 | San Francisco, California Cosponsored with: American Academy of Family Physicians and American College of Physicians, Inc.

Gastrointestinal Cancers Symposium

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January 21-23, 2016 | San Francisco, California Cosponsored with: American Gastroenterological Association Institute, American Society for Radiation Oncology, and Society of Surgical Oncology

Celebrating Ten Years

ASCO Quality Care Symposium

quality.asco.org

February 26-27, 2016 | Phoenix, Arizona

Markers in Cancer Diagnostic Development Tutorial May 2-3, 2016 | Bethesda, Maryland In collaboration with European Organisation for Research and Treatment of Cancer and National Cancer Institute

Annual Meeting June 3-7, 2016 | Chicago, Illinois

Celebrating Ten Years

markersincancer.org

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The ASCO Post | JULY 10, 2015

PAGE 74

In Memoriam

Frederick Pei Li, MD, Pioneer of Cancer Genetics, Dies at 75

F

rederick Pei Li, MD, who helped inaugurate the era of cancer genetics by demonstrating that people can inherit a genetic susceptibility to develop certain malignancies, died on June 12 at the age of 75. A Profes-

Frederick Pei Li, MD

sor at Dana-Farber Cancer Institute, Harvard Medical School, and Harvard T.H. Chan School of Public Health, Dr. Li laid the groundwork for today’s genetic counseling services for people with an inherited risk of cancer—and for efforts to develop cancer prevention strategies for such individuals.

Unprecedented Discoveries In the late 1960s, Dr. Li and his colleague at the National Cancer Institute (NCI), Joseph Fraumeni, MD, MSc, began tracking patterns of cancer in children. Together, they identified a small number of families in which the same rare cancers had arisen across multiple generations. Their research

led them to describe what is now known as Li-Fraumeni syndrome, a rare but devastating condition in which people are highly prone to develop a variety of serious cancers at an early age.

For the next 2 decades, Dr. Li and his colleagues worked to identify the mutated gene or genes responsible for the syndrome. In 1990, they published a paper identifying a mutation in p53, a tumor-suppressor gene, as the culprit.

It was one of the first times an inherited abnormal gene was linked to cancer in humans. The finding paved the way for the discovery of other cancer-susceptibility genes such as BRCA1 and BRCA2.

For their breakthrough research, Drs. Li and Fraumeni received the prestigious Charles S. Mott Prize of the General Motors Cancer Research Foundation. Their work led to the development of a genetic test for Li-­ Fraumeni syndrome, which became a paradigm for the evolving field of genetic ­epidemiology.

“I was attracted to studies of cancer families, because epidemiological studies show that virtually all cancers manifest a tendency to aggregate in families,” Dr. Li wrote about his ­research.

Following his discovery of a connection between mutated p53 and Li-Fraumeni Syndrome, Dr. Li helped create a center at Dana-Farber to test people for inherited risks for cancer.

That center, the Friends of Dana-Far-

ber Cancer Institute Cancer Risk and Prevention Clinic, became a model for genetic testing and counseling centers across the country.

Dr. Fraumeni, of the Division of

in the NCI’s Epidemiology Branch and became an Attending Physician in 1976. He joined the Dana-Farber faculty in 1981 as an Associate Physician, was Head of the Division of Can-

Collaborators were drawn not only to the scientific ideas generated by Fred, but also by his friendly, calm, and thoughtful demeanor and his generosity of spirit.

—Joseph Fraumeni, MD, MSc

Cancer Epidemiology and Genetics at NCI, said, “Fred had a knack for making important clinical and epidemiological observations and taking them to the next level. This often meant crossing disciplines, which in my experience is not always easy, but collaborators were drawn not only to the scientific ideas generated by Fred, but also by his friendly, calm, and thoughtful demeanor and his generosity of spirit.”

A Multidisciplinary Background Born in Canton, China, in 1940, Dr. Li was raised in New York City, where his parents operated a Chinese restaurant. He received a BA in physics from New York University, an MD from the University of Rochester, and an MA in demography from Georgetown University. In 1967, he joined the Epidemiology Branch of the NCI. He first came to Dana-Farber in the early 1970s as a Medical Officer

 In Memoriam

Frederick Pei Li, MD 1940 – 2015 

cer Epidemiology and Control from 1991–1998, and served as Vice Chair for Population Sciences in the Department of Adult (now Medical) Oncology from 1998–2002.

He was Professor of Clinical Cancer Epidemiology at Harvard T.H. Chan School of Public Health and Professor of Medicine at Harvard Medical School, where he held the position of Harry and Elsa Jiler American Cancer Society Clinical Research Professor. In 1996, Dr. Li was appointed by President Bill Clinton to the NCI’s National Cancer Advisory Board.

Dr. Li served as Editor-in-Chief of the journal Cancer Epidemiology Biomarkers & Prevention and was on the editorial boards of numerous professional publications, including Cancer Research, the Journal of Clinical Oncology, and the American Journal of Medical Genetics. In 1999, he was awarded the American Cancer Society Medal of Honor in Clinical Research. n

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