Tap Vol 6 Issue 14 by Harborside Press LLC

Glioblastoma and Immunotherapy

| Advanced Breast Cancer

17, 18

| Adolescents and Young Adults With Cancer

VOLUME 6, ISSUE 14

AUGUST 10, 2015

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

ASCO Plenary Report

Value: What Do We Mean, Who Should Decide?

Bevacizumab More Cost-Effective Than Cetuximab in Metastatic Colorectal Cancer By Caroline Helwick

he landmark CALGB/SWOG 80405 concluded that bevacizumab (Avastin) and cetuximab (Erbitux) provide comparable benefit in the treatment of metastatic colorectal cancer. However, in terms of cost, bevacizumab was recently declared the winner. In an economic analysis presented at the 2015 ASCO Annual Meeting, researchers reported that treatment with bevacizumab cost $39,000 less per patient than cetuximab.1 “Chemotherapy plus bevacizumab costs less and achieves very similar survival and quality-adjusted survival as chemotherapy plus cetuximab for first-line treatment of KRAS wild-type metastatic colorectal cancer,” announced Deborah Schrag, MD, MPH, of Dana-Farber Cancer Institute, Boston. The results of the CALGB/SWOG 80405 headto-head comparison of the drugs were presented at the 2014 ASCO Plenary Session last year by Venook and colleagues.2 At a median follow-up of 24 months,

By John F. Smyth, MD

median overall survival was 29 months in the bevacizumab arm and 29.9 months in the cetuximab arm, and median progression-free survival was 10.8 months and 10.4 months, respectively.

From Clinical to Cost Findings

O Deborah Schrag, MD, MPH

The current analysis evaluated the regimens in terms of their cost-effectiveness, an analysis that was prospectively planned for CALGB/SWOG 80405, “given the high costs of all the study arms,” Dr. Schrag said. For the average patient, the 2014 cost for one 8-week cycle of treatment was $9,324 for bevacizu continued on page 4

Issues in Oncology

Is Proton-Beam Therapy Facing a Difficult Future? By Ronald Piana

ealth-care experts are questioning whether pro- in 1946.1 The first treatments were performed in the ton-beam therapy is on the verge of an economic Berkeley Radiation Laboratory in 1954. The first hosbubble—ie, a rapid surge in growth for the industry pital-based proton-beam center in the United States beyond its intrinsic value, inevitably leading to a dras- was at the Loma Linda University Medical Center, tic drop in earnings for which began operation proton centers when in 1990. Proton-beam therapy is the biggest the “bubble bursts.” A Despite the stickerproton-beam facility can shock price to build a and most expensive technology cost upward of $250 milproton center and the on the market. But is it the best? lion to construct. With high cost of treatment, 13 proton centers in In prostate cancer, there are no data to proton-beam therapy operation in the United has surged in use over sufficiently answer that question. States, 6 more centers set the past several decades, to open by the end of this and much of that growth year, and another 10 planned to open by 2018, a “pro- has been in prostate cancer. The chief selling point for ton bubble” would spell financial havoc for that sector men diagnosed with prostate cancer is the purported of the health-care system. precision dosing of proton therapy, which decreases the risk of the two most feared side effects: incontiUpswing in Usage Despite High Costs nence and impotence. The suggestion that protons could be effective in Moreover, when a hospital-based proton center treating cancers was made by the American physi- incurs a $200-plus million debt, it must amortize that continued on page 41 cist Robert R. Wilson, PhD, in a paper published Send your comments to editor@ASCOPost.com

scar Wilde famously defined a cynic as “a man who knows the price of everything and the value of nothing.” I do not think that oncologists need to be as cynical as this, but it was very appropriate that a major theme of this year’s ASCO Annual Meeting was the concept of “value.” It is clear that there are widely differing attitudes to what we mean by value in oncology, and I would suggest that all members of society need to consider this in a timely fashion—balancing the extraordinary success of medical research vs the pressure of finding the resources to translate this knowledge into practical health care. continued on page 77

Dr. Smyth is Emeritus Professor of Medical Oncology, University of Edinburgh, United Kingdom. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage ASCO Annual Meeting Metastatic Colorectal Cancer �� 1 Value in Cancer Care �� 1, 5, 9–10 Glioblastoma �� 3 National Cancer Policy Forum ��52–53 High-Risk Prostate Cancer �� 12 Direct From ASCO �� 37–40 Emil J Freireich, MD, Pioneer in Oncology ��56 In Memoriam ��62 Richard J. Boxer, MD, on Cost vs Values �� 66

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The ASCO Post | AUGUST 10, 2015

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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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ASCO Annual Meeting Neuro-oncology

Glioblastoma: Novel Immunotherapy Approaches Generate Responses and Excitement By Caroline Helwick

heckpoint inhibitors were major attention grabbers at the 2015 ASCO Annual Meeting, but studies suggested there are other encouraging means of harnessing the immune system in the treatment of glioblastoma.

EGFRvIII-Targeted Vaccine David A. Reardon, MD, Clinical Director of the Center for Neuro-Oncology, Dana-Farber Cancer Center, Boston, presented the results of the ReACT study, which evaluated rindopepimut plus bevacizumab (Avastin) vs bevacizumab alone in patients with recurrent glioblastoma.1 Rindopepimut is an investigational vaccine that targets the tumor-specific oncogene EGFRvIII, which is a variant of the epidermal growth factor receptor (EGFR). Expression of EGFRvIII correlates with increased tumorigenicity in mouse models and poor long-term survival in clinical studies of patients with glioblastoma multiforme. ReACT was a randomized, controlled phase II exploratory study in 73 patients treated with rindopepimut plus bevacizumab or bevacizumab plus a placebo vaccine. All patients were EGFRvIII-positive and bevacizumab-naive and were enrolled after a first or second recurrence. The study met its primary endpoint of progression-free survival at 6 months. Given the exploratory nature and size of the trial, the study required a one-sided P value of .2 for positivity. The 6-month progression-free survival rate was 28% in the rindopepimut arm and 16% in the control arm (P = .12) by intent-to-treat analysis and 30% and 12%, respectively (P = .03) in the per-protocol analysis. The drug also significantly improved overall survival, with 12-month rates of 45% vs 31%, respectively, and 18-month rates of 30% and 15%. Median overall survival was 11.6 months vs 9.3 months, respectively, a 43% reduction in risk (P = .04) in the intent-to-treat analysis, Dr. Reardon reported. Similarly, objective response rates were higher with rindopepimut/bevacizumab (30% vs 18%). Response duration exceeded 6 months for five patients on rindopepimut and exceeded 1 year for three of these patients. “The results of the ReACT study are striking because we are observing an ex-

tremely rare overall survival advantage that is now translating into long‐term survival for a number of patients— something not seen in highly aggressive, EGFRvIII‐positive glioblastoma,” Dr. Reardon offered. “Patients on the rindopepimut arm are not only surviving longer, they are experiencing a notable decrease in the need for steroids.” Fabio M. Iwamoto, MD, of Columbia University Medical Center, New York, noted that the data so far on rindopepimut have been consistent and positive. However, he took issue with the fact that there were more patients in the rindopepimut arm (92%) than in the control arm (76%) treated after first relapse.

Heat Shock Protein–Based Vaccine Other investigators reported on a heat shock protein–based vaccine in 46 newly diagnosed patients with glioblastoma.2 Patients underwent surgery and then a course of radiation therapy;

Fig. 1: Prolonged immune surveillance—patient is alive 8 years postsurgery. Slide courtesy of David S. Baskin, MD.

23.8 months, and median progressionfree survival was 18.0 months, which he noted was much better than in historical controls. Patients with MGMT [O(6)methylguanine-DNA methyltransferase] methylation had a median overall survival of 44.7 months, compared with 18 months for unmethylated patients (P < .001).

The results of the ReACT study are striking because we are observing an extremely rare overall survival advantage that is now translating into long‐term survival for a number of patients—something not seen in highly aggressive, EGFRvIII-positive glioblastoma. —David A. Reardon, MD

those with stable disease were offered biweekly vaccination involving the use of heat shock proteins for antigen delivery (HSPPC-96 vaccine). “If you extract heat shock proteins with their bound antigens and deliver them in naked form into the systemic circulation, there is uptake into antigen-presenting cells through the CD91 receptor, where the peptide is dissociated, cleaved, and cross-presented on major histocompatibility complex class 1 and 2 peptides for stimulation of both the CD8- and CD4-positive T-cell response,” explained Orin Bloch, MD, of Northwestern University, Chicago. Dr. Bloch reported that median overall survival in this single-arm study was

PD-L1 (programmed cell death ligand 1) expression on circulating myeloid cells independently predicted clinical response to the vaccine. Patients with low PD-L1 expression had significantly improved survival, he added.

Gene-Mediated Immunotherapy A phase Ib/II study found a significant benefit for gene-mediated cytotoxic immunotherapy after surgical resection in newly diagnosed patients with glioblastoma.3 Gene-mediated cytotoxic immunotherapy introduces an adeno-associated nonreplicating viral vector expressing thymidine kinase directly

into the tumor. Patients then receive oral valacyclovir (Valtrex), which thymidine kinase phosphorylates to form a cytotoxic nucleotide analog that halts DNA replication and repair. As the tumor dies, tumor-associated antigens are released, and this ultimately stimulates proinflammatory cytokines, explained David S. Baskin, MD, of Houston Methodist Hospital. “We believe this stimulates an immune response, and we have laboratory data to support that,” he said. The study was completed with 48 patients from multiple centers matched against 134 historical controls from Brigham and Women’s Hospital. In addition to the study drug, patients received radiation therapy and temozolomide. Dr. Baskin reported a 27% relative improvement in overall survival with gene-mediated cytotoxic immunotherapy. The strategy improved median overall survival from 13.5 months in controls to 17.1 months (P = .0417) and improved progression-free survival by 25%, from 6.5 to 8.1 months (P = .0100), respectively. The intervention appeared most striking in patients who underwent gross total resection of tumor (vs subtotal excision), whose median overall survival was 25.0 months, vs 16.9 months for controls, a 48% relative improvement (P = .0492). It is possible that the immunosuppressive environment is ameliorated by the removal of more tumor, as patients with incompletely resected tumors derived less benefit from gene-mediated cytotoxic continued on page 4

The ASCO Post | AUGUST 10, 2015

PAGE 4

ASCO Annual Meeting Bevacizumab vs Cetuximab continued from page 1

mab and $20,856 for cetuximab. This was based on an average selling price of $66.6 per 10 mg of bevacizumab, given at 5 mg/kg every 2 weeks, for a total of 1,400 mg, and $53.3 per 10 mg of cetuximab, given at 250 mg/m2 every 2 weeks (400 mg/m2 for the first dose), for a total of 3,913 mg for an 8-week cycle. The two strategies were analyzed for incremental cost-effectiveness and cost-utility ratios, taking into account a number of measures. These included the utilization and cost of chemotherapy with either FOLFOX (folinic acid, fluorouracil, oxaliplatin) or FOLFIRI (folinic acid, fluorouracil, irinotecan), similar costs for end-of-life care, postprogression treatment, hospitalizations, genomic testing, and chair time, and

major care episodes related to treatment. Dr. Schrag and colleagues determined that not only were the regimens equally efficacious, they were also similar in terms of quality-adjusted life years (QALYs). Life-years and QALYs hovered around the 3.00 mark for all health outcome measurements on the EQ-5D instrument. The only difference in a subjective measurement was greater “skin satisfaction” with bevacizumab.

One Drug Just Costs More The sizable difference in cost between the treatment arms largely stemmed from the difference in the cost of the two biologics. The analysts figured that the cost difference would neutralize if the average selling price of cetuximab was reduced by 45%. Dr. Schrag said the findings have in-

Cost of First-Line Treatment in Metastatic Colorectal Cancer ■■ The cost of treating first-line metastatic colorectal cancer was significantly less with bevacizumab than with cetuximab, according to the results of CALGB/SWOG 80405. ■■ In this trial, the drugs (given with chemotherapy) were equally effective, producing a median overall survival of approximately 29 months. ■■ The mean cost of treating the patients in the study was $39,000 less with bevacizumab, based on a prospectively planned economic analysis.

fluenced her practice. “There’s a good argument” for using bevacizumab firstline, she said. “That’s what I do.” n

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

References 1. Schrag D, Dueck AC, Naughton MJ, et al: Cost of chemotherapy for metastatic colorectal cancer with either bevacizumab or cetuximab. 2015 ASCO Annual Meeting.

Abstract 6504. Presented May 30, 2015. 2. Venook AP, Niedzwiecki D, Lenz HJ, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin or oxaliplatin/5-FU/leucovorin with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum. 2014 ASCO Annual Meeting. Abstract LBA3. Presented June 1, 2014.

EXPERT POINT OF VIEW

eter B. Bach, MD, MAPP, Director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center (Memorial), New York, discussed Dr. Schrag’s study at the ASCO Health Services Research and Quality of Care session.

Peter B. Bach, MD, MAPP

Immunotherapy in Glioblastoma continued from page 3

immunotherapy, he noted. The “most remarkable” response to gene-mediated cytotoxic immunotherapy was observed in a patient with a high-grade, suboptimally resected glioma. Dr. Baskin performed an anterior temporal lobectomy followed by genemediated cytotoxic immunotherapy injection into the cavity. “Three months later, the patient’s MRI scan looked terrible, but it turns out this was likely the initiation of the immune effect. At 6 months, he looked better, and at 5 years, we saw no abnormality,” reported Dr. Baskin. “The patient is now 8.5 years out, off all therapy, and doing well with no

“Dr. Schrag’s analysis could have been ‘back of the envelope,’ but she spent lots of effort to lay this out. And she found no statistically significant difference, whether in life years or quality-adjusted life years, with two drugs that cost considerably different against dealer’s choice backbone chemotherapy,” he said. “We are in an era when we have decided on a hierarchy of comparative decision-making in cancer that begins with efficacy, then is followed by toxicity and then cost,” he said. “Benefits to some extent are constrained by biology, as are harms. But prices and costs? We accept

tumor seen on MRI scans (see Fig. 1 on page 3). This suggests the mechanism of action is immune stimulation and surveillance, as the effect of the drug is long gone.”n Disclosure: Dr. Reardon has received honoraria from Amgen, Merck, Midatech, Momenta Pharmaceuticals, Novartis, Roche Pharma AG, and Stemline Therapeutics; has served as a consultant or advisor to Amgen, Genentech/Roche, Merck, Midatech, Momenta Pharmaceuticals, Novartis, and Stemline Therapeutics; has been on the speakers bureau of Genentech/Roche and Merck; and has received institutional research funding from Incyte and Midatech. Dr. Iwamoto is a consultant for Novocure and Regeneron. Drs. Bloch and Baskin reported no potential conflicts of interest.

References 1. Reardon DA, Schuster J, Tran DD,

Leonard Saltz, MD

these prices, put them into our costeffectiveness analysis…. Why not close this loop?” he suggested. “Why treat these prices as immutable? Why would we pay an infinite amount for microscopic benefit? If drugs are equal except for cost, why not just say

et al: ReACT: Overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. 2015 ASCO Annual Meeting. Abstract 2009. Presented May 31, 2015. 2. Bloch O, Raizer JJ, Lim M, et al: Newly diagnosed glioblastoma patients treated with an autologous heat shock protein peptide vaccine: PD-L1 expression and response to therapy. 2015 ASCO Annual Meeting. Abstract 2011. Presented May 31, 2015. 3. Aguilar LK, Wheeler LA, Manzanera AG, et al: Phase II multicenter study of gene mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. 2015 ASCO Annual Meeting. Abstract 2010. Presented May 31, 2015.

no to the higher-cost agent?” Leonard Saltz, MD, Chief of Gastrointestinal Oncology at Memorial, agreed with Dr. Bach in a presentation he delivered at the 2015 ASCO Plenary Session. “Chemotherapy plus bevacizumab or cetuximab: The outcome is identical, the quality of life is identical, but the cost of the antibody for bevacizumab is less than half that of cetuximab. That doesn’t leave us with two equivalent regimens and dealer’s choice, but one regimen that is clearly the better choice,” Dr. Saltz said. n Disclosure: Drs. Bach and Saltz reported no potential conflicts of interest.

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ASCO Annual Meeting Issues in Oncology

ESMO’s Magnitude of Clinical Benefit Scale Brings Unbiased Perspective to Cancer Drugs’ Worth By Caroline Helwick

n anticancer therapy may be hailed as a breakthrough in some corners, whereas its value may be hotly contested in others. In an effort to bring clear, unbiased perspective to new expensive therapies, the European Society for Medical Oncology (ESMO) has created a valuable tool for oncologists, patients, and policy-makers. The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) was described at the 2015 ASCO Annual Meeting at the ASCO/ESMO Joint Session: Global Perspective on Value,1

v1.0, which was recently published online in the Annals of Oncology,2 provides field testing results for novel cancer drugs across 10 cancer types. ESMO plans to apply the scale prospectively to new anticancer drugs approved by the European Medicines Agency (EMA). Drugs obtaining the highest scores on the scale will be highlighted in the ESMO Clinical Practice Guidelines, with the hope that they will rapidly be made available by health authorities across the European Union. At the 2015 ASCO Annual Meeting,

More mature data of clinical trials will allow for fine-tuning the grade for efficacy and toxicity. Version 1.0 is a ‘lively’ instrument that will be regularly updated. —Elisabeth de Vries, MD, PhD

by Elisabeth de Vries, MD, PhD, of the University Medical Center Groningen, Netherlands. The clinical benefit of cancer therapies can range from trivial to substantial. The ESMO-MCBS is the first standard tool—although it is dynamic and will be regularly refined—that grades their magnitude of clinical benefit. The tool uses a rational, structured, and consistent approach to derive a relative ranking of benefit that can be anticipated from any new treatment. It is part of ESMO’s effort to highlight treatments that bring substantial improvements to the duration of survival or quality of life, Dr. de Vries said.

Thirteen Drafts, One Final Scale The manuscript, developed by a team of 8 ESMO representatives, went through 13 drafts and 2 rounds of fieldtesting in a range of settings and scenarios. The final report, ESMO-MCBS

Dr. de Vries described the underlying premise of the scale as follows: • Cure takes precedence over deferral of death. • Direct endpoints such as survival and quality of life take precedence over surrogates such as progression-free survival or response rate. • Disease-free survival in curative disease is a more valid surrogate than progression-free survival or response rate in noncurative disease. • Interpretation of the evidence of benefit derived from surrogate outcomes (such as progression-free survival) may be influenced by secondary outcome data. Factors taken into account for the scale included overall survival and progression-free survival; long-term survival, hazard ratios, and response rate; prognosis of the condition; quality of life; and toxicity. “Cost was not taken into account, in view of the significant heterogeneity in costs across Europe,” she added.

The highest grades are assigned to trials with adequate power for a relevant magnitude of benefit, with appropriate adjustments for toxicity and quality-of-life issues. Data were derived from comparative research, emphasizing large phase III trials; careful analyses of the control arm and identification of endpoints; and properly conducted subgroup analyses. The authors also constructed a number of “rules” regarding hazard ratios and confidence intervals. “Given the profound differences between curative and noncurative settings, we created separate forms for these,” she said. Substantial improvements were defined in the curative setting, for adjuvant and other treatments with curative intent, as an A and B score (C is worse), whereas scores of 5 and 4 reflected substantial benefit in the noncurative setting (vs 3, 2, 1). The final adjustment of the ranking can downgrade a drug for serious toxicity or upgrade it one level for better quality of life or less grade 3/4 toxicity.

The Scale in Action Dr. de Vries offered several examples of the scale in breast, lung, and colorectal cancers and melanoma. For instance, the HERA trial in early breast cancer, in which trastuzumab (Herceptin) conveyed an improved disease-free survival and earned an A rating. The EMILIA trial, obtained a grade 5 for ado-trastuzumab emtansine (formerly known as T-DM1, Kadcyla) showing a 7-month gain in survival and delayed deterioration vs capecitabine/lapatinib (Tykerb) in the metastatic setting. In contrast, regorafenib (Stivarga), in the third-line metastatic colorectal cancer setting, improved overall survival by only 1.4 months in the C ORRECT trial and so earned a grade of 1, the lowest rating. Such information from the ESMOMCBS will not only help to determine which drugs should be “immediately

ESMO Magnitude of Clinical Benefit Scale ■■ ESMO created a Magnitude of Clinical Benefit Scale to stratify new cancer drugs through a structured, validated, unbiased approach. ■■ The ESMO-MCBS v1.0 is the first version of this validated tool for stratifying the magnitude of clinical benefit for new treatments and is applicable over a range of solid tumors. ■■ The tool, which uses a rational, consistent approach to derive a relative ranking of benefit that can be anticipated from any new treatment, will be regularly updated.

required” for all European patients but can also support clinical decision-making and counseling of patients, she said. “More mature data of clinical trials will allow for fine-tuning the grade for efficacy and toxicity,” she added. “Version 1.0 is a ‘lively’ instrument that will be regularly updated.” n Disclosure: Dr. de Vries has received research grants from Roche/Genentech, Amgen, Novartis, Pieris, and Servier and is a consultant for Synthon Pharmaceuticals and BioMarin, which she has made available to her hospital.

References 1. De Vries E: ESMO Magnitude of Clinical Benefit Scale for new anticancer drugs. 2015 ASCO Annual Meeting. ASCO/European Society for Medical Oncology Joint Session: Global Perspective on Value. 2. Cherny NI, Sullivan R, Dafni U, et al: A standardized, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol. May 30, 2015 (early release online).

Visit The ASCO Post website at ASCOPost.com

APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS* mCRC

VECTIBIX

FOLFOX In an exploratory analysis of the PRIME† study, Vectibix® improves median OS in the first line by 4.4 months vs FOLFOX alone in WT KRAS mCRC1

+4.4 MONTHS MEDIAN OS1

• Phase

3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC

• Vectibix®

+ FOLFOX extended the prespecified major efficacy measure of PFS vs FOLFOX alone (9.6 months vs 8.0 months, respectively)

• In

an exploratory analysis of OS, median OS in Vectibix® -treated patients was 23.8 months vs 19.4 months with FOLFOX alone

• No

benefits in OS or PFS were observed in patients with mutant RAS mCRC

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy Limitation of Use Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

Important Safety Information WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. • In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis).

Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. • Vectibix® is not indicated for the treatment of patients with colorectal

cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as“RAS”.

• Retrospective subset analyses across several randomized clinical trials

were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents.

Important Safety Information • Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors

received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01–1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone.

• Progressively

decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of

patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe

diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal

and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.

• In

patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

• Exposure

to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis

and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate

in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As

a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

• Advise patients of the need for adequate contraception in both males

and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

• Because

many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women

who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix®

were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction.

• In

Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix® -treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

• In an interim analysis of an open-label, multicenter, randomized clinical

trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

Visit VectibixData.com to learn more

mCRC = metastatic colorectal cancer; OS = overall survival; PFS = progression-free survival; WT = wild type. *Exon 2 on codons 12 or 13. † PRIME = The Panitumumab Randomized Trial In Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy. Reference: 1. Vectibix® (panitumumab) prescribing information, Amgen. Please see Brief Summary of full Prescribing Information on adjacent pages.

KING SIZE (6 pt condensed type) S:9.25”

Vectibix® (panitumumab) BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

VECT15CDLA0437_B_Vectibix_BS_9.25x13_v23_Mar2015_r11_MBS.indd 1

Study 1

SYSTEM ORGAN CLASS Preferred Term

Vectibix® Plus Best Supportive Care (N = 229)

Best Supportive Care (N = 234)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

1 (< 1)

EYE DISORDERS Growth of eyelashes

13 (6)

GASTROINTESTINAL DISORDERS Nausea

52 (23)

2 (< 1)

37 (16)

Diarrhea

49 (21)

4 (2)

26 (11)

Vomiting

43 (19)

6 (3)

28 (12)

Stomatitis

15 (7)

2 (< 1)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue

60 (26)

10 (4)

34 (15)

Mucosal inflammation

15 (7)

1 (< 1)

2 (< 1)

57 (25)

4 (2)

7 (3)

INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea

41 (18)

12 (5)

30 (13)

Cough

34 (15)

1 (< 1)

17 (7)

Erythema

150 (66)

13 (6)

2 (< 1)

Pruritus

132 (58)

6 (3)

4 (2)

Acneiform dermatitis

131 (57)

17 (7)

2 (< 1)

Rash

51 (22)

3 (1)

2 (< 1)

Skin fissures

45 (20)

3 (1)

1 (< 1)

Exfoliative rash

41 (18)

4 (2)

Acne

31 (14)

3 (1)

Dry skin

23 (10)

Nail disorder

22 (10)

Skin exfoliation

21 (9)

2 (< 1)

Skin ulcer

13 (6)

1 (< 1)

8 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%). In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)]. In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix ®-treated patients [see Dosage and Administration (2.3)]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported. Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®. Table 2: Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type (WT) KRAS Tumors Treated with Vectibix® and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 3) Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

58 (18)

5 (2)

10 (3)

Diarrhea

201 (62)

59 (18)

169 (52)

29 (9)

Stomatitis

87 (27)

15 (5)

42 (13)

1 (< 1)

EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inflammation

82 (25)

14 (4)

53 (16)

1 (< 1)

Asthenia

79 (25)

16 (5)

62 (19)

11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

Anorexia

116 (36)

14 (4)

85 (26)

6 (2)

INFECTIONS AND INFESTATIONS Paronychia

Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

179 (56) 104 (32) 75 (23) 68 (21) 50 (16) 50 (16) 47 (15) 44 (14) 32 (10)

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1)

24 (7)

1 (< 1)

10 (3) 4 (1)

14 (4) 13 (4) 14 (4) 1 (< 1) 30 (9) 1 (< 1) 4 (1)

30 (9)

4 (1)

9 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix ® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®. 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 the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vectibix ®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy. Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Hypomagnesemia

96 (30)

21 (7)

26 (8)

1 (< 1)

Hypokalemia

68 (21)

32 (10)

42 (13)

15 (5)

Dehydration

26 (8)

8 (2)

10 (3)

5 (2)

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

46 (14)

30 (9)

This brief summary is based on the Vectibix ® Prescribing Information v23, 03/15. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2015 Amgen Inc. All rights reserved. v23 03/15

4/27/15 6:12 PM

S:13”

INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)]. Limitation of Use Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)]. DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as “RAS ” [see Indications and Usage (1.1), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents [see Indications and Usage (1.1), and Clinical Pharmacology (12.1)]. Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone [see Indications and Usage (1.1)]. Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.1) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)]

• Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an openlabel, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

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ASCO Annual Meeting Issues in Oncology

The Value Proposition in Oncology: ASCO Session Weighs Points of View By Chase Doyle

he value proposition in health care is often represented with the following equation: Value = Outcomes/ Cost. The simplicity of this equation, however, belies the complexity of its parts, which are the contributions of multiple stakeholders with unique perspectives. A session presented at the 2015 ASCO Annual Meeting addressed these differing perspectives—the physician’s, the payer’s, the patient’s, and ASCO’s own value initiative—on the financial challenges in cancer care.1-4 If there are common denominators, they are the recognition of the need for change and the acknowledgment that achieving it will be anything but easy.

be greater with a cancer diagnosis than with other chronic diseases.” According to Dr. Meropol, this burden can directly impact patient outcomes. Patients who have to pay more for a potentially lifesaving therapy are less likely to be compliant, he said, a correlation that contributes to disparities of

are rewarded for the quality of their care, not the volume of services they provide. Most of all, though, Dr. Meropol stressed the need for discussing the relative value of different treatment options with patients at the point of care. “I would love to have models and deci-

Our patients want to discuss cost of care with us. They want to know out-of-pocket costs before starting treatment. —Neal J. Meropol, MD

The Physician Perspective “Oncologists won’t be gatekeepers based on cost. But oncologists do have the opportunity to become gatekeepers based on value in helping our patients choose between different therapies that may have the same cost but different value,” said Neal J. Meropol, MD, Chief of Hematology and Oncology at University Hospitals Case Medical Center and Case Western Reserve University, Cleveland. This is an opportunity borne of necessity. As Dr. Meropol explained, the rising costs of drugs and medical services coupled with high-deductible insurance plans have combined to make cancer a financial, as well as a physical, hardship. “The out-of-pocket burden on cancer patients is enormous,” he said. “Regardless of the type of insurance that you have, the financial burden tends to

care. There is, in fact, a limit to what patients are willing and able to pay for their survival; demand for cancer therapy is more elastic than once believed. “Annual household income and whether or not a patient is working directly affect their stated preference for therapy,” Dr. Meropol reported. “Patients who are out of work are more likely to favor low-cost therapy than patients with higher incomes.” In Dr. Meropol’s opinion, better value begins with improved communication. “Our patients want to discuss cost of care with us,” he said. “They want to know out-of-pocket costs before starting treatment, and in many cases, they would like their doctor to know how much they’re spending themselves on their cancer treatment.” The creation of new payment models is also critical so that physicians

sion tools that would help me predict the benefits and toxicities for my individual patient, and I’d like to know, in real time, the anticipated out-of-pocket costs for my patients based on their insurance…. In this way, I might help them make the best decision based on their understanding of the value of the treatment options,” he concluded.

before they ever get diagnosed with cancer that impact their out-of-pocket costs and what they choose. If they pick a high-deductible plan because they can only afford low premiums, that leaves them in a situation of facing much higher out-of-pocket costs,” she said. In Dr. Malin’s opinion, the key to understanding value lies in the negotiation of clinical benefit, toxicity, and cost. An initiative called the Cancer Care Quality Program is Anthem’s attempt to evolve the current health-care model and reward practices that pursue highvalue care. “What a pathway does is try to identify the most high-value regimens and put them out there as a benchmark,” she explained. “Oncologists participating in the Cancer Care Quality Program will receive additional payment for treatment planning and care coordination when they select a treatment regimen that is on pathway.”

The Payer Perspective According to Jennifer Malin, MD, PhD, Staff Vice President of Clinical Strategy, Anthem, Inc., delivering value to a multitude of stakeholders requires consideration of future patients, not just the ones making treatment decisions. This means factoring the total cost of care, including next year’s insurance premiums and out-ofpocket costs. “Patients are making decisions way

Jennifer Malin, MD, PhD

Ultimately, said Dr. Malin, it is the payer’s responsibility to balance the needs of several stakeholders at different points in time; the pathway model is one part of the solution. “It’s important to think about val-

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ASCO Annual Meeting The Value Proposition continued from page 9

ue from the position of all stakeholders,” she concluded. “We need to have quality and affordable cancer care, reimbursement needs to be aligned for providers so they can achieve desired outcome, and we need to encourage clinically meaningful therapeutic innovations.”

The Patient Perspective Despite the mounting costs of cancer care and bankruptcy rates for patients with cancer that are nearly twice the general population’s, according to one breast cancer advocate, when patients are asked to define value in the context of their care, cost is not their first concern.

Beverly E. Canin

“If you push patients to share [their thoughts] about value in the context of cancer treatment, they invariably refer to communication and the relationship with the doctor as being paramount,” said Beverly E. Canin, Vice President of Breast Cancer Options, Inc. A survey shared by Ms. Canin revealed that only 7.5% of patients de-

fined value in terms of an exchange. On the other hand, more than 38% of patients defined value in terms of a personal value. Financial cost relative to benefit or treatment efficacy was rarely mentioned, she observed. “When we are in your office or clinic in treatment, we care the most about our relationships and trust with you, our doctors…. I speak of ‘we,’ but we patients are not some all-inclusive single entity. The ‘we’ is a collective of individuals that must be seen, communicated with, and treated as individuals,” she concluded.

ASCO Value Initiative According to the Chair of the ASCO Task Force on Value in Cancer Care, Lowell E. Schnipper, MD, ASCO’s vision is to provide all patients with lifelong access to affordable, compassionate, and high-quality care. Accomplishing this feat, however, involves rethinking how oncologists value treatment options so they can help patients make informed decisions. “Ultimately,” said Dr. Schnipper, Chief of Hematology/Oncology and Clinical Director of Beth Israel Deaconess Medical Center, Boston, “we are optimizing a tool that a physician would have at his or her disposal in the office that would help patients understand, for a given clinical indication, what are the possible regimens, what are the ups and downs, and [how to] integrate those with their personal preferences.” (For more information on ASCO’s Task Force on Value in Cancer Care, see the June 25, 2015, issue of The ASCO Post.)

Dr. Schnipper foresees the day when a tool such as this might be incorporated into decisions that health-care systems might make in striving to provide patients with high value cancer care.

People exhaust their savings so their kids may have to delay going to college. Second mortgages on the house are taken, and adherence to the medication is shown to be reduced.” n

We are optimizing a tool that a physician would have at his or her disposal in the office that would help patients understand what are the possible regimens, what are the ups and downs, and [how to] integrate those with their personal preferences. —Lowell E. Schnipper, MD

The value framework developed by the task force is designed to compare a standard-of-care therapy with a new regimen (or single agent) and distinguishes between small or large improvements when compared to the standard of care for overall or progression-free survival and palliation of symptoms in advanced disease. Comparisons of toxicity of the standard of care and test regimens are weighed as well, and the sum of clinical benefit and toxicity is then derived to yield a net health benefit of the test regimen when compared with the standard of care. Finally, cost was an unavoidable variable in the value conversation, a critical emphasis of discussion at the physicianpatient interface. “As the cost of care increases, I’m not talking about the U.S. economy,” he said. “I’m talking about the patient sitting across from you.

Disclosure: Dr. Meropol is a consultant for BioMotiv. Dr. Malin is an employee and shareholder of Anthem, Inc. Dr. Schnipper is a member and on the advisory board of Eviti, Inc; and is Co-Editor-in-Chief of UpToDate Oncology.

References 1. Meropol NJ: The physician perspective: The value proposition in oncology: Different approaches to understanding value in cancer care. 2015 ASCO Annual Meeting. Presented May 29, 2015. 2. Malin J: Case considerations: Value from the payer perspective. 2015 ASCO Annual Meeting. Presented May 29, 2015. 3. Canin BE: Patient priorities on value in treatment choices. 2015 ASCO Annual Meeting. Presented May 29, 2015. 4. Schnipper LE: Assessing value in cancer care: An ASCO initiative. 2015 ASCO Annual Meeting. Presented May 29, 2015.

Study Shows Current Blood Cancer Drug Prices Are Not Justified

he costs associated with cancer drug prices have risen dramatically over the past 15 years, a trend concerning to many oncologists. In a new analysis, researchers at The University of Texas MD Anderson Cancer Center concluded the majority of existing treatments for hematologic cancers are currently priced too high to be considered cost-effective in the United States. Their findings were published by Chhatwal et al in the journal Cancer.1

Past Research A 2015 study2 by Saret et al suggesting that hematologic cancer drugs provide good value for money raised concerns for MD Anderson researchers Jagpreet Chhatwal, PhD, lead investigator and Assistant Professor in the Department of Health Services Research, and Hagop Kantarjian, MD, senior

However, those cost-effectiveness calculations were performed using drug prices at the time of the original studies and often included prices from countries outside of the United States. Therefore, Drs. Chhatwal and K antarjian performed a critical reanalysis of the prior study using current drug prices in U.S. dollars. Hagop Kantarjian, MD “We found that, in a majority of the author and Professor and Chair of the studies, the incremental cost-effectiveDepartment of Leukemia. ness ratios … were substantially higher The prior study calculated cost- than the previously reported values,” effectiveness for these drugs based on 29 said Dr. Chhatwal. studies of 9 treatments for hematologic cancers, including chronic myeloid leu- Skyrocketing Costs Cost-effectiveness is commonly inkemia, chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple terpreted in terms of the cost needed myeloma. The results indicate that these to gain an additional quality-adjusted drugs provided reasonable value for the life-year. A threshold value of $50,000 is widely accepted, below which the treatmoney in the United States.

Issues in Oncology

ment can be considered cost-effective. The researchers were able to reanalyze 20 of the 29 studies with updated drug prices in the current U.S. market. Upon doing this, they found that 63% of those studies had costs per additional life-year higher than the $50,000 threshold. Several studies resulted in costs of $210,000 to $426,000 per additional life-year, many times higher than conventionally accepted levels. This indicates that, although the drugs may have been cost-effective originally, their current prices cannot be justified based upon improved quality of life. One of the drugs evaluated, imatinib (Gleevec), was priced at $26,000 per year of therapy in 2001 and $132,000 per year in 2014. The price increase in imatinib and other drugs evaluated is not the result of new and improved vercontinued on page 11

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FDA Update

FDA Grants Orphan Drug Designation to Antitropomyosin Drug for Neuroblastoma

he U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation to Novogen Limited’s chemotherapy candidate drug Anisina for neuroblastoma. Anisina is a small molecule belonging to a family of compounds called antitropomyosins. It has been designed to inhibit Tpm3.1, a structural protein that is a core component of the cytoskeleton of cancer cells.

compound, vincristine, in an animal model of neuroblastoma. The data from these studies were recently announced and presented at Eighth Annual Cancer Molecular Therapeutics Research Asso-

ciation meeting in Boston. Researchers have demonstrated efficacy in an animal model of neuroblastoma both as monotherapy and in combination with vincristine, and preclinical

studies to further validate the combinatorial effect of the drug with a range of microtubule-targeting compounds are now being conducted in animal models of adult cancer. n

The decision was based on preclinical data demonstrating that the antitropomyosin drug significantly improved the effectiveness of the standard-of-care microtubule targeting

Blood Cancer Drug Prices continued from page 10

sions, but instead is simply the result of rising prices, explained Dr. Chhatwal. Perhaps more disturbing are the long-term implications of rising prices, explained Dr. Chhatwal. Many of these

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Jagpreet Chhatwal, PhD

drugs need to be taken daily for years to manage cancer. Current drug prices could cause extremely large financial burdens, even for the well insured. The authors concluded that regulating the cost of new treatments, as done in many European countries, will make health care more affordable and valuable for patients and providers in the United States. n References 1. Chhatwal J, Mathisen M, Kantarjian H: Are high drug prices for hematologic malignancies justified? A critical analysis. Cancer. June 23, 2015 (early release online). 2. Saret CJ, Winn AN, Shah G, et al: Value of innovation in hematologic malignancies: A systematic review of published cost-effectiveness analyses. Blood 125:1866-1869, 2015.

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Journal Spotlight Genitourinary Oncology

Magnetic Resonance Imaging/Ultrasound Fusion–Guided Biopsy Improves Detection of High-Risk Prostate Cancer By Matthew Stenger

n a study reported in JAMA, M. Minhaj Siddiqui, MD, currently of the University of Maryland School of Medicine, and colleagues found that targeted magnetic resonance imaging (MRI)/ultrasound fusion– guided prostate biopsy increased diagnosis of high-risk prostate cancer and reduced detection of low-risk disease compared with standard (extended-sextant) ultrasound-guided biopsy.1

Study Details In the study, 1,003 men underwent multiparametric prostate MRI to identify regions suspicious for prostate cancer followed by both targeted and standard biopsy at the National Cancer Institute between 2007 and 2014. Patients had elevated prostate-specific antigen (PSA) levels or abnormal digital rectal examinations, most with prior negative biopsy results. The primary objective was to compare targeted and standard biopsy for detection of high-risk prostate cancer (Gleason score ≥ 4 + 3). Secondary outcomes included detection of lowrisk prostate cancer (Gleason score 3 + 3 or low-volume 3 + 4) and biopsy ability to predict whole-gland pathology at prostatectomy. In total, 196 patients had no prior biopsy and 170 ultimately underwent prostatectomy. Among all patients: mean age was 62 years; median PSA level was 6.7 ng/mL; median prostate volume was 49 cm3; cancer suspicion score on multiparametric MRI was low for 18%, moderate for 72%, and high for 11%; tumor stage was T1c in 89% and T2a in 9%; 44% had anterior lesions; mean number of lesions on multiparametric MRI was 2.7; mean number of targeted MR/ultrasound biopsy cores was 5.3; and mean number of standard biopsy cores was 12.3. Compared with patients with a prior biopsy, those with no prior biopsy had lower prebiopsy PSA level (median, 5.3

vs 7.1 ng/mL; P = .002), smaller prostate volume (median, 42 vs 52 cm3; P < .001), lower proportion with anterior lesions (34% vs 47%, P = .001), and more MRI lesions to biopsy (mean, 2.9 vs 2.6; P = .001). Compared with all patients who underwent study biopsy, those who ultimately underwent prostatectomy were younger (mean age, 60.2 vs 62.1 years; P < .001), had smaller prostate volume

targeted biopsy led to diagnosis of 103 more cancer cases (22%); of these, 86 (83%) were low-risk and only 5 (5%) were high-risk. On this approach, the number needed to biopsy with standard biopsy plus targeted biopsy was 200 to diagnose 1 additional high-risk cancer; for each additional case of high-risk cancer diagnosed, 17 additional cases of low-risk cancer would be diagnosed.

Among men undergoing biopsy for suspected prostate cancer, targeted [MRI]/ultrasound fusion biopsy, compared with standard extendedsextant ultrasound-guided biopsy, was associated with increased detection of high-risk prostate cancer and decreased detection of low-risk prostate cancer. —M. Minhaj Siddiqui, MD, and colleagues

(median, 39 vs 49 cm3; P < .001), and had more MRI lesions (mean, 3.1 vs 2.7; P < .001).

Diagnosis and Risk Categories Targeted MR/ultrasound fusion biopsy diagnosed 461 prostate cancer cases, and standard biopsy diagnosed 469 cases. There was agreement between targeted and standard biopsy in 690 cases (69%). Targeted biopsy diagnosed 30% more high-risk cancers vs standard biopsy (173 vs 122 cases, P < .001) and 17% fewer low-risk cancers (213 vs 258 cases, P = .002). Higher risk category was indicated by targeted biopsy in 167 cases (17%) and by standard biopsy in 146 cases (15%). Among the targeted biopsy cases, 112 (67%) were upgraded to intermediate- or high-risk compared with 60 cases (41%) on standard biopsy (P < .001). Combining standard biopsy and

Combining standard and targeted biopsy led to no change in Gleason score risk stratification in 857 cases (85%). Of those with a change in risk category, 86 (9%) increased from no cancer to low-risk cancer, whereas only 19 (2%) increased from no cancer or low- or intermediate-risk disease to high-risk disease.

Biopsy Diagnosis vs Whole-Mount Pathology Among the 170 patients who underwent radical prostatectomy, 17 patients were diagnosed with cancer only on standard biopsy; of these, 3 (18%) had intermediate- or high-risk cancer on whole-mount pathology. Of 20 patients diagnosed only on targeted biopsy, 12 (60%) had intermediateor high-risk cancer on whole-mount pathology. Overall, targeted vs standard biopsy had a sensitivity of 77% vs 53% and a

specificity of 68% vs 66% for wholegland pathology findings. The area under the receiver operator characteristic curve for targeted biopsy was 0.73, significantly greater than that for standard biopsy (0.59, P = .005) or combined biopsy (0.67, P = .04).

Patients With No Prior Biopsy Among the 196 patients with no prior biopsy, cancer was diagnosed in 110; of these, 42% had low-risk, 16% had intermediate-risk, and 42% had high-risk disease. There was no significant difference between targeted biopsy risk distribution in this group compared with patients with prior biopsies (P = .52). The standard biopsy risk distribution was higher among patients without prior biopsy and did not differ significantly from the targeted biopsy distribution in the group. Combining standard and targeted biopsy in this group resulted in no change in risk status for 85%, the same proportion as in the total study group. Combined biopsy use resulted in upgrading to high-risk disease in 7 patients without prior biopsy (4%). The investigators concluded: “Among men undergoing biopsy for suspected prostate cancer, targeted [MRI]/ultrasound fusion biopsy, compared with standard extended-sextant ultrasound-guided biopsy, was associated with increased detection of high-risk prostate cancer and decreased detection of low-risk prostate cancer. Future studies will be needed to assess the ultimate clinical implications of targeted biopsy.” n Disclosure: For full disclosures of the study authors, visit jama.jamanetwork.com.

Reference 1. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al: Comparison of MR/ ultrasound fusion–guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA 313:390-397, 2015.

A Promising Technology for Image-Guided Prostate Biopsy See discussion by Richard G. Abramson, MD, and Sandeep S. Arora, MBBS, on page 14.

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Perspective

Magnetic Resonance Imaging/Ultrasound Fusion: A Promising Technology for Image-Guided Prostate Biopsy By Richard G. Abramson, MD and Sandeep S. Arora, MBBS

n elegant study by Siddiqui et al1—reviewed in this issue of The ASCO Post—offers compelling evidence for the diagnostic utility of “targeted” prostate biopsy using multiparametric magnetic resonance imaging (MRI) data fused with ultrasound images. The technique involves first performing a dedicated prostate MRI examination in which several pieces of complementary anatomic and functional data are acquired in a single combined scan. During a separate biopsy procedure performed at a different time and location, the MRI data are then fused with real-time ultrasound to provide guidance for biopsy passes targeted at suspicious foci within the gland. In their prospective study of 1,003 men referred for elevated prostate-specific antigen levels or abnormal digital rectal examinations, the authors found

Dr. Abramson is Assistant Professor of Radiology and Radiological Sciences, and Dr. Arora is Instructor in Clinical Radiology and Radiological Sciences at Vanderbilt University Medical Center, Nashville.

that targeted biopsy yielded 30% more high-risk cancers and 17% fewer lowrisk cancers compared to standard ex-

Technique and Equipment The study gives rise to a number of unanswered questions and av-

[T]his technology offers the enticing prospect of more effectively triaging prostate cancer patients to appropriate therapeutic pathways. —Richard G. Abramson, MD (left), and Sandeep S. Arora, MBBS (right)

tended-sextant biopsy. Given the evolving understanding that low-risk prostate cancers may be amenable to observational strategies rather than immediate surgery or radiation,2 this technology offers the enticing prospect of more effectively triaging prostate cancer patients to appropriate therapeutic pathways.

enues for further investigation. First, the technique for acquiring, interpreting, and fusing multiparametric MRI of the prostate is far from standardized, and further work is required to understand how diagnostic performance changes with different methods. In this study, MRI was per-

formed on a 3.0 Tesla Philips scanner using an endorectal coil, but all major magnetic resonance hardware vendors offer prostate imaging packages with slight variations between the systems, and clinical MRI is currently performed at different field strengths and either with or without an endorectal coil. The authors interpreted the multiparametric MRI scans using a qualitative scale of their own design,3 but approaches for interpreting and reporting multiparametric MRI of the prostate are still rapidly evolving. The European Prostate Imaging and Reporting and Data System (PIRADS) classification system,4 which had not yet been released when the current study was launched, has already spawned a PI-RADS version 2 revision describing a slightly different methodology,5 and many authors continue to investigate alternative reporting schemes that may have higher inter-reader reproducibility.6 This study incorporated functional MRI information from dynamic contrastcontinued on page 15

Don’t Miss These Important Reports in This Issue of The ASCO Post Neal J. Meropol, MD, on The Value Proposition see page 9

Tito Fojo, MD, on Necitumumab in Squamous NSCLC see page 16

Peter A. Kaufman, MD, on Eribulin vs Capecitabine in Advanced Breast Cancer see page 17

Stephen T. Sonis, DMD, DMSc, on Genetic Analysis and Treatment Toxicity see page 24

Michael Kastan, MD, PhD, on Dogs and Humans in the Laboratory Setting see page 52

Emil J Freirich, MD, Looks Back on His Illustrious Career see page 56

Chris Feudtner, MD, PhD, MPH, on Adolescent/Young Adult Patients With Cancer and Advance Care Planning see page 63

Richard J. Boxer, MD, FACS, on Cost vs Value in Cancer Care see page 66

James F. Holland, MD, FASCO, Honored on His 90th Birthday see page 73

Visit The ASCO Post online at ASCOPost.com

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PAGE 15

Perspective

Richard G. Abramson, MD targeted biopsy strategy holds true for and Sandeep S. Arora, MBBS patients with no prior biopsy, in whom continued from page 14

enhanced MRI, diffusion-weighted MRI, and magnetic resonance spectroscopic imaging, but the latter is a technique performed more commonly in Europe than in the United States and was in fact omitted from PI-RADS version 2. This study used an electromagnetic tracking system (UroNav, Philips-Invivo) for co-registering or “fusing” the MRI data to the ultrasound images, but other technologies are available, including robotic tracking via a mechanical arm with built-in encoders (Artemis, Eigen; BioJet, Geoscan) and tracking with a three-dimensional ultrasound probe (Urostation, Koelis). It should be noted that all of these technologies appear to improve over “in-bore” magnetic resonance– guided biopsy, which is expensive, time-consuming, requires MRIcompatible equipment, and cannot be performed as an in-office urology clinic procedure.

Decision Analysis Second, further work is required to understand how this technology should be integrated into diagnostic and therapeutic algorithms. The authors present a decision analysis suggesting that targeted biopsy may be superior to both standard biopsy and combined (targeted plus standard) biopsy strategies at intermediate threshold probabilities (ie, when an individual patient is not so desirous of treatment that the optimal strategy would be “always treat” and not so averse to treatment that the optimal strategy would be “never treat”). The decision analysis model apparently used data from 170 patients who underwent radical prostatectomy and therefore had whole-gland pathology specimens available for comparison to the biopsy results. In this subset of patients, targeted biopsy had intermediate sensitivity (77%) for intermediate- or high-risk prostate cancer compared to standard biopsy (53%) or combined biopsy (85%) but had higher specificity (68% compared to 66% and 49%) and a higher area under the receiver operating characteristic curve (AUC = 0.73 vs 0.59 and 0.67). However, it is unclear from the paper whether the dominance of the

standard biopsy appears to have a higher sensitivity for high-risk prostate cancers. For patients with no prior biopsy, future studies may help us understand whether targeted biopsy should be deployed alone, in combination with standard biopsy, or only if standard biopsy yields a negative result. Also, this study was confined to patients who had at least one lesion detected on multiparametric MRI. Recent retrospective studies have yielded somewhat conflicting data on the ability of mp-MRI to detect high-risk prostate cancer.7,8 Large prospective trials are required to determine whether a negative multiparametric MRI alone may be enough to warrant forgoing biopsy altogether and triaging patients to an active surveillance strategy.

Costs and Outcomes Finally, a comprehensive assessment of this emerging technology will require evaluation of its effects on costs and long-term patient outcomes. Widespread adoption of MRI/ultrasound fusion–guided biopsy would be expensive but may turn out to be cost-effective from a societal perspective after accounting for reductions in overdiagnosis and overtreatment.9 Moreover, as noted in a JAMA editorial by Schwartz and Basch,10 it remains to be proven that use of targeted biopsy will translate into an improvement in clinically meaningful long-term outcomes, including symptoms, functional status, and survival. We eagerly await further results, ideally from randomized controlled clinical trials, to guide the dissemination and utilization of this promising technology. n Disclosure: Drs. Abramson and Arora reported no potential conflicts of interest.

References 1. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al: Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA 313:390-397, 2015. 2. Ganz PA, Barry JM, Burke W, et al: National Institutes of Health State-of-theScience Conference: Role of active surveillance in the management of men with localized prostate cancer. Ann Intern Med 156:591-595, 2012. 3. Yerram NK, Volkin D, Turkbey B, et al: Low suspicion lesions on multipara-

metric magnetic resonance imaging predict for the absence of high-risk prostate cancer. BJU Int 110:E783-E788, 2012. 4. Barentsz JO, Richenberg J, Clements R, et al: ESUR prostate MR guidelines 2012. Eur Radiol 22:746-757, 2012. 5. American College of Radiology: Prostate Imaging and Reporting and Data System: Version 2 (PI-RADS v2). Available at http://www.acr.org/~/media/ ACR/Documents/PDF/QualitySafety/ Resources/PIRADS/PIRADS%20V2. pdf. Accessed July 16, 2015. 6. Rosenkrantz AB, Lim RP, Haghighi M, et al: Comparison of interreader reproducibility of the prostate imaging reporting and data system and Likert scales for evaluation of multiparametric prostate MRI. AJR Am J Roentgenol 201:W612-W618, 2013. 7. Meng X, Rosenkrantz AB, Mendhiratta N, et al: Relationship between prebiopsy multiparametric magnetic resonance

imaging (MRI), biopsy indication, and MRI-ultrasound fusion-targeted prostate biopsy outcomes. Eur Urol. June 22, 2015 (early release online). 8. Tan N, Margolis DJ, Lu DY, et al: Characteristics of detected and missed prostate cancer foci on 3-T multiparametric MRI using an endorectal coil correlated with whole-mount thin-section histopathology. AJR Am J Roentgenol 205:W87-92, 2015. 9. de Rooij M, Crienen S, Witjes JA, et al: Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: A modelling study from a health care perspective. Eur Urol 66:430-436, 2014. 10. Schwartz LH, Basch E: MR/ultrasound fusion-guided biopsy in prostate cancer: What is the evidentiary standard? JAMA 313:367-368, 2015.

Human Fibroblast Cell

n this scanning electron micrograph, several 1-micron-sized, nontoxic silica beads (yellow) are seen on the surface of a human fibroblast cell, which produce the structural materials found outside of cells in the body, such as collagen. However, aberrant activation of fibroblasts is found in various pathologic states; for example, they can support the growth and spread of a tumor. Understanding transport mechanisms of drugs and particles on the single-cell scale is important to support the development of nontoxic therapeutics that have increased efficacy and reduced side effects. This image captures the transport processes involved in the internalization of particles by a fibroblast cell line. Image by Matthew Ware and Biana Godin, Vilentchouk, Biomedical Engineering Society, Houston Methodist Research Institute, Houston. Research supported by the National Cancer Institute of the National Institutes of Health. Send your high-resolution photo or image and caption to editor@ ASCOPost.com.

The ASCO Post | AUGUST 10, 2015

PAGE 16

FDA Update Thoracic Oncology

ODAC Discussion ‘Constructive’ About Necitumumab for Squamous NSCLC By Kirsten Boyd Goldberg

he U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) favored the approval of necitumumab in combination with gemcitabine and cisplatin for use in first-line treatment of patients with locally advanced or metastatic squamous non–small cell lung cancer (NSCLC).

Richard Pazdur, MD

In an unusual move, the FDA did not ask ODAC to vote on approval at its July 9 meeting. Instead, Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said he was more interested in the committee’s discussion weighing the therapy’s risks and benefits. Necitumumab is a recombinant hu-

months in the group that received necitumumab compared with 9.9 months in the patients who received gemcitabine/ cisplatin alone. The median progression-free survival was 5.7 months in the necitumumab arm compared with 5.5 months in the control arm (HR = 0.85 [95% CI = 0.74–0.98], P = .02). There was no statistically significant difference in objective response rate (31% vs 29%). The study enrolled 1,093 patients from 26 countries. The SQUIRE trial included a patient population typical of one seen in clinical practice. Patients with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were eligible for inclusion in the trial. Notably, 55% of patients had metastases to more than two organ systems. A second randomized phase III trial, INSPIRE, provided additional safety data. Patients with advanced nonsquamous NSCLC who had not received prior chemotherapy for metastatic disease received either necitumumab with pemetrexed (Alimta) and cisplatin, or pemetrexed and cisplatin alone. The data monitoring committee recommended that enrollment in the study be stopped

I certainly think the survival benefit is modest, but it’s real. —Deborah Armstrong, MD

man immunoglobulin G1 monoclonal antibody designed to block the ligandbinding site of the human epidermal growth factor receptor (EGFR) 1.

Clinical Trial Data In this randomized phase III trial supporting the drug’s efficacy, called SQUIRE, the addition of necitumumab to gemcitabine/cisplatin for patients with squamous NSCLC who had not received prior chemotherapy for metastatic disease resulted in a statistically significant improvement in median overall survival (hazard ratio [HR] = 0.84 [95% CI = 0.74–0.96], P = .01), the primary endpoint of the study. The median overall survival was 11.5

prematurely due to an imbalance in the number of deaths attributed to thromboembolic events and deaths of all causes observed in the necitumumab arm compared with the control arm. There was no difference in overall survival. The safety profile of necitumumab generally is consistent with the adverse events observed with the class of antiEGFR antibodies, according to the FDA’s analysis. In SQUIRE, significant adverse events of grade 3 or greater included hypomagnesemia (9%), skin rash (7%), and hypersensitivity/infusion reaction (0.4%) Fatal cardiopulmonary arrest or sudden death was observed in 2.2% of the patients receiving necitumumab compared with 0.5% in the control arm.

The incidence of thromboembolic events was higher in the necitumumabcontaining arms in both SQUIRE and INSPIRE. The incidence of grade 3 or higher thromboembolic events was 9% vs 5% in SQUIRE and 11% vs 6% in

“I certainly think the survival benefit is modest, but it’s real,” said ODAC Chairperson Deborah Armstrong, MD, Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. “When

At the end of the day, this trial doesn’t provide me the comfort of saying that the risk-benefit is a favorable one. —Tito Fojo, MD

INSPIRE. The most common venous thromboembolic events, some fatal, were pulmonary emboli and deep vein thrombosis, whereas the most common arterial thromboembolic events were myocardial infarction and cerebrovascular accidents. Eli Lilly and Company proposed drug labeling to address the safety issues, including recommending that prophylactic anticoagulation be used according to current guidelines, monitoring of serum electrolytes prior to each necitumumab injection and for 8 weeks following treatment completion, and using electrolyte repletion as necessary.

Approval Decision Expected Later This Year First-line treatment of metastatic squamous NSCLC has not changed in about 20 years, since the introduction of gemcitabine, even as molecularly targeted therapies have resulted in survival improvements for patients with nonsquamous NSCLC. Five-year survival of squamous NSCLC stands at less than 5%. In a round-robin discussion, it appeared that about 10 or 11 of the 12 ODAC members favored approval of necitumumab. “While there is a very modest benefit, this is a population that needs options,” said ODAC consumer representative Virginia Mason, RN, BSN, Executive Director and President of the Inflammatory Breast Cancer Research Foundation, West Lafayette, Indiana. “If I could be assured that people are going to have good monitoring and good discussions about the risk-benefits, I can feel comfortable with this moving forward.”

I talk to the patients who are going on trials, they all want a magic bullet or a home run, but frankly we tend to build in small baby steps and move forward that way, and this would have to be considered one of those.” Tito Fojo, MD, Director of the Medical Oncology Fellowship Program at the National Cancer Institute, questioned whether the drug offered a positive riskbenefit profile. “At the end of the day, this trial doesn’t provide me the comfort of saying that the risk-benefit is a favorable one. It sure would be nice to have better data and additional data,” he said. ODAC provides the FDA with independent expert advice and recommendations, but the Agency makes the final decision regarding approval. The FDA plans to make that decision on necitumumab by the regulatory deadline later this year, Dr. Pazdur said. “We are encouraged by the committee’s constructive discussion on the benefit-risk profile of necitumumab, as few advances have been made over the past two decades in the first-line treatment of advanced squamous NSCLC, leaving a significant unmet medical need,” said Richard Gaynor, MD, Senior Vice President, Product Development and Medical Affairs for Lilly Oncology. “We believe necitumumab with gemcitabine and cisplatin represents a meaningful advance in the search for a new first-line treatment option and look forward to working closely with the FDA as they continue their review.” n Disclosure: Drs. Pazdur, Armstrong, Fojo, and Gaynor reported no potential conflicts of interest.

ASCOPost.com | AUGUST 10, 2015

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JCO Spotlight Breast Cancer

No Survival Benefit for Eribulin vs Capecitabine in Advanced Breast Cancer By Matthew Stenger

ribulin (Halaven) currently is indicated in the United States for treatment of patients with metastatic breast cancer who previously received at least two chemotherapy regimens for metastatic disease and an anthracycline and a taxane in either the adjuvant or metastatic setting. Its approval was based on a phase III trial showing a survival advantage for eribulin vs single-agent treatment of the physician’s choice.1 In a phase III trial reported in the Journal of Clinical Oncology, Peter A. Kaufman, MD, of Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, and colleagues found no overall survival advantage for eribulin vs capecitabine.2

teristics considered. Overall, 20%, 52%, and 27% received study therapy as firstline, second-line, and third-line treatments for advanced disease.

Survival Data Median overall survival was 15.9 months (95% confidence interval [CI] = 15.2–17.6 months) in the eribulin group

Adverse Events The most common adverse events of any grade were neutropenia (54%), alopecia (35%), leukopenia (31%), global peripheral neuropathy (27%), and nausea (22%) in the eribulin group and hand-foot syndrome (45%), diarrhea (29%), and nausea (24%) in the capecitabine group. The most

[T]his trial did not demonstrate superiority of eribulin versus capecitabine for either [overall survival] or [progression-free survival]. —Peter A. Kaufman, MD, and colleagues

Study Details In this open-label trial, 1,102 women with locally advanced or metastatic breast cancer who had received up to three chemotherapy regimens and up to two prior chemotherapy regimens for advanced and/or metastatic disease with an anthracycline and a taxane were randomly assigned to receive eribulin at 1.4 mg/m2 IV on days 1 and 8 (n = 554) or oral capecitabine at 1.25 g/m2 twice daily on days 1 to 14 (n = 548) every 21 days. The primary endpoints were overall survival and progressionfree survival. The eribulin and capecitabine groups were generally balanced for all charac-

vs 14.5 months (95% CI = 13.1–16.0 months) in the capecitabine group (hazard ratio [HR] = 0.88, 95% CI = 0.77– 1.00, P = .056). Median progressionfree survival was 4.1 months (95% CI = 3.5–4.3 months) vs 4.2 months (95% CI = 3.9–4.8 months; HR = 1.08, 95% CI = 0.93–1.25, P = .30). Objective response rate on independent review was 11.0% vs 11.5% (P = .85). A prespecified exploratory analysis suggested an overall survival benefit for eribulin in HER2negative patients; however, there was no significant interaction between treatment effect and HER2 status.

Eribulin vs Capecitabine for Locally Advanced or Metastatic Breast Cancer ■■ Eribulin was not associated with a significant overall survival advantage compared with capecitabine. ■■ No difference in progression-free survival was observed.

common grade 3 or 4 adverse events were neutropenia (46%), leukopenia (15%), and global peripheral neuropathy (7%) in the eribulin group, and hand-foot syndrome (15%) in the capecitabine group. Febrile neutropenia occurred in 2.0% vs 0.9%. Colonystimulating factor treatment was required in 15% vs 4%. Adverse events led to discontinuation, reduction, and delay in treatment in 8% vs 10%, 32% vs 32%, and 32% vs 36%. The most common causes of treatment discontinuation were neutropenia (1.7%) in the eribulin group and hand-foot syndrome (2.2%) and dyspnea (1.1%) in the capecitabine group. Serious adverse events occurred in 18% of the eribulin group vs 21% of the capecitabine group. Fatal adverse events occurred within 30 days of the last study dose in 4.8% of eribulin recipients and 6.6% of capecitabine

recipients; these events were considered treatment-related in five eribulin patients (sepsis, pericardial effusion, sudden death, toxic hepatitis, and renal failure) and four capecitabine patients (sepsis, pneumonia, cardiogenic shock, and pancytopenia). Global health status/overall quality of life was assessed by the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (version 3.0) and breast module Quality-of-Life Questionnaire BR23. Both groups had improvement in average scores during the study, with no between-group differences being observed. The investigators concluded: “[T] his trial did not demonstrate superiority of eribulin versus capecitabine for either [overall survival] or [progression-free survival]. The effects on [quality of life] in this population of patients with [metastatic breast cancer] and the [adverse event] profiles of eribulin and capecitabine were consistent with their known [adverse events].” n Disclosure: This study was supported by Eisai. For full disclosures of the study authors, visit www.jco.org.

References 1. Cortes J, O’Shaughnessy J, Loesch D, et al: Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomised study. Lancet 377:914-923, 2011. 2. Kaufman PA, Awada A, Twelves C, et al: Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 33:594-601.

Comparing Regimens Guides Therapeutic Decisions in Previously Treated Advanced Breast Cancer See discussion by Linda T. Vahdat, MD, on page 18.

The ASCO Post | AUGUST 10, 2015

PAGE 18

Perspective

Comparing Regimens Guides Therapeutic Decisions in Previously Treated Advanced Breast Cancer By Linda T. Vahdat, MD

aufman and colleagues recently reported findings of a phase III trial comparing eribulin (Halaven) vs capecitabine in pa tients with advanced breast cancer who had previously received anthracycline and taxane therapy,1 and a review of their study appears in this issue of The ASCO Post. Although this large study did not achieve its primary endpoints of improvement in progression-free survival and overall survival, it is an important clinical trial that can help guide clinical practice. This study established eribulin (a drug that is indicated in later-line therapy) as a drug that is no worse Dr. Vahdat is Professor of Medicine and Director of the Breast Cancer Research Program, Weill Cornell Medical College, New York.

gives insight into how frequently used drugs in breast cancer measure up to each other from an efficacy and a toxicity perspective.

Efficacy and Toxicity

Linda T. Vahdat, MD

than capecitabine in an earlier line of therapy than its U.S. Food and Drug Administration label. This is valuable information for practicing oncologists who treat patients with breast cancer, because there is no preferred sequence of therapies for HER2negative/nonamplified breast cancer. Since treatment decisions require balancing of risks and benefits, it is essential to know how therapeutics directly compare with each other. This study

Kaufman et al randomized more than 1,000 patients with breast cancer who had received less than two regimens in the metastatic setting to treatment with eribulin or capecitabine. The study was designed for superiority of eribulin over capecitabine for both progression-free survival and overall survival. Both arms were well balanced with respect to age, prior therapy, and burden of disease. Study therapy represented first or second line of therapy for advanced disease in 72% of patients. The median progression-free survival was similar at 4.2 months with eribulin and 4.1 months with capecitabine.

Visit ASCOPost.com for Interviews Filmed During the 2015 ASCO Annual Meeting The ASCO Post presents these and other important discussions: ■■

■■ ■■

Whole-Brain Radiation and Radiosurgery in Patients With Brain Metastases Issues of Value in Melanoma Treatment PALOMA3 Study on Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer Global Oncology: Cancer Care in Resource-Challenged Areas Ibrutinib, Bendamustine, and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Visit The ASCO Post online at ASCOPost.com

The response rates were also similar at 11%. As expected, severe (grade 3 and 4) adverse events were predictable, with hand-foot syndrome (14.5%) and diarrhea (5.3%) more prominent with capecitabine, and neutropenia (46.7%) and neuropathy (7%) more prominent with eribulin. In my opinion, this study lends some clarity to how regimens compare and adds significantly to the available body of literature that we use to choose therapies for our patients. n

Disclosure: Dr. Vahdat is on the speakers bureau for Eisai.

Reference 1. Kaufman PA, Awada A, Twelves C, et al: Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 33:594-601, 2015.

ASCOPost.com | AUGUST 10, 2015

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Expert’s Corner Quality of Care

Past President of ASCO Takes on New Role at Memorial Sloan Kettering Cancer Center to Improve Patient Care and Public Health A Conversation With Clifford A. Hudis, MD, FACP By Jo Cavallo

Clifford A. Hudis, MD, FACP

n June, Memorial Sloan Kettering Cancer Center (Memorial) in New York announced it had appointed Clifford A. Hudis, MD, FACP, Chief of Breast Medicine Service, to a newly created position of Vice President for Government Relations and Chief Advocacy Officer. In addition to his new role, Dr. Hudis will maintain his position as Chief of Breast Medicine Service and will remain on the CancerLinQ Board of Governors. With this new position Memorial has a designated physician leader to liaison with key stakeholders in health care, including insurers, patients, industry, and public health policymakers, to better understand and meet the changing forces and emerging needs in cancer care, said Dr. Hudis. Dr. Hudis’ responsibilities as President of ASCO (2013–2014), a member of ASCO’s Board of Directors for the past 6 years, and a member of the CancerLinQ™ Board of Governors overseeing the development of ASCO’s big-data health system, have prepared him for the range of tasks in his new position, he said. The ASCO Post talked with Dr. Hudis about his new position and his goals for advancing oncology care for all patients.

Strategic Position Why did Memorial create the position of Vice President for Government Relations and Chief Advocacy Officer, and why at this particular time? This new position addresses a strategic opportunity for Memorial. It further organizes our institutional activities and initiatives to make sure that Memorial’s value proposition is well understood by all health-care stakeholders, including government regulators and public health policymakers, payers, patients, and everyone with an interest in cancer care.

Our overall goal is to ensure that patients will have continued access to Memorial’s resources and that the environment fosters the innovation and scientific advances we seek. In the end, this benefits not only Memorial, but the entire research and cancer care ecosystem. To accomplish these goals we have to tell our story and explain the benefits of our approach to research and cancer care. At the same time, as an institution, we need to continuously learn where and how we need to evolve in response to changing conditions in terms of funding and other resources for research and care. All of this should be aided by having an experienced investigator, administator, and clinical leader providing insights and guidance, and that is this feels like a great opportunity to me.

More Than Just Cost of Care When you say “value proposition,” are you referring to the cost of oncology drugs? Although the rising cost of cancer drugs is one of many important com-

ing new opportunities modern science is providing, we need to continually invest in our faculty and our facilities, and to do that, we need partners across the health-care spectrum, including insurers, government regulators, and healthcare policymakers. Convincing them that we are a great investment means telling our story with clarity and vision.

What Is Good for Memorial… Why did you decide to accept this new position, and what do you hope to accomplish? The answer is both personal and professional. One of the highlights of my career was the opportunity I’ve had to serve as the President of ASCO in 2013–2014. In addition, I’ve now spent a total of 6 years on ASCO’s Board of Directors, and in that capacity, I’ve come to understand some of the ways in which a highly functional and effective professional society governs itself, makes decisions, responds to challenges, interacts with the rest of society, and creates opportunities for

If I can help increase the effectiveness of Memorial’s voice in this effort, then my expectation is that everyone— patients, payers, policymakers, and faculty—everywhere should benefit too. —Clifford A. Hudis, MD, FACP

ponents of the overall cost of care, and one my institutional colleagues have not shied away from addressing, it is by no means the only issue, and my new position is not narrowly focused on any single component of the cost of medication or care. The value that Memorial brings to the care of patients with cancer is through our development of novel and better treatments and interventions; the establishment of new models of care; and new strategies for cancer prevention based on scientific insights. Value can be difficult to define, but we aim to accomplish this by demonstrating the long-term benefits to patients—and to all of society—from the advances and innovations made here as well as the everyday high-quality care we provide. All of this has been part of what Memorial has sought to provide to the world since its founding in the 19th century as the first specialty hospital solely dedicated to cancer. To meet the excit-

growth. Building on the tremendous support Memorial provided over the years while I focused on meeting my responsibilities at ASCO, I think the leadership here saw an unusual opportunity to get something back by leveraging my experience for the benefit of the institution. I the end, I firmly believe that what is good for Memorial is what is good for America, which is paraphrasing a quote sometimes attributed to Alfred P. Sloan, Jr, who along with Charles F. Kettering established the Sloan-Kettering Institute for Cancer Research in 1945. Along with Charles E. Wilson, Alfred Sloan has been cited as saying essentially that, “What’s good for General Motors is good for the country.” I think it is similarly true that what is good for Memorial is what is good for the world in terms of research funding, insurance reform, and access to care. My goal is to continue to help the entire oncology community through my advocacy for Memorial.

A Patient Connection Why did you decide to maintain your position as Chief of Breast Medicine Service? I love caring for patients and conducting research. Our Breast Medicine Service at Memorial is large in terms of clinical volume, translational research, and faculty, and it enables me to have an ongoing connection to patients both on a personal level and a professional level. This continuously informs my understanding of the challenges we face in routine patient care, research funding, and public policy so that when I speak with faculty and ASCO members, I share the issues they are confronting. I have always been fascinated by the big picture in cancer care, and my time at ASCO both enlightened and inspired me. On the one hand, I care for individual patients just like so many ASCO members; on the other hand, I am intrigued by the ways in which we can help further cancer advances through public policy and education to achieve better health. I don’t want to sound grandiose, and I know I represent only a small part of what has become a worldwide effort, but my goals with this new role are similar to those that have motivated my interest in studying the obesity/inflammation/cancer problem. I am intrigued by both the exciting molecular biology and also the huge public health and policy impact enhanced understanding can enable. For me, this new role offers the hope of meaningful and broad impact. At the same time, we recognize that we are not the only institute providing excellent cancer care or the onlgy center engaged in cutting-edge research. But the progress we make here can support improved care everywhere, and the issues we address touch all of us no matter where we work. The public and regulatory policies that enable us to do our work at Memorial better will also help others who are pursuing these same goals. In the end, all of us are aligned in our goal of improving cancer care. But if I can help increase the effectiveness of Memorial’s voice in this effort, then my expectation is that everyone—patients, payers, policymakers, and faculty—everywhere should benefit too. n Disclosure: Dr. Hudis reported no potential conflicts of interest.

The ASCO Post | AUGUST 10, 2015

PAGE 20

Announcements

Jimmie C. Holland, MD, Receives ‘Woman of Influence’ Award By Jo Cavallo to assess pain. A patient who scores 4 or higher on the distress thermometer should be further evaluated and, if necessary, referred to a mental health-care specialist and monitored closely.

Dr. Holland spoke at the awards ceremony, saying “The quote that best describes psycho-oncology is from my husband, Jim: ‘Psycho-oncology is the only specialty that is involved in the

care of every patient, at every age, at every visit, with every treatment in every country of the world,’” said Dr. Holland. See page 73 for a story about James F. Holland, MD, FASCO. n

arlier this spring, the T.J. Martell Foundation, which supports research in leukemia, other cancers, and AIDS, announced the honorees of its 2015 Women of Influence Awards, which celebrate the achievements of outstanding women in a variety of fields. Among this year’s seven recipients was Jimmie C. Holland, MD, Wayne E. Chapman Chair in Psychiatric Oncology at Memorial Sloan Kettering Cancer Center, New York. The other honorees included radio personality Delilah; Natalie Morales, cohost of the Today show; LaTonya Crisp- Sauray, third-ranking officer in New York’s Transit Union Local 100; Elaine Turner, apparel and accessory designer; JuE Wong, CEO of StriVectin, a skin care company; and Kelli Turner, Executive Vice President and CFO of SESAC, a performing rights organization. The awards were given out on May 1, 2015, in New York.

Celebrating a Stellar Career The award is fitting recognition of Dr. Holland’s efforts over the past 4 decades. Recognized as the founder of the subspecialty of psycho-oncology, in 1977, Dr. Holland launched the Psychiatry Service at Memorial Sloan Kettering Cancer Center. Under her leadership, Memorial’s Psychiatry Service became the country’s leading training and research program dedicated to the field of psycho-oncology. Dr. Holland is also the founder of the International Psycho-Oncology Society and the American Psychosocial Oncology Society. Her efforts to raise awareness of the psychological side effects of cancer have resulted in the launch of psycho-oncology programs in hospitals and oncology practices nationwide. To help oncologists easily evaluate patients’ distress levels, Dr. Holland and her colleagues at the National Comprehensive Cancer Network developed a “distress thermometer” that measures a patient’s distress on a 0-to-10 scale, similar to the pain scale oncologists use

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ASCOPost.com | AUGUST 10, 2015

PAGE 21

Announcements

St. Jude to Receive $12 Million in Grants From NIH

nvestigators at St. Jude Children’s Research Hospital have received grants totaling more than $12 million from the National Institutes of Health’s (NIH) Pharmacogenomics Research Network (PGRN) for a new Center for Precision Medicine in Leukemia

Mary Relling, PharmD

and for the Clinical Pharmacogenetics Implementation Consortium. “This funding is essential for bringing together experts in pharmacogenomics and leukemia therapy for collaboration,” said the PGRN’s new Chair, Mary Relling, PharmD, who is also Chair of

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the Pharmaceutical Sciences Department at St. Jude. “Individually, we are all doing great work, but with this funding, we can work together to improve medication therapy for patients with leukemia and other diseases.” continued on page 22

The ASCO Post | AUGUST 10, 2015

PAGE 22

Announcements St. Jude to Receive Grants continued from page 21

St. Jude received one of three P50 grants awarded by the National Institute of General Medical Sciences (NIGMS), part of the NIH, to establish specialized research centers for pharmacogenomics in precision medicine. The NIGMS has awarded a Center for Precision Medicine in Leu-

kemia to Dr. Relling and her Coprincipal Investigator Mignon Loh, MD, Division Chief of Pediatric Hematology Oncology at the University of California San Francisco. The Center aims to find cures for acute leukemia by translating genomics into more effective and less toxic treatment. Scientists in the Center also intend to provide a paradigm for other diseases by integrating

rapidly changing genomic methods and knowledge into precision medicine. Dr. Relling co-leads the Clinical Pharmacogenetics Implementation Consortium with Teri Klein, PhD, Director of PharmGKB at Stanford University. The Consortium’s goal is to provide upto-date clinical guidelines for specific genes and drugs and to facilitate the use

of genetic testing to guide prescribing of medications. “These grants are key elements of the NIH Pharmacogenomics Research Network, a network of scientific groups focused on understanding how a person’s genes affect his or her responses to medicines,” said NIGMS’ Rochelle M. Long, PhD, who directs the program. n

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ASCOPost.com | AUGUST 10, 2015

PAGE 23

Announcements

Stephen Szabo, MD, Named Director of Community Oncology at Winship Cancer Institute

mory Saint Joseph’s Hospital announced Stephen Szabo, MD, as the new Director of Community Oncology at the hospital’s Winship Cancer Institute. The new program combines

the best aspects of community and academic oncology by providing seamless patient care within one medical system. “This is a powerful model of care,” said Dr. Szabo. “Our patients have the

advantage of receiving state-of-the-art treatment right in their own community, with the resources of a nationally recognized university system. This program provides great depth of care to our

patients, ranging from a compassionate team of nurses, nurse practitioners, and social workers to the technical expertise of very specialized physicians.” The Community Oncology Program at Emory Saint Joseph’s treats patients with a variety of cancers with a team of medical oncologists, radiation oncologists, and surgical specialists. The Program offers infusion services, radiation oncology, Gamma Knife, and interventional radiology services.

Stephen Szabo, MD

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“Our patients have access to the latest clinical trials and research in cancer care, and they benefit directly from the basic science research being conducted at the university. This truly is unique for a community oncology program,” Dr. Szabo said. Dr. Szabo received his medical degree from Cornell University Medical College. He completed his internal medicine residency at the University of Michigan Medical Center and his fellowship in hematology and oncology at Emory University’s Winship Cancer Institute. n

Coming in Future Issues of The ASCO Post Reports from the

2015 Debates and Didactics in Hematology and Oncology Course Directors

Sagar Lonial, MD Fadlo R. Khuri, MD, FACP Winship Cancer Institute of Emory University Presented by Winship Cancer Institute of Emory University and prIME Oncology, held July 22–July 26, 2015, at The Cloister, Sea Island, Georgia.

The ASCO Post | AUGUST 10, 2015

PAGE 24

Palliative Care in Oncology Genomics/Genetics

Using Gene Analytics to Identify Patients at Risk for Treatment Toxicity A Conversation With Stephen T. Sonis, DMD, DMSc By Jo Cavallo

enomic applications are now an accepted part of oncologic science and practice. Differences in gene expression have been used to understand and predict tumor behaviors and response to treatment. And now it seems likely that genomics may also play a pivotal role in guiding treatment preferences by identifying a patient’s risk for treatment toxicities. Understanding the fundamental pathobiologic processes triggered by cancer drugs or radiation therapy, identifying the genetic factors that predispose patients to treatment toxicities, and developing effective interventions to counter those toxicities are the focus of the laboratory and clinical research of Stephen T. Sonis, DMD, DMSc. Although Dr. Sonis’ earlier career

whether a patient will develop side effects from cancer treatment? When we talk about using genomics to identify a patient’s risk of regimenrelated toxicity, the low-hanging fruit has typically been associated with genes that control the metabolism of cancer drugs—pharmacokinetics. For example, if a patient who is being treated with fluorouracil (5-FU) has a genetically controlled deficiency in one enzyme (dihydropyrimidine dehydrogenase [DPD]) that metabolizes the drug, he or she will accumulate levels of the drug that will increase the likelihood of the development of associated toxicity. In fact, a test for the gene associated with the enzyme, TheraGuide 5-FU, was approved some time ago.

To throw the biggest net possible, we’ve studied the most common form of genetic variations—single nucleotide polymorphisms—and identified specific groups of them that predict regimenrelated side effects. —Stephen T. Sonis, DMD, DMSc

centered on the biologic pathways that are associated with the generation of severe cancer regimen–related oral mucositis, his current research has expanded to include a broad range of treatmentinduced side effects, including fatigue, fibrosis, neuropathy, nausea and vomiting, diarrhea, and cognitive dysfunction. Dr. Sonis wrote about the application of genomics in the supportive care of patients with cancer in the 2015 ASCO Educational Book.1 The ASCO Post talked with Dr. Sonis, Senior Surgeon, Brigham and Women’s Hospital and Dana-Farber Cancer Institute; Professor, Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine; Chief Scientific Officer of Biomodels, LLC; and Cofounder and Chief Scientific Advisor of Inform Genomics, a privately held company, about the role genomics plays in the development of cancer treatment toxicities and how to identify patients who are at risk.

Biologic Toxicity Triggers What is your research showing regarding the role genomics plays in determining

Enzyme deficiencies, however, are relatively rare compared with the overall number of patients who develop regimen-related toxicities. The more common risk drivers of genomic toxicity, whether from chemotherapy, radiation therapy, or targeted therapy, are associated with the genes controlling the biologic actions of anticancer treatment. These genes are usually associated with specific pathways, which may act alone or synergistically to cause a cascade of disruptive biologic signals that target key cells in normal tissue to produce damage. We now know that many tissuebased chemotherapy-associated toxicities, such as oral mucositis, esophagitis, proctitis, pneumonitis, radiation-induced dermatitis, and fibrosis, share common genetically controlled underlying biologic etiologies. Interestingly, other toxicities, such as cognitive dysfunction and fatigue, are impacted by many of the same biologic mediators. Understanding these biologic toxicity triggers initiated by chemotherapy or radiation therapy allows us to look for the patient-specific differences in genes that are associated with risk.

Single Nucleotide Polymorphisms How do you identify patients who are at greater risk for treatment side effects? Our goal is to prospectively identify the genetic and nongenetic elements that define an individual’s risk for side effects. To distinguish the genomic factors, our approach has focused on the premise that risk is best defined by groups of cooperating genes, rather than a single “star.” To throw the biggest net possible, we’ve studied the most common form of genetic variations—single nucleotide polymorphisms—and identified specific groups of them that predict regimen-related side effects. Although there are “only” 25,000 genes, there are about 10 million single nucleotide polymorphisms, which means that we have an enormous big-data challenge to evaluate the associations between these gene variants and the patient’s reported toxicities. Since single nucleotide polymorphisms are a component of DNA, they are easily attainable via a saliva sample that can be used to extract DNA. To effectively translate these concepts to patients, we cofounded Inform Genomics in July 2010. The company is currently developing precision medicine products designed to accurately create a predictive toxicity risk profile for patients about to undergo chemotherapy for the treatment of solid tumors or for individuals about to receive high-dose chemotherapy conditioning regimens prior to hematopoietic stem cell transplantation. Results from two preliminary stud2,3 ies have confirmed our ability to identify clusters of single nucleotide polymorphisms that are associated with an increased likelihood of a range of common treatment side effects in both treatment populations.

Clinical Use of Gene Analytics When will this type of gene analytics be ready for clinical use? I’m hoping within 2 to 3 years. How do you envision genomic analytics will actually be used in the clinic? Identification of toxicity risks prior to the initiation of therapy will provide the oncologist and patient with critical information that can help guide treatment choices. For example, multiple drug regimens are available for almost all tumor types, each with unique toxicity profiles.

GUEST EDITOR

Jamie H. Von Roenn, MD

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science, and Professional Development Department.

For example, neuropathy might be common with one, whereas gastrointestinal toxicities may dominate another. For a patient who uses a computer keyboard, the first option might be intolerable, whereas in a frail individual, the consequences of gastrointestinal toxicities might preclude the second option. Although it may not be possible to completely prevent the onset of toxicities, knowledge of risk will provide oncologists and patients with actionable information for individual riskbased consent and cost-effective preemptive supportive care measures, patient education, and more frequent surveillance for patients at high risk for treatment toxicities. n

Disclosure: Dr. Sonis is Chief Scientific Officer of Biomodels, LLC, and Cofounder and Chief Scientific Advisor of Inform Genomics. He also is on the medical advisory boards of several biotechnology and pharmaceutical companies.

References 1. Sonis ST: Genomics, personalized medicine, and supportive cancer care. 2015 ASCO Educational Book. Available at asco. org/edbook. Accessed July 8, 2015. 2. Sonis S, Antin J, Tedaldi M, et al: SNPbased Bayesian networks can predict oral mucositis risk in autologous stem cell transplant recipients. Oral Dis 19:721-727, 2013. 3. Sonis ST, Schwartzberg LS, Walker MS, et al: Predicting risk of chemotherapyinduced side effects in patients with colon cancer with single-nucleotide polymorphism Bayesian networks. 2013 Gastrointestinal Cancers Symposium. Abstract 344.

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The ASCO Post | AUGUST 10, 2015

PAGE 26

Book Review

An Oncologist’s Memoir By Ronald Piana

eading a good book produces various sensory responses; a skilled author exerts his or her narrative power on each page, which exerts its own power on the reader. Sometimes the reader yawns, and sometimes the reader cries or laughs. Reading Megalies: A Memoir, by geriatric oncologist Lodovico Balducci, MD, is at times like getting caught in a torrential downpour without an umbrella, and at other times it’s like sitting in a church listening to hymnals; then a few pages later, you’re back out in the raw weather, and this time it’s a hailstorm.

of the introduction: “You are now and always will be my beloved son!” With those words, the mother of serial killer Ted Bundy bade farewell to her son a few hours before he was strapped into the electric chair at Florida State Prison. Bundy was a monster, having savagely killed 30 innocent women, yet Dr. Balducci notes: “His mother expressed no wish to prevent her son’s execution. She elected instead to make a statement that defied both the hatred that demanded his execution and the electric chair that killed him. Her love survived all instruments of death, and no-

Of course I support medical ethics. What I do not support is the lie that a cumbersome process [informed consent] that increases the cost of medical care to the point of becoming unaffordable is essential to protect patients. —Lodovico Balducci, MD

This intensely drawn book narrates the journey of Dr. Balducci in his discovery of the living truth: the ability to give and receive unconditional love. Dr. Balducci blends his personal life with the practice of oncology, within the larger religious and social events, to form a model for a life worth living. Buckle up: It’s a wild ride.

Early Years Dr. Balducci was born toward the end of World War II in the Northern Italian town of Borgonova. After the war, he returned with his parents to his father’s hometown of Rimini, which was one of the wars most bombed cities. It was a time when the town priest and doctor were most revered, caring for the souls and bodies of the citizens. Reared in an academic family, Dr. Balducci’s first inclination was to study the humanities. However, being a socially awkward child suffering from early depression, he chose medicine, in part because it would force him into intimate relations with colleagues and patients. He is considered a pioneer of geriatric oncology, a discipline he has fostered over the past 25 years.

Unconditional Love What he has drawn from that rich career informs much of his book, which asserts its daring content in the first line

body could take that away from her nor her son….” The words of Bundy’s mother condense the message of this book, which concerns unconditional love, transfiguration, and redemption. Using serial killer Ted Bundy is a gutsy way to drive home one of the book’s central themes, but it comes with risk. Dr. Balducci spends most of the introduction on the Bundy analogy, writing, “Through her [Bundy’s mother] love, his actions became an occasion for universal forgiveness.” He’s asking a lot of the reader, especially those old enough to have followed Bundy’s horror-story life. But Dr. Balducci is a deeply religious man and wants the reader to trust him and let him make his case.

Ethical Minefields Organized in 31 well-written chapters, Dr. Balducci uses vignettes from his years in the clinic, historical flashbacks, biblical references, and personal experiences from his childhood and marriage to wind through ethical minefields in medicine and life, exposing what he sees as Megalies. For instance, in one of the book’s shorter chapters, “Uncle Titti,” Dr. Balducci describes a swashbuckling uncle of his, who among other things was a war hero, a philanderer, a spendthrift, and a world-class vagabond. Toward the end of

his life, Dr. Balducci and others put the uncle in an old-age home, a place he described as a “prison,” which robbed the old man of dignity. Here, Dr. Balducci takes the elder care system to task and lashes out at himself for “conspiring to imprison Uncle Titti in a retirement center that, despite Uncle Titti’s shortcomings, ran over his values with disdain.” Next up is “Uniformed Consent: Dr. Mengele and the Ethics Committee,” which is a tough look at the lengthy informed consent procedure that Dr. Balducci feels, in some cases, does more harm than good. He writes: “Of course I support medical ethics. Ethical behavior is the only acceptable form of human interaction…. What I do not support is the lie that a cumbersome process that increases the cost of medical care to the point of becoming unaffordable is essential to protect patients…or the mother of all lies is that there is an objective truth independent from the human truth.” In short, Dr. Balducci advocates to consent, but nothing that is ironclad, preventing a doctor from thinking outside the box in the best interest of his or her patient.

Profit-Over-Patient Ethos This is not a breezy book full of entertaining and poignant human anecdotes. But every page is heartfelt and meant to engage the reader in difficult conversations. In one of the least allegorical, but most important, chapters, “A Tale of Two Frauds,” Dr. Balducci dissects the prostate cancer industry, using the androgen-deprivation drug Lupron (leuprolide) as an example of profit-over-patient ethos that our feefor-service payment system encourages. He will not make any friends in the urology community with scorching sentences such as, “Prominent urology professors roamed the country using the gloom-and-doom M-word (malpractice). With their pockets lined by hefty Big Pharma honoraria, they claimed that from then on it would be malpractice to use estrogen in men with metastatic prostate cancer…declaring Lupron a superior form of treatment…. The current cost of administering Lupron is more than $50,000 per year.” Dr. Balducci does temper his tone, offering a well-reasoned argument against chummy relationships between doctors and the companies they buy their drugs from. Many in the oncology community will find this tough-love chapter one of the books best.

Bookmark

Title: Megalies: A Memoir Author: Lodovico Balducci, MD Publisher: Resource Publications Publication date: February 28, 2014 Price: $33.00; hardcover, 304 pages A Living Piece of Literature If Dr. Balducci were a boxer, he would not be one who dances in the ring, exhibiting the art of self-defense. He would be a chin-out slugger, every punch meant for a knockout, which is part of this book’s visceral charm. He tackles abortion and physician-assisted suicide; makes peace with his wife, Claudia; and spends time ministering to the dying. Moreover, his passion bleeds into the narrative, making his memoir a living piece of literature. Make no mistake, this book challenges the reader and is not for someone looking for a relaxing bedtime read. “I keep hammering on redemption because my experience has taught me that redemption is the ultimate goal of life, not just an option,” writes Dr. Balducci. He doesn’t live by options; Dr. Balducci firmly believes that, among other virtues, personal sacrifice is necessary for a life worth living. And for that, vulnerable patients with cancer, many near the end of their lives, are fortunate to have him by their bedsides. Megalies is full of truths and is highly recommended for readers of The ASCO Post. n

ASCOPost.com | AUGUST 10, 2015

PAGE 27

Book Review

The Human Heart: Tales of Science and Mystery By Ronald Piana

o part of the human anatomy has been as mythologized, analogized, and poeticized as the heart. For good reason, because the human heart is, in fact, the living metronome that keeps time to our life. Fueling our body with oxygen-rich blood, the heart is the source of our strength and vitality. Our hearts are also our greatest weakness. About 610,000 Americans die each year of heart disease, making it the nation’s leading cause of death. Why does the heart break so much more often than other parts of our bodies? The fascinating answer to that question and more is part of a multifocal story that begins hundreds of millions of years ago. And it is the subject of a fine new book by Rob Dunn called The Man Who Touched His Own Heart. Mr. Dunn, Associate Professor of Ecology and Evolution at North Carolina State University, is the author of two other highly acclaimed books: The Wild Life of Our Bodies and Every Living Thing. In his new book, Mr. Dunn looks at the heart as a mysteriously animated object, which is still more of a mystery than it is understood. He asks thoughtprovoking questions. Why do most animals get only one billion heartbeats in a lifetime, and how did modern humans get more than two billion beats? Why are heart and vascular disease epidemics for humans but not for our closest relatives, chimpanzees? The answers to or scientific ponderings around these questions bring the reader deep inside the science and history of the heart and, for the most part, prove to be a page-turning and informative reading experience. Books developed around a single subject, such as the heart, need interesting narrative and background stories to lead the reader into the scientific meat of the book’s subject. It is a fine balancing act between too much and too little, one that Mr. Dunn negotiates with skill.

The Heart of the Matter He opens his book in Chicago in July 1893, with a tale about a young AfricanAmerican man, Daniel Hale Williams, who became one of the first African

Americans to graduate with an MD degree from Northwestern University. Ambitious to serve the black community, Dr. Williams eventually opened a small hospital in a rough side of town. One night, the victim of a stab wound was wheeled in. The wound appeared superficial, and Dr. Williams stitched him up and put him in recovery. However, it turned out that the knife had punctured the heart. In a do-or-die moment of decision, Dr. Williams performed the first-ever open-heart surgery and saved the patient. Mr. Dunn uses this medical drama to give a thorough description of the heart’s anatomy, function, and reasons why “before 1983, and Dr. Williams surgery, the heart was simply not touched.”

A Backward Glance at Cardiac Pioneers The book is structured into 16 wellorganized chapters. Some of the most interesting sections are centered on innovative medical procedures involving the heart and the doctors who pioneered them, such as Werner Forssmann. In 1929, this young doctor “imagined a whole new science and medicine of the

Bookmark Title: The Man Who Touched His Own Heart: True Tales of Science, Surgery, and Mystery Author: Rob Dunn Publisher: Little, Brown and Company Publication date: February 3, 2015 Price: $27.00; hardcover, 384 pages the cardiac catheterization on himself. Over time, he repeated the procedure on himself about ten times, convincing the hospital supervisors that the procedure could not only be used for diagnostics, but also for treating damaged hearts. For his role in developing this lifesaving procedure, he was awarded the Nobel Prize in Medicine.

Each of us has a chance to have two billion heartbeats, with which to do as we please. Time will tell what we do with those billions of gifts: moments to change the world or to just sit back and admire it. —Rob Dunn

human heart in which the heart could be studied and treated without anyone having to open the patient’s chest.” Of course, Dr. Forssmann’s dream was cardiac catheterization, a routine process today. But at that time, the heart was still viewed as both fragile and inviolable. Dr. Forssmann’s story should serve as inspiration for any young doctor wanting to change or advance medical practice, and the author does a superb job in telling it. In short, against the wishes of his superiors, Dr. Forssmann, who had spent hours studying the veins and hearts of cadavers, numbs his arm and does

Scientific history is enthralling because it breathes life into past challenges and the giants upon whose shoulders we now stand. It also adds perspective to where we are and what it takes to move our science ahead. But all history and no present or glimpse into the future might leave the reader wanting to know more about the heart as he or she closes the book. Although Mr. Dunn clearly likes to write about adventurous scientists and doctors of the past, he wisely devotes the last five chapters to some heady and provocative discussions about current issues and theoretical musings on the heart.

In one of his most intellectually exciting chapters, “Escaping the Laws of Nature,” Mr. Dunn introduces Geoffrey West, a physicist and mathematical thinker who began to seriously consider the general laws of the heart. Sounds simple, but it’s not. Based on the understanding of the capillaries and a model of the fractal connections of blood vessels, of larger and smaller diameters, Mr. West can predict, in a simulated world, how the body works and how it will fail. The author writes, “Bodies fail on some sort of schedule, and West thinks he can explain when and why…. Could our human fates be predicted simply on the number of beats of our hearts, and if so, what do such predictions say about our fates?”

Two Billion Heartbeats Arresting openings are difficult to write, but endings that leave the reader fully satisfied are even harder. Here’s Mr. Dunn’s closing: “Each of us has a chance to have two billion heartbeats, with which to do as we please. Time will tell what we do with those billions of gifts: moments to change the world or to just sit back and admire it.” The Man Who Touched His Own Heart, an interesting and lively romp through the human heart, is strongly recommended for readers of The ASCO Post. n

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | AUGUST 10, 2015

PAGE 28

Reflections

Blame

Given the ups and downs of life, common clues of a cancer diagnosis are often ignored. By Karen J. Krag, MD

The following essay by Karen J. Krag, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon. com and thebigcasino.org.

t is easier to blame than to acknowledge that in most instances, we have little control over who develops cancer. It’s easy for patients to blame themselves as well as their current and past physicians. It’s also easy for us as physicians to blame our patients, prior physicians, our staff, and ourselves. Patients come to us with awful diagnoses. Even those with a curable disease have to go through the angst of having cancer, making decisions about treatment, getting conflicting reports on the Internet and from friends, facing their own mortality, and worrying about whether they are getting the right care. Those who have taken good care of Dr. Krag is a medical oncologist, Department of Hematology/Oncology, Massachusetts General Hospital North Shore Cancer Center, Danvers, Massachusetts.

their bodies can’t believe the diagnosis; those who have not also can’t believe it. But patients look back and try to find a reason for their cancer. Was it food they ate, additives they consumed, secondhand (or firsthand) smoke, pesticides from the dump in the next town, genetics, the street they grew up on, or cleaning supplies they used? Many things could be responsible, and some likely are. But it is easier to blame cancer on something than it is to acknowledge that we do not understand the whims of nature. Patients also look back and question, “Why didn’t I know?” It’s easy to notice after a diagnosis that there was some abdominal pain, a cough, a lump, a vague headache, or a little fatigue. But these things are so common given the ups and downs of life that they get ignored. Once cancer is discovered, however, patients wonder whether more attention to such symptoms would have actually prevented the disease or resulted in a diagnosis of earlier-stage disease. Patients also blame physicians. Would a more careful doctor have paid attention to the back pain? Would a better radiologist have noticed something on my scan? Could the surgeon have removed more tissue ensuring that the cancer would not recur? Primary care physicians also go through the blame game at the time of a patient’s diagnosis. They blame themselves and other doctors: Why did I not pay more attention? How could the radiologist have missed the finding on the chest x-ray or mammogram? Why did I not pay greater attention to the patient’s anemia? Those same physicians also blame the patient: Why did you ignore your weight loss? Why did you keep smoking? Why didn’t you call about your back pain? Why didn’t you do breast self-exams?

Pointing Fingers When oncologists see a new patient, the same questions are often asked: How could your primary care doctor have missed this? What was the pathologist thinking? Why didn’t you seek a second opinion? As treatment progresses, oncologists blame themselves: Why did I choose that chemotherapy? Why did I choose that dose?

Why did you not place the portacath correctly?

The Uncertainty of Life Although blame is a tool for all of us to use to deal with the uncertainty of life, it is not a positive force. If you look at those patients who don’t look back and question why, they have much more peace. What gives them that sense of peace?

This is the only life we have and to spend any energy looking at the past takes away from the enjoyment of life. While we can have no control over the past or the future, and no control of others, we do have control of our own present. —Karen J. Krag, MD

Why did the patient with early-stage breast cancer relapse? What could I have done to prevent it? Why didn’t I tell my patient that he would likely die soon from cancer? Why didn’t I refer my patient to hospice earlier? Why couldn’t I convince my patient to stop smoking? There is plenty of blame to go around. There is the medical staff to question: Why did you not tell me that the patient’s blood pressure was a little bit low? Why did you schedule this patient at this time? Why did you not tell me she hadn’t had a mammogram in 15 months? Why wasn’t she in the exam room faster? There are the nurses to question: Why did you not recognize this rash as an allergic reaction? Why did you tell me she was OK? Why did you not send her for the test I asked for? And there are the other physicians to question: Why did you not compare the x-rays? Why did you not deal with the patient’s blood sugar?

Sometimes it’s faith and the serenity that comes from knowing that life has a greater meaning than the time spent on earth. Yet others who aren’t religious can have the same sense of peace. Why? What I’ve been able to figure out from talking with my patients is that living in the moment is the best way to gain this sense of being—not to look back at what happened and try to find the why of it, but to enjoy every minute of each day, week, month, and year.

Living in the Present This is the only life we have and to spend any energy looking at the past takes away from the enjoyment of life. While we have no control over the past or the future, and no control of others, we do have control of our own present. If we can learn this lesson from some of our patients and find a way to teach it to others, each of us—patient and physician alike—would live a more peaceful existence. n

Visit The ASCO Post website at ASCOPost.com

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.

AGENTS.

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%

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

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.

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

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

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

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

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

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 | AUGUST 10, 2015

PAGE 37

Direct From ASCO

Collective Wisdom: Patient-Centered Care and Research By Julie M. Vose, MD, MBA, FASCO

B:14.25 in

T:14 in

S:13 in

n 1964, when the first seven physicians who founded ASCO met, I doubt they imagined what a successful Society they were forming. At that time, cancer treatments were just beginning to have some early successes with a few cytotoxic therapies, new radiation modalities, and improved surgical techniques. Over the ensuing 50 years, the advancements in cancer care and research have been extraordinary. Fast forward to 2015—ASCO has over 35,000 members from over 120 countries, and the ASCO Annual Meeting in Chicago has in excess of 37,000 attendees. Our founders would be so proud of what ASCO provides in education, information, support, mentorship, and research funding. I am very honored to be the 52nd President of ASCO and to represent our membership. I chose the theme of Collective Wisdom: Patient-Centered Care and Research to represent the importance of the multimodality care that is necessary for our patients. As this figure demonstrates (Fig. 1), patients are at the center of a very complex system trying to assist them through their journey of cancer care. Today, the ability to deliver the optimum care to our patients is becoming ever-more challenging. We have so many more options for treatment than in years past, but the ability to provide the therapies is sometimes met with obstacles. The availability and affordability of the new therapies vary by

Fig. 1: Patient-centered care and research.

country and health-care system. As the health-care systems change from a reimbursement-based system to a value-based system, we must continue to modify our models of care. Clinical research must also include a component of cost-effectiveness in studies to help physicians and patients make informed decisions. However, we must always remember that the patient is the center of the circle, and the goal is to assist him or her in informed decision-making. The multidisciplinary aspects of cancer care and research continue to be very important with advances in the

understanding of the biology and genomics of different malignancies. This emphasizes the importance of education and communication between the team members on a regular basis. In addition, as we make improvements in cancer care, there will be many more cancer survivors who will need medical and supportive care to get beyond cancer treatment and back to a normal life. A medical team that, by necessity, is much broader than an oncology team will carry much of this care out. All of the improvements made in cancer care over the past decades de-

pended on the clinical and research data gathered and analyzed to improve future care. To continue to make advances, we must find ways to streamline and efficiently use the data gathered from all patients to inform our treatment patterns. Clinical trials will need to be optimized and a broader range of data on all patients will need to be obtained and analyzed. Over the next year, the issues that I and the ASCO leadership will be addressing include value-based care models; workforce-shortage issues; clinical cancer research best practices and optimization; big data analysis through CancerLinQ; quality measures through the Quality Oncology Practice Initiative (QOPI); and improvement in care delivery globally. As medical professionals and as a Society, we must all continue to evolve and transform cancer care and research with each new discovery. We can only hope that 50 years from now, future medical professionals who care for patients with cancer and who perform cancer research can look back and thank us for the pioneering aspects of treatments that were developed in our era. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Collective Wisdom: Patient-Centered Care and Research.” https://connection.asco. org/commentary/collective-wisdom-patient-centered-care-and-research. All rights reserved.

2015–2016 ASCO President Julie M. Vose, MD, MBA, FASCO: Leading During a Year of Historic Changes By Shira Klapper, Senior Writer/Editor

ulie M. Vose, MD, MBA, FASCO, began her term as the 2015–2016 President of ASCO at the 2015 Annual Meeting on June 1, 2015. Dr. Vose, a leading expert in the treatment of patients with lymphoma, is the current Neumann M. and Mildred E. Harris Professorial Chair and Chief of the Oncology/Hematology Division in the Department of Internal Medicine and a Professor of Internal Medicine in the Division of Hematology and Oncology at the University of Nebraska Medical Center (UNMC). Dr. Vose will serve as President of ASCO during a time of historic mile-

Julie M. Vose, MD, MBA, FASCO

stones for the organization. After years of dedicated work on the part of leadership and volunteers, ASCO will roll out the first version of CancerLinQ, a cutting-edge health in-

formation technology platform that will aggregate data from health information systems across the country to provide real-time quality feedback to providers and uncover patterns to improve care. Dr. Vose’s presidency will also coincide with a time of rapid change on the medical policy front, as just this past April Congress repealed the Sustainable Growth Rate formula, signaling its readiness to embrace new payment models. Dr. Vose is ready to meet these challenges. “These are times of great change—and opportunity—in oncology. We see changes in treatments,

changes in techniques, and also changes in the economics of health care. This year, we will see the launch of CancerLinQ, which will begin a new era of how we collect data. CancerLinQ will revolutionize oncology care by giving us extensive information about the 97% of all patients who aren’t on clinical trials, allowing us to improve the overall quality of cancer care and enabling us to generate hypotheses for future clinical trials and future treatments. It’s an exciting accomplishment for all of us who have been involved with ASCO for many years.” continued on page 38

The ASCO Post | AUGUST 10, 2015

PAGE 38

Direct From ASCO ASCO President Julie M. Vose continued from page 37

Immediate Past President Peter Paul Yu, MD, FACP, FASCO, noted the unique skills and strengths Dr. Vose brings to the presidency. “Each year, the ASCO President brings a different perspective and background to the position, and Dr. Vose will contribute her own special blend of skills and creativity,” said Dr. Yu. “Dr. Vose is an internationally respected hematologic oncologist with a particular interest in survivorship, one of oncology’s fastest growing areas, and the launch of the Cancer Survivorship Symposium in 2016 will be one of the highlights of her presidency. In addition, she has a strong management background and an MBA, both of which will be of critical value as ASCO looks to support our membership in all aspects of their professional careers.” An ASCO member since 1991, Dr. Vose has served on the Board of Directors and the Journal of Clinical Oncology ( JCO) Editorial Board, as well as numerous other ASCO committees, including as Chair of the Cancer Education and Publications Committees, and as a member of the Scientific Pro-

gram Committee. In 2014, Dr. Vose received the distinction of Fellow of the American Society of Clinical Oncology (FASCO).

Peter Paul Yu, MD, FACP, FASCO

An Early Introduction to the World of Medicine Growing up in the small town of Mitchell, South Dakota, Dr. Vose was introduced to the laboratory at an earlier age than most. “My father was a pathologist and my mother was a nurse, so I grew up in a medical household,” said Dr. Vose. “I spent summers and time after school working in my dad’s lab and looking at cancer cells under the microscope, and I became fascinated with the subject. I wanted to understand how they grew and how they died, so when it came time to go to

college and medical school, I decided I wanted to work on cancer.” As an undergraduate at South Dakota State University, Dr. Vose majored in medical technology, with the goal of embarking on a career in laboratory research. However, she changed paths as she realized she wanted to work directly with patients, a decision which led her to medical school at UNMC. While attending UNMC, Dr. Vose came under the mentorship of James O. Armitage, MD, FASCO, the renowned lymphoma and stem cell transplant specialist. Dr. Armitage is the founder of the Nebraska Medicine Stem Cell Transplantation Program, which pioneered autologous transplantation. He served as ASCO President from 1996–1997 and currently serves as Co-Chair of the White Blood Cell Growth Factors Expert Panel, the Editor-in-Chief of The ASCO Post, and as a member of the JCO Editorial Board. He is also the Deputy Editor of a new clinical section of the Journal of Oncology Practice ( JOP). In speaking about the mentorship, Dr. Vose said Dr. Armitage’s guidance laid the groundwork for her future success as a practicing oncologist and

a clinical researcher. “In general, I believe that to be successful, you have to have a great mentor, you have to have the skill, you have to be given great opportunities, and you have to take advantage of those opportunities. I was very fortunate in my life to be in a good place where all those things could come together,” she said.

James O. Armitage, MD, FASCO

A Leader in Lymphoma Research Throughout her career, Dr. Vose has focused her research on the treatment of lymphoma, and the reason is close to home: Nebraska, like other rural states, has a disproportionate number of lymphoma cases. This trend created opportunities for Dr. Vose to research the etiology of lymphoma and new treatments

Disease Prevention, Practice Issues Put ASCO Center Stage at AMA House of Delegates Meeting

SCO represented the oncology community at the American Medical Association’s (AMA) Annual House of Delegates (HOD) Meeting, held June 6–10 in Chicago. W hile AMA’s chief policymaking body worked to shape its priorities and initiatives, ASCO delegates and alternates represented the cancer care perspective on a range of disease prevention and practice issues. ASCO Delegate Edward P. Balaban, DO, FACP, FASCO, spoke on the house floor in support of a resolution—which passed—that will result in AMA working with accrediting organizations to analyze the state of obesity education in medical schools and for physicians-in-training and addressing any gaps that are uncovered. ASCO also weighed in heavily during deliberations on e-cigarettes, in-office ancillary services, “incident

to” billing, and the undertreatment of pain in cancer care. Additionally, ASCO cosponsored a resolution on the value-based modifier and flawed drug cost attribution. Resolution 236 was adopted as amended and asks that the American Medical Association work with the Centers for Medicare & Medicaid Services to modify value-based modifier cost attribution with regard to drug costs, so that the cost calculation does not unfairly disadvantage certain providers. The HOD also held elections for AMA’s Board of Trustees. Family medicine physician Stephen R. Permut, MD, JD, is the new Chair; psychiatrist Patrice A. Harris, MD, MA, is Chair-Elect; and ASCO member Barbara L. McAneny, MD, a medical oncologist/hematologist, assumed the office of Immediate Past Chair.

The AMA HOD is made up of more than 500 voting delegates who help shape medicine’s broad and influential advocacy platform. Along with Dr. Balaban, ASCO is represented by its other delegate Thomas A. Marsland, MD. The Society’s alternate delegates are Kristina Novick, MD, and Ray Page, DO, PhD, F ACOI.

ASCO also leads the HOD’s Cancer Caucus, which provides a forum to address ongoing oncology-specific issues that are either being discussed or should be discussed by the HOD. n © 2015. American Society of Clinical Oncology. All rights reserved.

egistration is open for the Community Research Forum (CRF) 2015 Annual Meeting, which will be held September 20– 21, at ASCO Headquarters in Alexandria, Virginia. Join fellow physician investigators and research staff from all types of community-based research sites and programs to dis-

cuss barriers and propose solutions to common challenges in conducting research. Visit www.asco.org/communityresearchforum to register and learn more about the Meeting. n © 2015. American Society of Clinical Oncology. All rights reserved.

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Direct From ASCO for the disease. Dr. Vose credits Dr. Armitage and UNMC with giving her the support to carry out groundbreaking work. “The Stem Cell Transplantation Program was one of the early centers evaluating the use of white-bloodcell colony-stimulating factors for transplant, and that revolutionized the ability to do transplants safely,” said Dr. Vose. “We were also one of the first few centers in the world to use peripheral blood stem cells for transplants, as opposed to bone marrow. Both of these techniques are now standards of care at transplant centers thanks to early clinical trials.” Dr. Vose also credits ASCO with providing an early highlight of her career: her first oral presentation at the 1988 Annual Meeting. “It was nervewracking at the time,” she joked, “but certainly beneficial in the long run.” Today, Dr. Vose is involved with multiple clinical trials focused on novel therapies for Hodgkin lymphoma, nonHodgkin lymphoma, multiple myeloma, and chronic lymphocytic leukemia. More recently, Dr. Vose has focused her research on monoclonal antibodies, vaccines, radioimmunotherapy, transplantation, and pathway-directed agents. In addition to her work as a hema-

tologist and clinical researcher, Dr. Vose currently serves as the Associate Director of Clinical Research at the Fred and Pamela Buffet Cancer Center. She has previously served as a member of the U.S. Food and Drug Administration (FDA) Biologics Committee and the FDA Oncologic Drugs Advisory Committee. In addition, she has served as a member of the Board of Directors for the University of Nebraska Medical Center Physicians Group.

A Focus on Personalized Medicine As President, Dr. Vose will follow a long ASCO tradition and introduce initiatives that are close to her heart. One of these initiatives is personalized medicine. “Personalized medicine refers not only to identifying the best therapies for patients based upon molecular analysis, but also ensuring that individual patients receive the multidisciplinary care they need, from diagnosis to focused treatments, supportive care, palliative care, and survivorship,” said Dr. Vose. In large part, Dr. Vose’s interest in personalized medicine stems from her roots. In many sparsely populated areas, patients often have less access to the full array of medical services.

“Growing up in a small town gave me a greater understanding of how people have to travel long distances for specialty care,” Dr. Vose said. “Rural health care, specifically oncology, is a whole area of health care that needs additional supportive services. We need also to enhance tele-health and travel options for patients and ensure that patients receive the educational information they need.” Dr. Vose’s focus on individual patients’ needs comes across in her poignant essay in the anthology The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories (May 2014), coedited by Stanley H. Winokur, MD, and Vincent Coppola. In her essay, Dr. Vose describes Cindy, a 33-year-old woman diagnosed with advanced peripheral T-cell lymphoma. Cindy, along with her large, supportive family, exhibited what seemed like odd behavior— laughing and joking throughout treatment. This led Dr. Vose to wonder if the family understood the seriousness of the prognosis. Over time, however, as Dr. Vose came to know the family better, she realized what was going on: “laughter therapy,” as she later called it. “After a while, I began to under-

stand that laughter and joking were one family’s way of coping with a very stressful situation,” wrote Dr. Vose in her essay. “Of course, they’d always understood the seriousness of the situation. That realization helped me understand that every patient, every person, every family has a different way of coping. In Cindy’s case, it was: make sure you bring up the good things in life. Remember the fun times. Bring out the laughter. It can be a powerful tool.” Dr. Vose tries to carry this lesson over into caring for her patients. “I try to get to know each patient, their family, and their modus operandi so I can understand what works best in dealing with each unique situation,” said Dr. Vose. “I think it’s always beneficial to put the shoe on the other foot and think about a situation from the patient and family’s point of view, in respect to cancer care. In short: know your patient as a person.” n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “2015-2016 ASCO President Dr. Julie M. Vose: Leading During a Year of Historic Changes.” ASCO Connection, July 2015: 12-15. All rights reserved. ASCO President Julie M. Vose

Summer Travel: Help Your Patients Understand Why Getting Medical Clearance is Important

Community Oncologist Stephen Grubbs, MD, to Lead ASCO’s New Clinical Affairs Department

irect your patients to www.cancer. net/blog to get important information on traveling with cancer, including getting medical clearance before they

book their flight. This information includes questions to ask the doctor, how to get permission from the airline to fly, and information on packing prescriptions in a carry-on instead of a checked bag. n

tephen S. Grubbs, MD, a community oncologist and managing partner at Medical Oncology Hematology Consultants, PA, in Newark, Delaware, has been named the Senior

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.

has joined ASCO to lead our Clinical Affairs Department,” said Allen S. Lichter, MD, CEO of ASCO. “Dr. Grubbs understands and has fully experienced the rewards and challenges of providing care in his community. He has the knowledge and vision needed to assure that this department will provide on-the-ground support to oncology practices across the country.”

New Department to Provide Support to Oncology Practices Stephen S. Grubbs, MD

Director of ASCO’s new Clinical Affairs department. Dr. Grubbs is a longtime ASCO member and volunteer and the Principal Investigator of the Delaware Christiana Care National Cancer Institute (NCI) Community Oncology Research Program. He fully transitioned into his new role in July. “We are delighted that Dr. Grubbs

Announced in late 2014, ASCO’s Clinical Affairs Department is dedicated to providing education and resources to support oncology practices in all settings to promote the delivery of high-quality, high-value cancer care. To achieve this goal, the Clinical Affairs Department provides tools and services to facilitate innovation in cancer care delivery and respond to growing economic and administrative chalcontinued on page 40

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Direct From ASCO Stephen Grubbs, MD continued from page 39

lenges in oncology practice. “The health-care delivery and clinical research environment has dramatically changed. Oncology professionals are experiencing a broader range of issues and challenges than they faced even a few years ago,” said Dr. Lichter. “Our new Clinical Affairs department will provide on-the-ground support for oncology practices navigating today’s demanding environment.” The department provides support to oncology professionals around the country in the areas of business analytics, performance improvement, and practice management, with the ultimate aim of fostering more effective and efficient delivery of cancer care for the benefit of patients. “I am thrilled to be serving ASCO in this new and vital role,” said Dr. Grubbs. “I look forward to working with the Society’s staff and oncology practices across the country as we strive to consistently improve cancer care.”

led to the elimination of healthcare disparity for colorectal cancer. Dr. Grubbs has served on the NCI’s Clinical Trials Evaluation Working Group and Clinical Trials Advisory Committee and has been active in the Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B), serving on the Board of Directors and

Executive Committee. He was President of the Medical Society of Delaware and has held a number of other leadership positions in professional organizations. Dr. Grubbs earned his medical degree from Thomas Jefferson College and completed his residency and internship at Wilmington Medical Center. He performed his fellowship at Dartmouth-

Hitchcock Medical Center. He has previously held positions at Christiana Care Health System, Dartmouth Medical School, St. Francis Hospital, Memorial Hospital of Salem County, and Jefferson Medical College. n © 2015. American Society of Clinical Oncology. All rights reserved.

Longtime ASCO Volunteer and Board Representative for Community Oncologists An ASCO member since 1985, Dr. Grubbs serves on the ASCO Board of Directors as the community oncologist representative and is a member of the Finance and Ethics Committees. He has served on the Society’s Government Relations Committee, Cancer Research Committee, and as a Genitourinary Literature Reviewer for ASCO University. He has served as Chair of the Clinical Trials Participation Award Selection Subcommittee, Co-Chair of the NCI/ ASCO Clinical Trial Accrual Symposium, and the Clinical Trials Workshop Planning Committee. Dr. Grubbs serves on the advisory council of the Delaware Cancer Consortium, of which he has been a member since 2003. The Consortium actively worked with the Delaware state government to successfully develop a system for the uninsured to receive cancer screening and cancer therapy. This has resulted in universal cancer screening and care in Delaware and has

Save the Date Best of ASCO® Chicago August 28–29, 2015 For more information http://boa.asco.org

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Issues in Oncology Proton-Beam Therapy continued from page 1

liability with high-volume procedures. With 240,000 new prostate cancers diagnosed each year in the United States, this disease has been the mainstay of the proton therapy industry, accounting for two of every three claims and about 80% of Medicare spending on the procedure.

So while the cost of building a treatment center is high, up until now, proton-beam therapy has presented a lucrative opportunity for those who are willing to make the investment. Proton-beam therapy for prostate cancer is reimbursed at a much higher rate than traditional radiation treatment for the same condition. Medicare pays

about $19,000 for a full dose of standard radiation therapy for prostate cancer, but it pays more than $32,000 for proton therapy.

Data Still Lacking Given the rising costs of U.S. health care, experts across the board agree that it is increasingly important to prove

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through studies that paying more is associated with better outcomes. Proton therapy has proven beneficial for tumors surrounded by sensitive structures such as the eyes, brain, and spinal cord, where the potential for radiation damage is very high. The procedure also offers a distinct benefit in many childhood cancers due to the high risk of long-term side effects in children who receive standard conformal radiation therapy. In prostate cancer, however, there are no convincing data demonstrating that proton therapy is superior to intensity-modulated radiotherapy in the curative setting or in mitigating urinary or sexual side effects. Thus, until there are studies that show a distinct benefit, proton-beam therapy rests its case for use in prostate cancer on the theoretical promise that particle beams are better than photons. In 2012, the California Technology Assessment Forum concluded that while proton-beam therapy provided a net benefit in the treatment of prostate cancer, its comparative benefit to alternate treatment modalities has not been established.2 Its role as a therapeutic option for localized prostate cancer remains uncertain with respect to safety, efficacy, and improvement in patient outcomes. In a detailed patient guide updated in 2014, the American Cancer Society concluded that use of protons in prostate cancer may theoretically cause less damage to normal tissue surrounding the area of focus, but no current studies demonstrate the advantages of protons over photon therapy.3 The Society stated that comparative studies are necessary to evaluate the outcomes between the different modalities, with identification of the appropriate therapy for different kinds of cancer.

Prostate Model Is Challenged In December 2014, The Indiana University Proton Therapy Center closed its operations, marking the first time a proton-beam therapy center in the United States has shut down. University executives and an independent review committee attributed the shutdown to the center’s untenable financial losses. Not surprisingly, the losses are largely due to a decrease in the number of prostate cancer patients; insurers are beginning to push back on their coverage of proton-beam therapy until sufficient data prove its efficacy over less expensive modalities. Indeed, Blue Shield of California, Aetna, and Cigna Corp are no longer continued on page 42

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Issues in Oncology

American College of Physicians Releases High Value Care Screening Advice for Five Common Cancers

n a paper published in Annals of Internal Medicine1, the American College of Physicians (ACP) issued advice for screening average risk adults without symptoms for five common cancers: breast, colorectal, ovarian, prostate, and cervical. In a companion piece also published in Annals2, ACP outlined a framework for thinking about the value of varying intensities of cancer screening. “ACP hopes for smarter screening by informing people about the benefits and harms of screening, and encouraging them to get screened at the right time, at the right interval, with the right test,” said Wayne J. Riley, MD, MPH, MBA, President, ACP. “Many people have a lack of understanding about the

Wayne J. Riley, MD, MPH, MBA

trade-offs of screening. Study after study has consistently shown that patients and many physicians overestimate the benefits and are unaware of and/or downplay the potential harms of cancer screening.”

Synthesis of Guidelines In “Screening for Cancer,” ACP reviewed clinical guidelines and evidence synthesis issued by the United States Preventive Services Task Force, the American Academy of Family Physicians, the American Cancer Society, the American Congress of Obstetrics and

Proton-Beam Therapy continued from page 41

covering proton therapy as a treatment option for localized prostate cancer. But there is more afoot in the proton-beam therapy story than the debate over efficacy data. The Indiana University executive review committee also cited changing patterns in the care of prostate cancer patients as a reason for the center’s revenue losses. For instance, the number of cases diagnosed each year in the United States has fallen. Plus, there has been increased awareness about overtreat-

Gynecology, the American Gastroenterological Association, the American Urological Association, and ACP. “We found much common agreement on high value care screening among different organizations,” said Tanveer Mir, MD, MACP, Chair of ACP’s Board of Regents and a member

Tanveer Mir, MD, MACP

of ACP’s High Value Care Task Force, which developed the papers. “Our advice puts that agreement together in one convenient place for physicians and patients. Many major physician organizations are seeking to implement strategies that best optimize the known benefits and harms of cancer screenings.” Various screening strategies exist for each of the cancers highlighted in the paper. High intensity screening strategies (screening broader populations, more frequently, and/or with more sensitive screening tests) are not necessarily high value care. ACP defines high value care as the delivery of services providing benefits that make their harms and costs worthwhile. ACP encourages physicians to implement a health care strategy that focuses on tests or treatments that improve health, avoid harms, and eliminate wasteful practices. Screening average risk adults ages 50 to 75 for colorectal cancer with high sensitivity fecal occult blood testing every year ment, especially in those men with Gleason scores of 6 or less, giving rise to an increased use of active surveillance as a management technique. Equally important, the majority of cases diagnosed per year are in the low-risk category, and most of those men are being treated with robotic surgery. The experience of the Indiana University Proton Therapy Center highlights an important phenomenon in health care called “gizmo idolatry,” which has been written about in the literature.4 Simply put, Americans are infatuated with new,

is an example of high value care. Screening women without a cervix for cervical cancer is an example of low value care. “The largest harm that can result from overly intense screening is overdiagnosis and overtreatment,” Dr. Riley said. “The more sensitive the test we use or lower the threshold we establish for an abnormality, the more abnormalities we find—many of which will never lead to health problems. But because doctors cannot know which of these would or would not cause problems, we tend to treat them. Treatment for cell and tissue abnormalities that will likely not cause health problems cannot provide benefits.” Prostate cancer, for example, detected with the prostate-specific antigen (PSA) test, never becomes clinically significant in a patient’s lifetime in a considerable proportion of men. Screening using the PSA test in average-risk men under the age of 50 years, or over the age of 69 years, can open the door to more testing and treatment that might actually be harmful. If cancer is diagnosed, it will often be treated with surgery or radiation, which increases the risk for loss of sexual function and loss of control of urination compared to no surgery. This does not apply to those men considered to be in high-risk groups, such as African American men or those with a strong family history of prostate cancer.

Causes of Overscreening

find that subset of abnormalities that has the greatest probability of progressing to cause health problems, and that is more treatable at an early, asymptomatic stage. 3) Individuals are heterogeneous. Optimal intensity screening strategies focus on people with sufficient risk of having a potentially fatal cancer who also have low competing health risks from other causes. 4) Although screening leads to important benefits for some cancers and some people, it can also lead to significant harms to many more people than those receiving benefits. 5) Determining the value of screening strategies is complex, but not impossible.

About the High Value Care Initiative ACP’s High Value Care Initiative is designed to help doctors and patients understand the benefits, harms, and costs of tests and treatment options for common clinical issues so they can pursue care together that improves health, avoids harms, and eliminates wasteful practices. ACP defines High Value Care as the delivery of services providing benefits that make their harms and costs worthwhile. ACP’s High Value Care Task Force papers focus on value by evaluating the benefits, harms, and costs of a test or intervention. n

In “A Value Framework for Cancer Screening,” ACP speculates about pressures that encourage overly intensive low value screening. The paper lists and discusses five general concepts: 1) Screening is a cascade of events, rather than a single test. 2) Cancers are heterogeneous. Optimal intensity screening strategies seek to

References 1. Wilt TJ, Harris RP, Qaseem A: Screening for cancer: Advice for high-value care from the American College of Physicians. Ann Intern Med 162(10): 718-725, 2015. 2. Harris RP, Wilt TJ, Qaseem A: A value framework for cancer screening: Advice for high-value care from the American College of Physicians. Ann Intern Med 162(10): 712-717, 2015.

expensive, futuristic technology, even if there are no substantial data to support its adoption. It is a “new must be better than old” mentality. No doubt, proton-beam therapy is the biggest and most expensive technology on the market. But is it the best? In prostate cancer—the business model proton therapy was built on—there are no data to sufficiently answer that question. And until we have the supportive data, every center that opens runs the risk of becoming the next Indiana University Proton Therapy Center. n

References 1. Wilson RR: Radiological use of fast protons. Radiology 47:487-491, 1946. 2. Walsh J: Proton beam therapy for prostate cancer: A technology assessment. San Francisco, California Technology Assessment Forum, October 17, 2012. Available at ctaf.org. Accessed June 29, 2015. 3. American Cancer Society: Prostate cancer. Last medical review: 12/22/214. Available at www.cancer.org. Accessed June 29, 2015. 4. Leff B, Finucane TE: Gizmo idolatry. JAMA 299:1830-1832, 2008.

Change your perspective on whatâ&#x20AC;&#x2122;s possible for your patients with multiple myeloma

153

High-dose dex

6 9 Months (ITT population)

Hazard ratio (2-sided 95% CI) 0.45 (0.35, 0.59) Log-rank P-value=<0.001 (2-sided) Data cutoff: September 7, 2012

POMALYST + low-dose dexamethasone (dex) High-dose dex

Progression-free survival

Progression-free survival (PFS) based on the assessment by the Independent Review Adjudication Committee (IRAC) review at the final PFS analysis.

107

302

Number of patients at risk:

POMALYST + low-dose dex

0.0

0.2

0.4

0.6

0.8

1.0

Kaplan-Meier median: POMALYST + low-dose dex=3.6 [3.0, 4.6] Kaplan-Meier median: high-dose dex=1.8 [1.6, 2.1] Events: POMALYST + low-dose dex=164/302; high-dose dex=103/153

See where survival may lead

POMALYST + low-dose dex is the only approved therapy that delivered a survival benefit in patients who failed lenalidomide and bortezomib

POMALYST is only available through a restricted distribution program, POMALYST REMS速.

POMALYST速 (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Proportion of patients

Hazard ratio 0.45 (95% CI: 0.35, 0.59; P <0.001)

Patients >75 years of age started treatment with 20 mg dex using the same schedule.

Learn more about the survival beneﬁt of POMALYST at www.mmperspective.com

Study Design: Phase 3 multicenter, randomized, open-label study, where POMALYST + low-dose dex was compared with high-dose dex in patients with relapsed and refractory multiple myeloma, who had received at least 2 prior treatment regimens, including lenalidomide and bortezomib, and demonstrated disease progression on or within 60 days of the last therapy (N=455). Patients with creatinine clearance ≥45 mL/min qualified for the trial. Patients in the POMALYST + low-dose dex arm (n=302) were administered 4 mg POMALYST orally on Days 1-21 of each 28-day cycle. Low-dose dex (40 mga) was administered once per day on Days 1, 8, 15, and 22 of a 28-day cycle. For the high-dose dex arm (n=153), dex (40 mga) was administered once per day on Days 1-4, 9-12, and 17-20 of a 28-day cycle. Treatment continued until patients had disease progression.

VENOUS AND ARTERIAL THROMBOEMBOLISM • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Antithrombotic prophylaxis is recommended.

POMALYST is available only through a restricted program called POMALYST REMS®.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, and Important Safety Information on the following pages.

• POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST 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

CONTRAINDICATIONS: Pregnancy

• For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of 2 reliable methods of contraception.

EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects.

See full prescribing information for complete boxed warning

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM

Median OS for POMALYST + low-dose dex was 12.4 months (95% CI: 10.4, 15.3) vs 8.0 months (95% CI: 6.9, 9.0) for high-dose dex

Hazard ratio 0.70 (95% CI: 0.54, 0.92; P =0.009)

The difference in OS between the POMALYST + low-dose dex vs high-dose dex was statistically signiﬁcant, with a 30% reduced risk of death

POMALYST + low-dose dex signiﬁcantly prolonged overall survival (OS)

reduced risk of progression or death

55%

POMALYST + low-dose dex delivered signiﬁcantly longer progression-free survival vs high-dose dex

POMALYST® (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment.

POMALYST is only available through a restricted distribution program called POMALYST REMS®.

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST 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 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of POMALYST therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST POMALYST REMS® Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS®.” Prescribers and pharmacies must be certified with the program; patients must sign an agreement form and

comply with the requirements. Further information about the POMALYST REMS® program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436. Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboembolic events (ATE) (myocardial infarction and stroke) have been observed in patients treated with POMALYST. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with POMALYST and low-dose dexamethasone (Low-dose Dex) vs 3.3% treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with POMALYST and Low-dose Dex vs 1.3% treated with highdose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with POMALYST and Low-dose Dex vs 1.3% treated with high-dose dexamethasone. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Hematologic Toxicity: In Trials 1 and 2 in patients who received POMALYST + Low-dose Dex, neutropenia (46%) was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification. Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor

Venous and Arterial Thromboembolism • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.

WARNINGS AND PRECAUTIONS (continued) liver function tests monthly. Stop POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. Hypersensitivity Reactions: Angioedema and severe dermatologic reactions have been reported. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reactions, and do not resume therapy. Dizziness and Confusional State: In Trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 14% experienced dizziness and 7% a confusional state; 1% of patients experienced Grade 3 or 4 dizziness and 3% experienced a Grade 3 or 4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice. Neuropathy: In Trials 1 and 2, patients who received POMALYST + Low-dose Dex experienced neuropathy (18%) and peripheral neuropathy (~12%). In Trial 2, 2% of patients experienced Grade 3 neuropathy. Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) may occur in patients treated with POMALYST. Patients at risk are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Avoid the use of strong CYP1A2 inhibitors. If medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce POMALYST dose by 50%. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients >65 years of age were more likely than patients ≤65 years of age to experience pneumonia. Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

ADVERSE REACTIONS Nearly all patients treated with POMALYST + Low-dose Dex experienced at least one adverse reaction (99%). In Trial 2, the most common adverse reactions included neutropenia (51.3%), fatigue and asthenia (46.7%), upper respiratory tract infection (31%), thrombocytopenia (29.7%), pyrexia (26.7%), dyspnea (25.3%), diarrhea (22%), constipation (21.7%), Please see brief summary of full Prescribing back pain (19.7%), cough (20%), pneumonia (19.3%), Information, including Boxed WARNINGS, edema peripheral (17.3%), peripheral neuropathy (17.3%), on following pages. bone pain (18%), nausea (15%), and muscle spasms (15.3%). Grade 3 or 4 adverse reactions included neutropenia (48.3%), thrombocytopenia (22%), and pneumonia (15.7%). DRUG INTERACTIONS Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). POMALYST is only available through a restricted distribution program, POMALYST REMS®.

The ASCO Post | AUGUST 10, 2015

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Announcements

Michael Allen Pulsipher, MD, Joins Children’s Hospital Los Angeles

ichael Allen Pulsipher, MD, joined the Children’s Center for Cancer and Blood Diseases and the Division of Hematology, Oncology, and Blood and Marrow Transplantation at Children’s Hospital Los Angeles (CHLA) as Head of the Section of

Blood and Marrow Transplantation (BMT) and as BMT Clinical Research Chair. In addition, Dr. Pulsipher is a Professor of Pediatrics at the Keck School of Medicine of the University of Southern California (USC) and a Member of the USC Norris Compre-

hensive Cancer Center. These appointments became effective July 1, 2015. The pediatric BMT Program at CHLA is one of the largest in the world, having performed more than 1,300 transplants since 1983. In directT:7” program’s cliniing the pediatric BMT

cal care and clinical research activities, Dr. Pulsipher will closely collaborate in the further development of a leading research program that integrates laboratory and clinical science. “Children’s Hospital Los Angeles is very excited to have Dr. Pulsipher join

POMALYST® (pomalidomide) capsules, for oral use

2.2 Dose Adjustments for Toxicities

The following is a Brief Summary; refer to full Prescribing Information for complete product information.

Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities

Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles, or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS® [see Warnings and Precautions (5.2)]. Venous and Arterial Thromboembolism • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors [see Warnings and Precautions (5.3)].

2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST should be given in combination with dexamethasone. POMALYST may be taken with water. Inform patients not to break, chew, or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

Dose Modification • Interrupt POMALYST treatment, follow CBC weekly • Resume POMALYST treatment at 3 mg daily

• For each subsequent • Interrupt POMALYST drop <500 per mcL treatment • Return to more than or • Resume POMALYST equal to 500 per mcL treatment at 1 mg less than the previous dose Thrombocytopenia • Platelets <25,000 per mcL • Platelets return to >50,000 per mcL

• Interrupt POMALYST treatment, follow CBC weekly • Resume POMALYST treatment at 3 mg daily

• For each subsequent • Interrupt POMALYST drop <25,000 per mcL treatment • Resume POMALYST • Return to more than or equal to 50,000 per treatment at 1 mg less than previous dose mcL ANC, absolute neutrophil count To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL and the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. Permanently discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reaction [see Warnings and Precautions (5.6)]. For other Grade 3 or 4 toxicities, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. 2.3 Dose Adjustment for Strong CYP1A2 Inhibitors in the Presence of Strong CYP3A4 and P-gp Inhibitors Avoid co-administration of strong inhibitors of CYP1A2. If necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce POMALYST dose by 50%. No clinical efficacy or safety data exist [see Drug Interactions (7.1))]. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].

5.2 POMALYST REMS Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST, and comply with REMS requirements. Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436. 5.3 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke) have been observed in patients treated with POMALYST. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with POMALYST and low dose-dexamethasone (Low-dose Dex), and 3.3% of patients treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with POMALYST and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with POMALYST and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone.

T:10”

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST, in combination with dexamethasone, is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Toxicity Neutropenia • ANC <500 per mcL or febrile neutropenia (fever more than or equal to 38.5°C and ANC <1,000 per mcL) • ANC return to more than or equal to 500 per mcL

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Announcements

Michael Allen Pulsipher, MD

Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors. 5.4 Hematologic Toxicity In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, neutropenia was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 51% of patients in both trials. The rate of Grade 3/4 neutropenia was 46%. The rate of febrile neutropenia was 8%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly. Stop POMALYST upon elevation of liver enzymes and evaluate. After return to baseline values, treatment at a lower dose may be considered. 5.6 Hypersensitivity Reactions Angioedema and severe dermatologic reactions have been reported. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reactions, and do not resume therapy [see Dosage and Administration (2.2)].

5.8 Neuropathy In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 18% of patients experienced neuropathy, with approximately 12% of the patients experiencing peripheral neuropathy. Two percent of patients experienced Grade 3 neuropathy in trial 2. There were no cases of Grade 4 neuropathy adverse reactions reported in either trial. 5.9 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 5.10 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous and Arterial Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hepatotoxicity [see Warnings and Precautions (5.5)] • Hypersensitivity Reactions [see Warnings and Precautions (5.6)] • Dizziness and Confusional State [see Warnings and Precautions (5.7)] • Neuropathy [see Warnings and Precautions (5.8)]

to providing overall direction for our transplantation program, his research expertise will bring additional strength to our team of clinicians and scientists at CHLA who are leading the fight against refractory childhood leukemia.” Dr. Pulsipher most recently served at Primary Children’s Hospital and the University of Utah School of Medicine

• Risk of Second Primary Malignancies [see Warnings and Precautions (5.9)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low-dose Dex (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty-seven percent of patients in the study had a dose interruption of either drug due to adverse reactions. Forty-two percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to adverse reactions was 11%. In Trial 2, data were evaluated from 450 patients (safety population) who received treatment with POMALYST + Low-dose Dex (300 patients) or Highdose Dexamethasone (High-dose Dex) (150 patients). The median number of treatment cycles for the POMALYST + Low-dose Dex arm was 5. In the POMALYST + Low-dose Dex arm, 67% of patients had a dose interruption of POMALYST, the median time to the first dose interruption of POMALYST was 4.1 weeks. Twenty-seven percent of patients had a dose reduction of POMALYST, the median time to the first dose reduction of POMALYST was 4.5 weeks. Eight percent of patients discontinued POMALYST due to adverse reactions. Tables 2 and 3 summarize the adverse reactions reported in Trials 1 and 2, respectively. In Trial 1 of 219 patients who received POMALYST alonea (N=107) or POMALYST + Low-dose Dex (N=112), all patients had at least one adverse reaction.* Adverse reactions ≥10% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropeniab (53%, 49%), Anemiab (38%, 42%), Thrombocytopeniab (26%, 23%), Leukopenia (13%, 20%), Febrile neutropeniab (<10%, <10%), Lymphopenia (4%, 15%); General disorders and administration site conditions: Fatigue and astheniab (58%, 63%), Edema peripheral (25%, 17%), Pyrexiab (23%, 32%), Chills (10%, 13%); Gastrointestinal disorders: Nauseab (36%, 24%), Constipationb (36%, 37%), Diarrhea (35%, 36%), Vomitingb (14%, 14%); Musculoskeletal and connective tissue disorders: Back painb (35%, 32%), Musculoskeletal chest pain (23%, 20%), Muscle spasms (22%, 20%), Arthralgia (17%, 15%), Muscular weakness (14%, 13%), Bone pain (12%, 7%), Musculoskeletal pain (12%, 17%), Pain in extremity (8%, 14%); Infections and infestations: Upper respiratory tract infection (37%, 29%), Pneumoniab (28%, 34%), Urinary tract infectionb (10%, 17%), Sepsisb (<10%, <10%); Metabolism and nutrition disorders: Decreased appetite (23%, 19%), Hypercalcemiab (22%, 12%), Hypokalemia (12%, 12%), Hyperglycemia (11%, 15%), Hyponatremia (11%, 13%), Dehydrationb (<10%, <10%), Hypocalcemia (6%, 12%); Respiratory, thoracic and mediastinal disorders: Dyspneab (36%, 45%), Cough (17%, 22%), Epistaxis (17%, 11%), Productive cough (9%, 13%), Oropharyngeal pain (6%, 11%); Nervous system disorders: Dizziness (22%, 18%), Peripheral neuropathy (22%, 18%), Headache (15%, 13%), Tremor (10%, 13%); Skin and subcutaneous tissue disorders: Rash (21%, 16%), Pruritus (15%, 9%), Dry skin (9%, 11%), Hyperhidrosis (8%, 16%), Night sweats (5%, 13%); Investigations: Blood creatinine increasedb (19%, 10%), Weight decreased (15%, 9%), Weight increased (1%, 11%); Psychiatric disorders: Anxiety (13%, 7%), Confusional stateb (12%, 13%), Insomnia (7%, 16%); Renal and urinary disorders: Renal failureb (15%, 10%).

In Trial 1, Grade 3/4 at least one adverse reaction reported in 92% of patients treated with POMALYSTa alone (N=107) and 91% with POMALYST + Low-dose Dex (N=112).* Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropeniab (48%, 41%), Anemiab (23%, 21%), Thrombocytopeniab (22%, 19%), Leukopenia (7%, 10%), Febrile neutropeniab (6%, 3%), Lymphopenia (2%, 7%); General disorders and administration site conditions: Fatigue and astheniab (12%, 17%), Edema peripheral (0%, 0%), Pyrexiab (<5%, <5%), Chills (0%, 0%); Gastrointestinal disorders: Nauseab (<5%, <5%), Constipationb (<5%, <5%), Diarrhea (<5%, <5%), Vomitingb (<5%, 0%); Musculoskeletal and connective tissue disorders: Back painb (14%, 10%), Musculoskeletal chest pain (<5%, 0%), Muscle spasms (<5%, <5%), Arthralgia (<5%, <5%), Muscular weakness (6%, 4%), Bone pain (<5%, <5%), Musculoskeletal pain (<5%, <5%), Pain in extremity (0%, <5%); Infections and infestations: Upper respiratory tract infection (<5%, <5%), Pneumoniab (20%, 29%), Urinary tract infectionb (2%, 9%), Sepsisb (6%, 5%); Metabolism and nutrition disorders: Decreased appetite (<5%, 0%), Hypercalcemiab (10%, 1%), Hypokalemia (<5%, <5%), Hyperglycemia (<5%, <5%), Hyponatremia (<5%, <5%) Dehydrationb (5%, 5%), Hypocalcemia (0%, <5%); Respiratory, thoracic and mediastinal disorders: Dyspneab (8%, 13%), Cough (0%, 0%), Epistaxis (<5%, 0%), Productive cough (0%, 0%), Oropharyngeal pain (0%, 0%); Nervous system disorders: Dizziness (<5%, <5%), Peripheral neuropathy (0%, 0%), Headache (0%, <5%), Tremor (0%, 0%); Skin and subcutaneous tissue disorders: Rash (0%, <5%), Pruritus (0%, 0%), Dry skin (0%, 0%), Hyperhidrosis (0%, 0%), Night sweats (0%, 0%); Investigations: Blood creatinine increasedb (6%, 3%), Weight decreased (0%, 0%), Weight increased (0%, 0%); Psychiatric disorders: Anxiety (0%, 0%), Confusional stateb (6%, 3%), Insomnia (0%, 0%); Renal and urinary disorders: Renal failureb (8%, 7%). * Regardless of attribution of relatedness to POMALYST. a POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. b Serious adverse reactions were reported in at least 2 patients in any POMALYST treatment arm. Data cutoff: 01 March 2013 In Trial 2 of 450 patients who received POMALYST + Low-dose Dex (N=300) or High-dose-Dex (N=150), at least one adverse reaction was reported in 99% of patients. All Adverse Reactions ≥5% in POMALYST + Lowdose Dex arm, and at least 2% point higher than the High-dose-Dex arm included: Blood and lymphatic system disorders: Neutropeniab (51%, 21%), Thrombocytopenia (30%, 29%)a, Leukopenia (13%, 5%), Febrile neutropeniab (9%, 0%); General disorders and administration site conditions: Fatigue and asthenia (47%, 43%), Pyrexiab (27%, 23%), Edema peripheral (17%, 11%), Pain (4%, 2%)a; Infections and infestations: Upper respiratory tract infectionb (31%, 13%), Pneumoniab (19%, 13%), Neutropenic sepsisb (1%, 0%)a; Gastrointestinal disorders: Diarrhea (22%, 19%), Constipation (22%, 15%), Nausea (15%, 11%), Vomiting (8%, 4%); Musculoskeletal and connective tissue disorders: Back painb (20%, 16%), Bone Painb (18%, 14%), Muscle spasms (15%, 7%), Arthralgia (9%, 5%), Pain in extremity (7%, 6%)a; Respiratory, thoracic and mediastinal disorders: Dyspneab (25%, 17%), Cough (20%, 10%), Chronic obstructive pulmonary diseaseb (2%, 0%)a; Nervous system disorders: Peripheral neuropathy (17%, 12%), Dizziness (12%, 9%), Headache (8%, 5%), Tremor (6%, 1%), Depressed level of consciousness (2%, 0%)a; Metabolism and nutrition disorders: Decreased appetite (13%, 8%), Hypokalemia (9%, 8%)a, Hypocalcemia (4%, 6%)a;

in Salt Lake City. Among his many leadership roles, Dr. Pulsipher has served as Director of the Utah Blood and Marrow Transplant Program, as Medical Director of the Utah Cord Blood Program, and as current Group Chair of the Pediatric Blood and Marrow Transplant Consortium, an 80-member international clinical trials group. n

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5.7 Dizziness and Confusional State In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 14% of patients experienced dizziness and 7% of patients experienced a confusional state; 1% of patients experienced Grade 3 or 4 dizziness, and 3% of patients experienced Grade 3 or 4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.

us in this important leadership position, as we work to develop more effective and less toxic therapies for children with cancer and blood diseases,” said Alan Wayne, MD, Director of the Children’s Center for Cancer and Blood Diseases and Division Head of Hematology, Oncology, and Blood and Marrow T:7” Transplantation at CHLA. “In addition

The ASCO Post | AUGUST 10, 2015

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Announcements

Stephen L. Lessnick, MD, PhD, Named Director of the Center for Childhood Cancer and Blood Disorders at Nationwide Children’s Hospital, Columbus, Ohio

tephen L. Lessnick, MD, PhD, has joined the Research Institute at Nationwide Children’s Hospital, Columbus, Ohio as Director of the Center for Childhood Cancer and Blood Disorders.

As Director, Dr. Lessnick leads a team of pediatric researchers in the Center for Childhood Cancer and Blood Disorders working to expand the understanding of the development of

Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Cardiac disorders: Myocardial infarction, Atrial fibrillation, Angina pectoris, Cardiac failure congestive Ear and labyrinth disorders: Vertigo Gastrointestinal disorders: Abdominal pain General disorders and administration site conditions: General physical health deterioration, Non-cardiac chest pain, Multi-organ failure Hepatobiliary disorders: Hyperbilirubinemia Infections and infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis, Bacteremia, Pneumonia respiratory syncytial viral, Cellulitis, Urosepsis, Septic shock, Clostridium difficile colitis, Pneumonia streptococcal, Lobar pneumonia, Viral infection, Lung infection Investigations: Alanine aminotransferase increased, Hemoglobin decreased

plantation at Nationwide Children’s. Dr. Lessnick is also Professor of Pediatrics in the Division of Pediatric Hematology and Oncology at The Ohio State University College of Medicine. n

Injury, poisoning and procedural complications: Fall, Compression fracture, Spinal compression fracture Metabolism and nutritional disorders: Hyperkalemia, Failure to thrive Nervous System disorders: Depressed level of consciousness, Syncope Psychiatric disorders: Mental status change Renal and urinary disorders: Urinary retention, Hyponatremia Reproductive system and breast disorders: Pelvic pain Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease, Pulmonary embolism, Respiratory failure, Bronchospasm Vascular disorders: Hypotension

Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg/kg/day. Malformations or absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central, and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg/day. Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg/kg/day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg/kg/day. Additional malformations observed at 250 mg/kg/day included anomalies in limbs (flexed and/or rotated fore- and/ or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs, and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg/kg/day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg/day. Additional embryo-fetal toxicity included increased resorption.

6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide postmarketing experience with POMALYST: Pancytopenia, tumor lysis syndrome, allergic reactions (e.g., angioedema, urticaria), elevated liver enzymes, hepatic failure (including fatal cases). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 7 DRUG INTERACTIONS Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP1A2 inhibitors: Pomalidomide exposure is increased when POMALYST is co-administered with a strong CYP1A2 inhibitor (fluvoxamine) in the presence of a strong CYP3A4/5 and P-gp inhibitor (ketoconazole). Ketoconazole in the absence of a CYP1A2 inhibitor does not increase pomalidomide exposure. Avoid co-administration of strong CYP1A2 inhibitors (e.g. ciprofloxacin and fluvoxamine) [see Dosage and Administration (2.3)]. If it is medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, POMALYST dose should be reduced by 50%. The effect of a CYP1A2 inhibitor in the absence of a co-administered CYP3A4 and P-gp inhibitor has not been studied. Monitor for toxicities if CYP1A2 inhibitors are to be co-administered in the absence of a co-administered CYP3A4 and P-gp inhibitor, and reduce dose if needed. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. CYP1A2 inducers: Co-administration of POMALYST with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)] Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented, and mortality at or shortly after birth has been reported in about 40% of infants.

8.3 Nursing Mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of POMALYST in patients below the age of 18 years have not been established. 8.5 Geriatric Use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 44% were aged older than 65 years, while 10% were aged older than 75 years. No overall differences in effectiveness were observed between these patients and younger patients. In these studies, patients older than 65 years were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy.

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Skin and subcutaneous tissue disorders: Rash (8%, 1%), Pruritus (7%, 3%), Hyperhidrosis (5%, 1%); Investigations: Neutrophil count decreased (5%, 1%), Platelet count decreased (3%, 2%)a, White blood cell count decreased (3%, 1%)a, Alanine aminotransferase increased (2%, 1%)a, Aspartate aminotransferase increased (1%, 1%)a, Lymphocyte count decreased (1%, 1%)a; Renal and urinary disorders: Renal failure (10%, 12%)a; Injury, poisoning and procedural complications: Femur fractureb (2%, 1%)a; Reproductive system and breast disorders: Pelvic pain (2%, 2%)a. In Trial 2, Grade 3/4 at least one adverse reaction was reported in 86% of patients treated with POMALYST + Low-dose Dex (N=300) and 85% with High-dose Dex (N=150). Grade 3/4 Adverse Reactions ≥1% in POMALYST + Low-dose Dex arm, and at least 1% point higher than the High-dose-Dex arm, respectively, included: Blood and lymphatic system disorders: Neutropeniab (48%, 16%), Thrombocytopenia (22%, 26%)a, Leukopenia (9%, 3%), Febrile neutropeniab (9%, 0%); General disorders and administration site conditions: Fatigue and asthenia (9%, 12%)a, Pyrexiab (3%, 5%)a, Edema peripheral (1%, 2%)a, Pain (2%, 1%); Infections and infestations: Upper respiratory tract infectionb (3%, 1%), Pneumoniab (16%, 10%), Neutropenic sepsisb (1%, 0%); Gastrointestinal disorders: Diarrhea (1%, 1%)a, Constipation (2%, 0%), Nausea (1%, 1%)a, Vomiting (1%, 0%); Musculoskeletal and connective tissue disorders: Back painb (5%, 4%), Bone painb (7%, 5%), Muscle spasms (0%, 1%)a, Arthralgia (1%, 1%)a, Pain in extremity (2%, 0%); Respiratory, thoracic and mediastinal disorders: Dyspneab (6%, 5%), Cough (1%, 1%)a, Chronic obstructive pulmonary diseaseb (1%, 0%); Nervous system disorders: Peripheral neuropathy (2%, 1%)a, Dizziness (1%, 1%)a, Headache (0%, 0%)a, Tremor (1%, 0%)a, Depressed level of consciousness (1%, 0%); Metabolism and nutrition disorders: Decreased appetite (1%, 1%)a, Hypokalemia (4%, 3%), Hypocalcemia (2%, 1%); Skin and subcutaneous tissue disorders: Rash (1%, 0%), Pruritus (0%, 0%)a, Hyperhidrosis (0%, 0%)a; Investigations: Neutrophil count decreased (5%, 1%), Platelet count decreased (3%, 1%), White blood cell count decreased (3%, 0%), Alanine aminotransferase increased (2%, 0%), Aspartate aminotransferase increased (1%, 0%), Lymphocyte count decreased (1%, 0%); Renal and urinary disorders: Renal failure (6%, 5%); Injury, poisoning and procedural complications: Femur fractureb (2%, 1%); Reproductive system and breast disorders: Pelvic pain (1%, 0%). a Percentage did not meet the criteria to be considered as an adverse reaction for POMALYST for that category of event (i.e., all adverse events or Grade 3 or 4 adverse events). b Serious adverse reactions were reported in at least 3 patients in the POM + Low-dose Dex arm, AND at least 1% higher than the High-dose-Dex arm percentage. Data cutoff: 01 March 2013

childhood cancer and its diagnostic and treatment strategies. He will also foster close collaborations with the clinical team within the Division of Hematology/Oncology/BloodT:7”and Marrow Trans-

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Announcements

2015 Class of Pew–Stewart Scholars for Cancer Research Announced The Pew Charitable Trusts and the Alexander and Margaret Stewart Trust announced the newest class of Pew–Stewart scholars for cancer research on June 11.

8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 12 monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes, and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day.

ive standout scientists, nominated by the country’s leading cancer research institutions, will receive 4 years of flexible funding to pursue innovative work aimed at advancing progress toward a cure for cancer. T:7” “This year’s impressive class of

Pew–Stewart scholars is committed to excellence in every way,” said Rebecca W. Rimel, Pew’s President and CEO. “They are determined to unlock the complex biological mysteries that make cancer such a devastating disease. We hope that their contributions to the

In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males in this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females.

with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS. Provide patients with the telephone number and Web site for information on how to obtain the product. Venous and Arterial Thromboembolism Inform patients of the risk of developing DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Boxed Warnings and Warnings and Precautions (5.3)]. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia, and anemia and the need to report signs and symptoms associated with these events to their healthcare provider for further evaluation [see Warnings and Precautions (5.4)]. Hepatotoxicity Inform patients on the risks of developing hepatotoxicity, including hepatic failure and death, and to report signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.5)]. Hypersensitivity Inform patients of the risk for angioedema and severe skin reactions and to report any signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.6)]. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusional state with the drug, to avoid situations where dizziness or confusional state may be a problem, and not to take other medications that may cause dizziness or confusional state without adequate medical advice [see Warnings and Precautions (5.7)]. Neuropathy Inform patients of the risk of neuropathy and to report the signs and symptoms associated with these events to their healthcare provider for further evaluation [see Warnings and Precautions (5.8)]. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown [see Warnings and Precautions (5.9)]. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.10)]. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day. • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID®, THALOMID®, and POMALYST REMS® are registered trademarks of Celgene Corporation. Pat. http://www.celgene.com/therapies © 2005-2015 Celgene Corporation All rights reserved. POM HCP Bsv.004 04/15

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindications (4)]. POMALYST is a thalidomide analogue and may cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception, including at least 1 highly effective form, simultaneously during POMALYST therapy, during therapy interruption, and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch, or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm, and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program called POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Physician Agreement Form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements, and participate in monthly telephone surveys. Males must comply

cancer research landscape will echo for generations to come.” In 2014, Pew launched a partnership with the Stewart Trust—which has funded cancer researchers for more than 15 years—to begin supporting scientists trying to eradicate cancer. The 2015 Pew–Stewart scholars will pursue widely varied lines of inquiry in cancer biology, including the genetic basis of the disease, potential new therapeutics, and strategies that may bypass resistance to cancerfighting drugs.

We hope that their contributions to the cancer research landscape will echo for generations to come. — Rebecca W. Rimel

“The 2015 class of Pew–Stewart scholars is an exceptional group of outstanding young biomedical scientists, chosen by the committee with the expectation that they will be among the next generation’s leaders in cancer research,” said Peter M. Howley, MD, Chair of the Pew–Stewart National Advisory Committee. This year marks the 30th anniversary of Pew’s program to fund exceptional early-career researchers in the biomedical sciences, designed to encourage informed risk-taking to bring about unexpected, powerful discoveries. The 2015 Pew–Stewart scholars for cancer research are: • Trever Bivona, MD, PhD, University of California, San Francisco • Adam de la Zerda, PhD, Stanford University • Mitchell Guttman, PhD, California Institute of Technology Biology • Cigall Kadoch, PhD, Dana-Farber Cancer Institute, Harvard Medical School • Min Yu, MD, PhD, University of Southern California n T:10”

Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.

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National Cancer Policy Forum Cancer Research

Translational Research: Dogs and Humans Nearly Interchangeable in the Laboratory By Margot J. Fromer

“Between animal and human medicine there is no dividing line—nor should there be. The object is different but the experience obtained constitutes the basis of all medicine.” — Rudolf Virchow (1821–1902)

veryone has seen photographs of people who look like their dogs: the young woman with long straight hair and a thin face and her Afghan hound, the square-faced codger with an underslung jaw sitting cheek by jowl with his English bulldog, the middleaged woman with curly hair hugging her grey poodle. However, according to the scientists who spoke at the National Cancer Policy Forum’s workshop, “The Role of Clinical Studies for Pets With Naturally Occurring Tumors in Translational Cancer Research,” we resemble our doggie pals in far deeper ways than just furry bellies and goofy grins. Michael Kastan, MD, PhD, Executive Director, Duke Cancer Institute, described how dogs could serve well as preclinical models—for humans and for themselves. “Many novel drug candidates fail human clinical trials despite evidence of efficacy in murine model, because mice often lack key characteristics of human cancer, such as long latency, genomic instability, and heterogeneity among tumor cells and the surrounding microenvironment.” In fact, only 11% of antineoplastic drugs that showed efficacy in mice were approved for human use.

Drug Development “Oncology drug development is extremely expensive, crowded, and fiercely competitive,” said Anne Keane, JD, Director of Regulatory Affairs, Achaogen, San Francisco. There are more than 800 oncology compounds currently in the pipeline, 576 in late phase II and III trials, and a total of about 5,000 ongoing oncology drug studies. Moreover, the competition for research money is intense, and the time it takes to get a drug from the lab to market is critical. Ms. Keane said that even

a 1-month delay can mean millions of dollars of lost revenue each month. Human trials are fraught with problems from beginning to end. They take, on average, 70% longer than anticipated, patient recruitment is slow and unsteady (particularly in pediatrics), and they almost always cost more than the original estimate. Lee J. Helman, MD, Senior Investigator, National Cancer Institute (NCI) Pediatric Oncology Branch: Cancer, said drug development attrition rates are significantly higher in oncology than in other therapeutic areas—a 5% success rate compared with 20% for cardiovascular drugs. In fact, 70% of oncology drugs that enter phase II studies fail to move to phase III trials, and 59% of phase III drugs fail to gain approval— more often due to a lack of efficacy than to toxicity. There have been many attempts to solve the problem, most to

through three phases of clinical trials, tumor-bearing dog studies can determine activity, toxicity, pharmacokinetics, and pharmacodynamics (preclinical and phase I), as well as dose, regimen, schedule, biomarkers, responding histologies, and combination therapies (phases II and III). Wendy Levin, MD

and acquired resistance, recurrence, and metastasis,” said Dr. Kastan. Cancer is common in pets—80 million dogs and 90 million cats. Of U.S households, 47% own at least one dog, and every year, a million of them are treated for cancer. The disease kills 50% of dogs aged 10 and older and 33% of younger ones. One-third of cats die of their cancer. Pet owners, especially men for some reason, because they are so attached to these family members, are highly motivated to enroll pets in clini-

Recently, there has been renewed interest in studying tumors that spontaneously develop as a result of aging in companion animals (dogs mostly), because they share many characteristics with human cancers. —Michael Kastan, MD, PhD

no avail. Therefore, Chand Khanna, DVM, PhD, NCI Consultant, NCI Pediatric Oncology Branch, stated that a comparative and integrated approach to cancer drug development may be a solution.

Dogs May Be More Than Companions “Recently, there has been renewed interest in studying tumors that spontaneously develop as a result of aging in companion animals (dogs mostly), because they share many characteristics with human cancers, such as histologic appearance; tumor genetics; biologic behavior; molecular targets; therapeutic response;

cal studies. Wendy Levin, MD, Vice President, Clinical Development, Fate Therapeutics, San Diego, said that companion animals are large and outbred, thus showing strong genetic similarities to humans. Their cancers occur naturally, as do those of humans, and they are immune-competent and syngeneic. Other characteristics that make them ideal subjects in cancer trials include relevant tumor histology and genetics, tumor heterogeneity, biology of metastasis, relevant response to chemotherapy, and compressed times for disease progression. At the same time that human drugs are progressing from preclinical studies

Comparative Oncology Consortia Translational studies in pets, known as comparative oncology, can be a useful intermediary between traditional preclinical models and human clinical trials. After drug approval, comparative oncology can provide additional information about safety, dosage, and regimen. The main goal is to answer biologic questions about the development paths of new treatments for future use in human patients with cancer. The Comparative Oncology Trials Consortium (COTC), which is managed by the NCI Center for Cancer Research Comparative Oncology Program, provides an infrastructure and resources to integrate clinical trials for pets into development of new drugs, devices, and imaging techniques for human cancers. Trials are conducted by 20 veterinary academic centers, which provide owner education and obtain informed consent for research that eventually benefits both animals and humans. Progress to date includes 19 initiated letters of intent, 11 initiated study protocols, 9 studies completed (with 3 published), and 7 more in progress. “Trials conducted by COTC are pharmacokinetically and pharmacodynamically integrated into the design of human phase I and phase II human trials,” said Dr. Kastan. The Canine Comparative Oncology and Genomics Consortium (CCOGC), also part of the NCI Center for Cancer Research, was established in 2007 to facilitate strategic partnerships and collaborations to study cancer in dogs. The PfizerCCOGC Biospecimen Repository has amassed 60,000 specimens from about 2,000 canine patients with cancer of more

Visit The ASCO Post website at ASCOPost.com

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National Cancer Policy Forum than 100 breeds—52% male and 48% female. They include seven types of cancer (osteosarcoma, lymphoma, melanoma, pulmonary tumors, mast cell tumors, soft-tissue sarcomas, and hemangiosarcomas) and nine types of specimens, among them frozen tumor tissue, plasma, and normal tissue. The CCOGC has developed a mechanism to share reagents and resources as well as to develop a biospecimen repository, which is accessible to the public based on scientific merit.

The FDA Animal Testing Rule The U.S Food and Drug Administration (FDA) has established a rule about animal testing as a surrogate for approval of drugs and biologics when human efficacy studies are neither ethical nor feasible. Stipulations of the rule follow: • There is a reasonably well-understood pathophysiologic mechanism. • The study outcome is clearly related to the desired benefit in humans (reduced morbidity/mortality). • Effective dosage in humans can be extrapolated from the pharmacokinetics in animals. • Animal testing is not designed merely

Matthew Breen, PhD

as a shortcut to approval. • After adequate and well-controlled animal tests, the results of which establish that a product is reasonably likely to provide clinical benefit in humans, safety must still be demonstrated in human subjects.

Dogs Eat, Play, and Sleep With Us The vast majority of human cancers are the result of environmental exposures, and because pets share our environment (breathe the same air, chase tennis balls on lawns that we fertilize, swim in the same lakes, eat some of the same food, and possibly sleep in the same bed), they too are heir to the same cancers. Different breeds are suscepti-

ble to different cancers, said Dr. Kastan, and these differences can provide insight into how environmental exposure can lead to cancer development. So too can biobanks, said Matthew Breen, PhD, Oscar J. Fletcher Distinguished Professor of Comparative Oncology Genetics, North Carolina State University, College of Veterinary Medicine. They are critical for several reasons. First, research involving canine genetic or genomic information analyzed using biologic specimens from well-annotated patients is key to understanding complex diseases such as cancer. Second, these data are critical to advancing cancer detection, diagnosis, prognosis, intervention, treatment, and prevention. Third, establishing and sharing canine biologic samples and information derived from their analysis can create maximal research efficiency. Key elements of an effective biobank include specimen selection and storage for a variety of purposes, access to the specimens and patient data by researchers, and a workable data-sharing plan. These factors are critical, of course, but

the animals from whom these samples are taken are our family members, and most pet owners are utterly besotted by their “babies.” “Think of them as child patients,” said Patricia Olson, DVM, PhD, Independent Advisor on Animal Health and Welfare. She asked a number of questions that researchers should take into consideration: • Is the trial in question designed to prevent disease or provide a new therapy? • Who will serve as an independent advocate for the animal during a trial? • Animals cannot give consent; therefore, what are appropriate safeguards to ensure their welfare? • Should conventional therapy ever be delayed for an animal participating in a trial? • What are the limits on tissue and blood collections? • Do companion animals benefit from clinical research, especially phases 0 and I? n Disclosures: Ms. Keane, Drs. Kastan, Helman, Khanna, Levin, Breen, and Olson reported no potential conflicts of interest.

Announcements

Timothy L. Lash, DSc, MPH, Named Head of Winship’s Cancer Prevention and Control Program

Carrie Kitko, MD, Appointed Director of Vanderbilt’s Pediatric Stem Cell Transplant Program

inship Cancer Institute of Emory University has named Timothy L. Lash, DSc, MPH, Professor of Epidemiology in the Rollins School of Public Health and Win-

Timothy L. Lash, DSc, MPH

ship member, as the new Leader for the Winship Cancer Prevention and Control (CPC) Research Program. His position takes effect immediately. Andrew H. Miller, MD, will continue to serve as Coleader of the program. Dr. Lash replaces Roberd “Robin” Bostick, MD, MPH, who has served as Leader of the CPC Program since 2008. Dr. Lash joined Emory University

in 2013. His research focuses on molecular biomarkers that predict cancer recurrence. He also is interested in age-related disparities in the quality of cancer care. “Dr. Lash has quickly established himself as a valuable member of the Winship research community and the CPC program,” said Walter J. Curran, Jr, MD, Winship’s Executive Director. “ We are pleased to have him in his new role and look forward to working with him to grow the program.” Earlier this year, Dr. Lash was among a select group that received the Emory 1% Award recognizing faculty whose competitive research grant application is ranked in the first percentile. Dr/ Lash also serves as the editor-in-chief of the journal Epidemiology. He previously held faculty appointments at Wake Forest University School of Medicine, the University of Aarhus in Denmark, and Boston University’s Schools of Public Health and Medicine. n

arrie Kitko, MD, has joined Monroe Carell Jr Children’s Hospital at Vanderbilt as Associate Professor of Pediatrics and Director of the Pediatric Stem Cell Transplant Program in the Division of Hematology/Oncology.

Carrie L. Kitko, MD

Dr. Kitko was previously Assistant Professor of the Blood and Marrow Transplantation Program in the Department of Pediatrics and Communicable Diseases at the University of Michigan School of Medicine. While at University of Michigan, her research focused on understanding graft-vshost disease (GVHD). Dr. Kitko will continue her research at Vanderbilt and plans to start

a clinic focused on GVHD treatment. In her research, she studies biomarkers that can help determine which post-transplant patients are most likely to develop GVHD. She also looks at extracorporeal photopheresis for treatment and prevention of both acute and chronic GVHD. During a photopheresis treatment, the patient is connected to the photopheresis machine and their white blood cells are collected. Within the machine, the collected cells are treated with medicine that is activated by brief exposure to ultravioletA (UVA) light. The treated blood cells are then returned to the patient. Dr. Kitko will be the primary investigator on a national multicenter clinical trial investigating extracorporeal photopheresis for the treatment of pediatric acute GVHD, and plans to have the study open for patients at Vanderbilt. Dr. Kitko earned her medical degree at Ohio State University. She was a resident and chief resident at Duke University Medical Center and then went on to fellowship at University of Michigan Medical Center. n

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Announcements

CancerCare Announces National Study: Patient Access and Engagement Report

ancerCare, a national nonprofit organization that provides free psychosocial support, education, and financial assistance to anyone affected by cancer, has announced the launch of a bold, new research initiative. Through surveys among a nationally representative sample of thousands of people

is to more visibly and effectively represent the voice of people with cancer, advocate for their access to the best and most advanced care, and define and promote patient engagement

to enhance quality of life and optimize outcomes,” explained Patricia Goldsmith, CEO of CancerCare—a cancer survivor herself. “We have developed a unique research approach

that will use the Patient Activation Measure, a well-validated and widely used tool, to help us contextualize and understand the ways cancer patients are involved in their own care and en-

Patricia Goldsmith

with cancer, CancerCare will examine patients’ experiences and perceptions regarding access to care, clinical trials, treatment decisions, communication with providers, insurance and financial concerns, and end-of-life issues. “The goal of the CancerCare Patient Access and Engagement Report

Advisory Board

n advisory board of renowned experts in oncology and patient engagement is actively engaged in survey assessment for relevance to real-world issues and will be reviewing and interpreting the survey data. The members of the advisory board follow: Walter Baile, MD: Professor, Department of Behavioral Science, Division of OVP, Cancer Prevention and Population Sciences; Director, Program for Interpersonal Communication And Relationship Enhancement (I*CARE), The University of Texas MD Anderson Cancer Center, Houston Ethan Basch, MD, MSc: Director, Cancer Outcomes Research Program; Associate Professor, Medicine and Public Health, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina Jimmie Holland, MD: Wayne E. Chapman Chair in Psychiatric Oncology, Memorial Sloan Kettering Cancer Center, New York Marcia Kean, MBA: Chaircontinued on page 55

ASCOPost.com | AUGUST 10, 2015

PAGE 55

Announcements

gage with providers. Survey data will be assessed and interpreted by an advisory board of experts (see sidebar). We are also deliberately seeking a nationally representative sample of respondents that will be broader than the members of online communities and registries who are typically quite educated, vocal, and self-advocating.”

The report will be developed through six surveys on topics that include understanding of diagnosis, participation in treatment decisions, the role of caregivers, communication with the clinical care team, financial and insurance issues, quality of life and symptom management, and end-of-life care and hospice.

The final report will be available publically from the CancerCare website, www.cancercare.org, and is due for release at the end of the year. This project is being made possible by AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, Helsinn Therapeutics, US, Gilead Sciences, Incyte Corporation, Lilly, and PhRMA. n

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.

Advisory Board continued from page 54

man, Strategic Initiatives, Feinstein Kean Healthcare, Cambridge, Massachusetts Sandra Kurtin, RN, MSN, AOCN, ANP-C, Adjunct Associate Professor, The University of Arizona Cancer Center, Tucson Terry Langbaum, MHS: Chief Administrative Officer, Johns Hopkins Kimmel Cancer Center, Baltimore Michael Parisi, MBA: President, CancerCare Board of Trustees, and Managing Partner, Ogilvy CommonHealth Worldwide, New York Lee Schwartzberg, MD, FACP: Chief, Division of Hematology Oncology, The University of Tennessee Health Science Center, and Medical Director, The West Clinic, Memphis Michael K. Wong, MD, PhD, FRCPC: Berle and Lucy Adams Chair in Cancer Research, Professor of Clinical Medicine, and Section Chief, Solid Tumor, USC Norris Comprehensive Cancer Center, Los Angeles Thomas Workman, PhD: Principal Communication Researcher and Evaluator, American Institutes for Research, Washington, DC Patricia Goldsmith: Chief Executive Officer, CancerCare, New York Ellen Sonet, MBA, JD: Chief Strategy and Alliance Officer, CancerCare, New York n

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication

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.

The ASCO Post | AUGUST 10, 2015

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Pioneers in Oncology A Lasting Legacy

As Emil J Freireich, MD, gets ready to retire, he leaves behind a legion of oncology triumphs. By Jo Cavallo

hen Emil J Freireich, MD, retires from the University of Texas MD Anderson Cancer Center on September 1, he will have spent 50 years at the institution and a total of 60 years in the pursuit of curing childhood leukemia as well as other cancers and in the educational development of young physician-scientists. His accomplishments have earned him recognition as one of the legendary figures in the early history of oncology triumphs, alongside such other oncology luminaries as Emil “Tom” Frei III, MD; James Holland, MD; and C. Gordon Zubrod, MD. Born on March 16, 1927, just 2 years before the Great Depression, Dr. Freireich’s hardscrabble adolescence in the ghettos of Chicago did not portend a celebrated career in medicine. The son of Hungarian immigrants, Dr. Freireich was 2 years old when his father, David, died, forcing his mother, Mary, to take a job working very long hours each day in a hat factory to support her young son and daughter, Annette.

The Accidental Physician Hoping to prepare her son for a job after he completed high school, Mary encouraged him to study typing and shorthand, but in his senior year, Dr. Freireich’s physics teacher, spotting his intellect for science, steered him in another direction. “I loved physics and won first prize in a project I completed on Bernoulli’s principle of flight,” said Dr. Freireich. “My teacher said, ‘I think you’re smart enough to go to college. What would you like to do for your future?’ and my response was, ‘What is college?’ I had never heard of college.” At that moment, Dr. Freireich may not have understood the concept of college, but he had already made up his mind to be a doctor. “The ghetto neighborhoods of the 1930s were mostly populated by women, as the men were away all day digging ditches. The only man I ever saw was our family doctor, Dr. Rosenbloom. He worked for nothing and always wore a suit and tie and looked so dignified,” said Dr. Freireich. “So when my physics teacher asked me what I wanted to do, I thought about it a minute and said I wanted to be a doctor like Dr. Rosenbloom.” After securing the $25 necessary to apply to the University of Illinois in Champaign, Dr. Freireich worked menial jobs and received state aid to cover

his tuition and living expenses. With World War II now raging, university classes were accelerated, and after 15 months, Dr. Freireich graduated and moved back home to attend the University of Illinois College of Medicine at Chicago, graduating in 1949 at the age of 22. Still planning on becoming a family doctor, Dr. Freireich interned at Cook County Hospital, a public urban teaching hospital in Chicago, where he delivered 100 babies in a month and witnessed the inequities of medical care for the poor. “We would admit 20 to 25 patients a night, and the nurses would cull the dying patients from the living ones and put them in what they called the death room,” said Dr. Freireich. “A patient

army. He was later allowed to serve his time doing public health service at the fledgling National Institutes of Health (NIH), where he would alter the course of childhood leukemia for millions of children. “When I met Gordon Zubrod [then Clinical Director of the National Cancer Institute], he asked me what I did and I said that I had just completed my hematology fellowship, and he said I should cure leukemia. I said, ‘Yes, Sir.’ And I took it seriously,” said Dr. Freireich. The challenge forged a collaboration and friendship with his near-namesake Dr. Emil Frei, who was then Chief of the Leukemia Section and Medicine Branch at the National Cancer Institute (NCI), lasting until Dr. Frei’s death in

Medicine is man’s highest calling. Every day, including today, when I go to work, I help people, save lives, prolong lives, and relieve suffering. It doesn’t get any better than that. —Emil J Freireich, MD

had come into the hospital with heart failure and I worked hard on him and thought I could save him, but when I looked for him on the ward after I made rounds, a nurse said he was in the death room. I insisted that my patient be put back on the ward, but the nurse refused. The next morning, the hospital administrator called and fired me for being a troublemaker.”

Accepting the Charge to Cure Leukemia Determined more than ever to protect life and relieve suffering, Dr. Freireich went across the street to Presbyterian Hospital, where he became Chief Resident of Medicine but left soon after to do a fellowship in hematology at Mass Memorial Hospital in Boston. At Mass Memorial Hospital, a revolution in scientific medicine was underway, and Dr. Freireich subsequently made a discovery in anemia that led to the understanding of hemoglobin metabolism. By 1953, Dr. Freireich was on the fast track to a research faculty position when he was drafted into the

2013. This collaboration resulted in the development of multiagent combination chemotherapy, which led to cures in over 90% of children with acute lymphoblastic leukemia (ALL) and more effective treatments for various adult cancers, including Hodgkin lymphoma. In 1955, Drs. Freireich, Frei, and Zubrod devised a methodology for a controlled clinical trial in ALL to evaluate whether giving a combination of two effective antimetabolites—mercaptopurine and methotrexate—was more effective than giving the drugs sequentially. They were joined in this study, called Protocol I, by Dr. James Holland, who had begun the first combination chemotherapy program in acute leukemia at the NCI in 1953 and had left the Institute the following year to become Chief of Medicine and Director of the Cancer Clinical Research Center at Roswell Park Cancer Institute. The cooperative effort between the two institutions, called the Leukemia Group, became the basis of the development of the Cancer and Leukemia Group B (CALGB). The results of Protocol I confirmed

that the combination therapy was more effective in staving off cancer than giving the drugs sequentially.1 “Protocol I turned out to be quite important because it proved first of all how many children got responses to methotrexate, how many got responses to mercaptopurine, how long the responses lasted, and whether giving both drugs at the same time was better or worse,” said Dr. Freireich. “Everyone said it would be worse, because if you fail with the combination there is nothing else to give, whereas if you fail with one drug, you’ve got another one to use. But it turned out that the combination was better than the sequence, and we were off.”

Birth of the Randomized Trial The results from Protocol I were later tested in a larger three-arm trial called Protocol 2.2 That study, too, found that giving two agents simultaneously produced higher rates of remission than giving the drugs sequentially. “When Protocol 2 was being developed, 13 academic institutions had joined the study because by then everyone could see the road ahead was clear: Objective randomized clinical trials were the way to go,” said Dr. Freireich. The trials also helped to define quantitatively the natural history of childhood leukemia and provide early clues on the variables involved in treatment duration response and disease relapse. A third trial, Protocol 3,3 was launched in 1959 to test the efficacy of mercaptopurine vs placebo in maintaining clinical remissions in patients with ALL, a new concept at the time. The study results showed that not only was remission prolonged for patients treated with mercaptopurine, but also that a significant number of patients experienced a substantially prolonged remission—approximately 10% of patients were still in remission after over a year and a half of continued therapy. Although buoyed by the findings of these clinical trials, Dr. Freireich was devastated by the fact that many children brought to the NCI for treatment still died of their leukemia. “In the terminal stages of their disease, the children developed a hemorrhagic diathesis. They were bleeding to death before our eyes, and when we gave

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Pioneers in Oncology them these drugs, it made the bleeding worse,” said Dr. Freireich. “One day, Dr. Zubrod came on rounds to see how we were doing, and said, ‘Freireich, your ward has blood all over it, there is blood on the sheets, on the nurses’ uniforms, on the ceilings. Why don’t you do something about the bleeding?’ So that’s what I did.” Dr. Freireich examined the medical records of all the children and recorded their platelet counts. He found that there was a direct relationship between the degree of thrombocytopenia and the occurrence of hemorrhage. To prove his theory, Dr. Freireich collected platelets from his own blood and added them to the children’s blood. “Their clotting parameters immediately went to normal, and the bleeding stopped,” said Dr. Freireich. He then conducted a prospective randomized study4 of supportive platelet therapy in bleeding patients with acute leukemia, which showed that fresh blood was more effective in preventing hemorrhage than banked blood. “From that day forward, bleeding as a cause of death was essentially eliminated, and I consider that finding my greatest contribution to medicine, because we wouldn’t be able to treat patients with cancer today unless we had allogeneic platelet transfusions to prevent hemorrhage,” said Dr. Freireich. He later went on to develop the first continuous-flow blood cell separator, which collects peripheral blood stem cells for transplantation and is still used today in most pheresis centers.

Grooming the Next Generation of Physician-Scientists By 1965, Dr. Freireich had reached the limit of what he could accomplish in the leukemia program at the NIH and followed his friend and colleague Emil Frei to MD Anderson Cancer Center— now the University of Texas MD An-

derson Cancer Center—in Houston. There they established a chemotherapy program and launched the Department of Developmental Therapeutics, which has been instrumental in training the best minds in oncology. “We created the first grant to train fellows in medical oncology before there were boards in medical oncology,” said Dr. Freireich. “The people we have recruited and trained are all leaders in the field of oncology.” Some of the people Dr. Freireich has helped train include Kenneth B. McCredie, MD, who pioneered the use of combination agents, including interferon, in the 1980s; Michael J. Keating, MD, Professor of Medicine in the Department of Leukemia at MD Anderson and founder of the Chronic Lymphocytic Leukemia Global Research Foundation; and Hagop M. Kantarjian, MD, Department Chair of Leukemia at MD Anderson and an early developer of targeted therapy in the treatment of chronic myeloid leukemia. In addition to his landmark research and clinical work in leukemia, Dr. Freireich is renowned for the contributions he has made in medical education. He is the recipient of numerous awards for both his research and medical education efforts, including ASCO’s David A. Karnofsky Memorial Award and Lecture (1976), the First NIH Distinguished Alumni Award (1990), the Medical Oncology Fellows Outstanding Teacher Award, MD Anderson Cancer Center (1996), the Pollin Prize for Pediatric Research, Columbia University (2003), and the Paul Ehrlich Magic-Bullet Lifetime Achievement Award (2008), among others. Dr. Freireich became Director of MD Anderson’s Adult Leukemia Research Program in 1985 and is currently the cancer center’s Ruth Harriet Ainsworth Chair; Distinguished Teaching Professor; Director, Adult Leukemia Research Program; and Director, Special Medical Education Programs. Al-

though he is no longer doing research or seeing patients, Dr. Freireich plans to continue to be involved in the center’s medical education program and in Institutional Grand Rounds, which consists of weekly lectures of advances in oncology presented to faculty members and trainees, after he officially retires in September. “Dr. Freireich was a true pioneer that challenged the conventional wisdom at the time with a very high level of both courage and sense of urgency that changed the standard of care for children with cancer in a way that allowed those children to grow up to be grandparents,” said Ronald DePinho, MD, President of The University of Texas MD Anderson Cancer Center. “I’m very proud that he is a member of our faculty and very proud of the accomplishments that he and others made at that critical point in the history of the field, and it is my hope and aspiration that we can apply similar courage and urgency to the challenges that patients face today with leukemias and solid tumors.”

men. I have a wonderful wife and a beautiful family. I have had the privilege of working with outstanding people and have been blessed every day,” said Dr. Freireich. “I have also been fortunate to have opportunities that very few people have, and, of course, the secret of success is to grab opportunities when you see them. I’m good at that.”

The Love of Family and Friends

References 1. Frei E III, Holland JF, Schneiderman MA, et al: A comparative study of two regimens of combination chemotherapy in acute leukemia. Blood 13:1126-1148, 1958. 2. Frei E III, Freireich EJ, Gehan EA, et al: Studies of sequential and combination antimetabolite therapy in acute leukemia: 6-Mercaptopurine and methotrexate. Blood 18:431-454, 1961. 3. Freireich EJ, Gehan EA, Frei E III, et al: The effect of 6-mercaptopurine on the duration of steroid-induced remissions in acute leukemia: A model for evaluation of other potentially useful therapy. Blood 21:699-716, 1963. 4. Freireich EJ, Schmidt PJ, Schneiderman MA, Frei E III: A comparative study of the effect of transfusion of fresh and preserved whole blood on bleeding in patients with acute leukemia. N Engl J Med 260:611, 1959.

When asked to assess his life’s accomplishments, Dr. Freireich praised the work of Drs. Frei and Zubrod and the good fortune he had to be their friend. “I was friends with Emil Frei until the day he died,” said Dr. Freireich. “I loved Emil Frei and Gordon Zubrod. They were two enormously competent, compassionate, and intelligent people, and I was very lucky to be at the NIH during their tenure.” He also credits his wife of 62 years, Haroldine Lee Cunningham Freireich, with making it possible for him to attain his professional goals and providing him with a grounded family life. “My wife is the secret to my academic success,” he said. “She is just the most wonderful partner in life.” Dr. Freireich and his wife have four children, six grandchildren, and two great-grandchildren. “I have been the most fortunate of

Medicine Is Man’s Highest Calling Looking at what lies ahead, Dr. Freireich is optimistic about his future and the future of patients with cancer. “We will always have cancer, but we are curing cancers every day, and patients are doing great things after their disease,” said Dr. Freireich. “It’s the wonder of medicine. Medicine is man’s highest calling. Every day, including today, when I go to work, I help people, save lives, prolong lives, and relieve suffering. It doesn’t get any better than that.” n

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

Save the Date November 5-8, 2015 JW Marriott Phoenix Desert Ridge

Learn more at jadprolive.com A CE/CME Conference for Advanced Practitioners in Oncology

For conference exhibitor or sponsorship opportunities, contact David Horowitz at 631-935-7658 or email at david@harborsidepress.com

DISCOVERING HOW FAR THERAPY CAN GO IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®. The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA®. Monitor patients for fever and infections and evaluate promptly. Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification. Second Primary Malignancies - Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%). Tumor Lysis Syndrome - Tumor lysis syndrome has been reported with IMBRUVICA® therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. 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.

IMBRUVICA® (ibrutinib) is the ﬁrst and only FDA-approved therapy for use in patients with Waldenström’s macroglobulinemia (WM) IMBRUVICA® is approved for use in 4 indications IMBRUVICA® is indicated for the treatment of patients with Mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Chronic lymphocytic leukemia with 17p deletion. Waldenström’s macroglobulinemia (WM).

ADVERSE REACTIONS The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 52%, 43%), neutropenia* (47%, 51%, 44%), diarrhea (51%, 48%, 37%), anemia* (41%, 36%, 13%), fatigue (41%, 28%, 21%), musculoskeletal pain (37%, 28%†, NA‡), bruising (30%, 12%†, 16%†), nausea (31%, 26%, 21%), upper respiratory tract infection (34%, 16%, 19%), and rash (25%, 24%†, 22%†). *Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased). † Includes multiple ADR terms. ‡ Not applicable; no associated ADRs. The most common Grade 3 or 4 non-hematological adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%). Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse events. Approximately 5% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse events. Most frequent adverse © Pharmacyclics LLC 2015 © Janssen Biotech, Inc. 2015 06/15 PRC-01166

events leading to discontinuation were infections, subdural hematomas, and diarrhea in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS CYP3A Inhibitors - Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose. CYP3A Inducers - Avoid co-administration with strong CYP3A inducers. SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA® dose. Please review the Brief Summary of full Prescribing Information on the following pages.

To learn more, visit

www.IMBRUVICA.com

Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICA® (ibrutinib) capsules

INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in Full Prescribing Information]. Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in Full Prescribing Information]. Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in Full Prescribing Information]. Waldenström’s Macroglobulinemia: IMBRUVICA is indicated for the treatment of patients with Waldenström’s macroglobulinemia (WM) [see Clinical Studies (14.3) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in Full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. [See Adverse Reactions]. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly. Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in Full Prescribing Information]. Second Primary Malignancies: Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11 %). Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. 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 Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Cytopenias [see Warnings and Precautions] • Atrial Fibrillation [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience: Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis Fatigue Peripheral edema Pyrexia Asthenia

All Grades (%) 51 31 25 24 23 17 11 34 14 14 14 13 41 35 18 14

Grade 3 or 4 (%) 5 0 0 5 0 1 0 0 3 7 5 1 5 3 1 3

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) (continued) System Organ Class

Preferred Term

Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

All Grades (%)

Grade 3 or 4 (%)

30 25 11 37 14 11 27 19 11 21 12 14 13

0 3 0 1 0 0 4 0 0 2 4 0 0

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. Approximately five percent of patients receiving IMBRUVICA in Study 1 and Study 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 All Grades (%)

Grade 3 or 4 (%)

Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection Fatigue Pyrexia Peripheral edema Asthenia Chills Bruising Rash Petechiae Cough Oropharyngeal pain Dyspnea Musculoskeletal pain Arthralgia Muscle spasms Dizziness Headache Peripheral neuropathy Decreased appetite

63 23 21 21 19 15 13 48 21 17 10 10 31 25 23 13 13 54 27 17 19 15 10 27 23 19 21 19 10 17

4 2 2 0 2 0 0 2 6 6 8 0 4 2 0 4 0 2 0 0 0 0 0 6 0 2 0 2 0 2

Second malignancies*

10*

Laceration

Anxiety Insomnia Hypertension

10 10 17

0 0 8

System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders Metabolism and nutrition disorders Neoplasms benign, malignant, unspecified Injury, poisoning and procedural complications Psychiatric disorders Vascular disorders

Preferred Term

*One patient death due to histiocytic sarcoma.

IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenström’s Macroglobulinemia (N=63) (continued)

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) 71 10 54 27 44 0

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2. Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Vomiting General disorders and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue disorders Rash* Petechiae Bruising* Musculoskeletal and connective tissue disorders Musculoskeletal Pain* Arthralgia Nervous system disorders Headache Dizziness Injury, poisoning and procedural complications Contusion Eye disorders Vision blurred

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%)

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%)

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

28 17

2 1

18 7

1 0

14 11

1 0

6 5

0 0

Subjects with multiple events for a given ADR term are counted once only for each ADR term. The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%) 51 23 52 5 36 0

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%) 57 26 45 10 21 0

* Based on laboratory measurements per IWCLL criteria Waldenström’s Macroglobulinemia The data described below reflect exposure to IMBRUVICA in an open label clinical trial that included 63 patients with previously treated WM. The most commonly occurring adverse reactions in the WM trial (≥ 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue. Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients. Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 reflect exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial. Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenström’s Macroglobulinemia (N=63) System Organ Class Gastrointestinal disorders Skin and subcutaneous tissue disorders

Preferred Term Diarrhea Nausea Stomatitis* Gastroesophageal reflux disease Rash* Bruising* Pruritus

All Grades (%) 37 21 16 13 22 16 11

Grade 3 or 4 (%) 0 0 0 0 0 0 0

System Organ Class

Preferred Term Fatigue

All Grades (%) 21

Grade 3 or 4 (%) 0

General disorders and administrative site conditions Musculoskeletal and connective tissue disorders Infections and infestations

Muscle spasms Arthropathy

21 13

0 0

Respiratory, thoracic and mediastinal disorders Nervous system disorders Neoplasms benign, malignant, and unspecified (including cysts and polyps)

Upper respiratory tract infection Sinusitis Pneumonia* Skin infection* Epistaxis Cough

19 19 14 14 19 13

0 0 6 2 0 0

Dizziness Headache Skin cancer*

14 13 11

0 0 0

The system organ class and individual ADR terms are sorted in descending frequency order. * Includes multiple ADR terms. Table 8: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with WM (N=63)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=63) All Grades Grade 3 or 4 (%) (%) 43 13 44 19 13 8

* Based on laboratory measurements. Postmarketing Experience: The following adverse reactions have been identified during postapproval use of IMBRUVICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in Full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in Full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Nursing Mothers: It is not known whether ibrutinib 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 IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in Full Prescribing Information]. Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), and infections (pneumonia and urinary tract infection) occurred more frequently among elderly patients.

IMBRUVICA® (ibrutinib) capsules Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Hepatic Impairment: Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The safety of IMBRUVICA has not been evaluated in patients with hepatic impairment. Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. Plasmapheresis: Management of hyperviscosity in patients with WM may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions]. • Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. • Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions]. • Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in Full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in Full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration. Active ingredient made in China. Distributed and Marketed by: Pharmacyclics LLC Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics LLC © Pharmacyclics LLC 2015 © Janssen Biotech, Inc. 2015

PAGE 62

The ASCO Post | AUGUST 10, 2015

In Memoriam

Charles Rubin, MD, Pediatric Cancer Specialist, Dies at 62

harles M. Rubin, MD, Associate Professor of Pediatrics at the University of Chicago Medicine, a highly respected specialist in the care of children with cancer, died on July 17. He was 62.

men. His dedication to his family, his patients, and the University of Chicago was selfless and unparalleled. It was a privilege to work with him and an honor to learn from his example.”

Long Affiliation With University of Chicago

Charles M. Rubin, MD

An authority on all aspects of pediatric cancers, Dr. Rubin had a particular interest in brain tumors and cancer occurring in children with genetic syndromes. He combined considerable experience in basic laboratory research on the genetics of cancer with broad clinical expertise and a talent for informing, calming, comforting, motivating, and inspiring patients and their families.

Colleagues Remember Him “I can’t put into words how much I respected him,” said his colleague Tara Henderson, MD, Associate Professor of Pediatrics and Director of the Childhood Cancer Survivors Center at the University of Chicago’s Comer Children’s Hospital. “He was amazingly knowledgeable, compassionate and thoughtful—traits at the core of our program. I take his influence with me as I care for my patients.” The Head of Pediatrics remembered Dr. Rubin for his trusted guidance and his ability to put patients and colleagues at ease. “Chuck was highly respected by his research and clinical colleagues and was a popular mentor, not only for many medical students and pediatric residents, but also for fellows and junior faculty,” said John Cunningham, MD, Donald N. Pritzker Professor and Interim Chair of the Department of Pediatrics at the University. “Even his senior colleagues sought his ideas and counsel frequently on complex pediatric oncology and hematology problems.” “Chuck Rubin was one of the finest individuals I have ever known,” said Michelle Le Beau, PhD, Director of the University of Chicago Medicine Comprehensive Cancer Center. “He was a consummate academician and physician who blended compassion and sensitivity with brilliant clinical acu-

Dr. Rubin earned his medical degree from Tufts University School of Medicine in 1979. He completed his pediatric residency at the Children’s Hospital of Philadelphia in 1982, followed by a fellowship in pediatric hematology/ oncology at the University of Minnesota in 1985. He came to the University of Chicago in 1985 as a cytogenetics and molecular biology fellow in the laboratory of Janet Rowley, MD, an internationally recognized pioneer in understanding the genetics of cancer. Dr. Rubin joined the faculty as an Assistant Professor of Pediatrics and Medicine and a member of the University’s Cancer Research Center in 1987. In 1991, he and Funmi Olopade, MD, cofounded the University’s nationally recognized Cancer Risk Clinic. Although he continued to work closely with his basic science colleagues, contributing to more than 50 original reports in academic journals, his interests increasingly focused on patient care. At the same time, he took on several administrative roles. He served as Course Director for pediatric grand rounds and the medical center’s pediatric tumor board. He directed the pediatric hematology/oncology fellowship for 7 years and the pediatric neuro-oncology program for 10 years. He also volunteered for medical staff positions in various educational and rehabilitative summer camps for children with cancer. Dr. Rubin also was a leader in the University of Chicago Medicine’s efforts to take a research-driven approach to pediatric cancer care into the community, serving as Director of Pediatric Hematology/Oncology Outreach since 2008. Dr. Rubin is survived by his wife, Gretchen; their four daughters, Elizabeth, Jane, Lucy and Claire; brothers Michael, Peter and Richard; and many nieces and nephews. Donations may be made to the Charles M. Rubin Memorial Fund, Department of Pediatrics, University of Chicago, 5721 S. Maryland Ave, Chicago, IL 60637. n

ASCOPost.com | AUGUST 10, 2015

PAGE 63

Adolescent and Young Adult Oncology Advance Care Planning

The Importance of Including Adolescents and Young Adults With Cancer in Their Advance Care Planning A Conversation With Chris Feudtner, MD, PhD, MPH By Jo Cavallo

hree years ago, a study of adolescents and young adults aged 16 to 28 with metastatic or recurrent cancer or HIV/AIDS compared the usefulness of two previously developed advance care planning guides—one prepared specifically for adolescents and young adults and one specifically for adults. The study revealed that at the top of the list of concerns by adolescents and young adults were that they be allowed to choose the kind of care and medical treatment they wanted and to express their wishes to family and friends about how they wanted to be remembered.1

feel less alone or isolated, according to Chris Feudtner, MD, PhD, MPH, Director of the Department of Medical Ethics; Attending Physician and Director of Research for the Pediatric Advance Care Team at the Children’s Hospital of Philadelphia; and Professor of Pediatrics, Medical Ethics and Health Policy at the Perelman School of Medicine at the University of Pennsylvania. Although end-of-life directives have largely focused on the medical wishes of adult patients, over the past decade, there has been a growing movement by physicians to include discussions about

Before children or adolescents are developmentally ready to assent or dissent to a particular treatment course, they may be developmentally ready and eager to be given the chance to provide input regarding how they want to be treated. —Chris Feudtner, MD, PhD, MPH

The result of the study findings is oicing My Choices™: A Planning Guide V for Adolescents & Young Adults, which includes areas for adolescents and young adults to provide input on their medical care decisions, such as the type of life support treatment they want, how they want to be cared for and supported during their illness, who they want making medical decisions if they no longer can make them, and how they want to be remembered after death. The booklet can be previewed and ordered at agingwithdignity.org. According to the National Cancer Institute, over 69,000 adolescents and young adults between the ages of 15 and 39 were diagnosed with cancer in 2011, about six times the number of cases diagnosed in children under the age of 15. Only accidents, suicide, and homicide claimed more lives in this age group than cancer.2 Being able to participate in their own care plan and state their end-oflife wishes while they are still healthy enough to take part helps young patients get back some sense of independence and control and provides them with a chance to write their legacy and

advance care planning with their terminally ill young patients, said Dr. Feudtner. The ASCO Post talked with Dr. Feudtner about the importance of talking with adolescents and young adults about their end-of-life wishes and the potential ethical dilemmas posed by these conversations.

Emotionally Difficult Conversations Please talk about the attention now being paid to the end-of-life concerns of adolescents and young adults with terminal cancer. Health-care providers have been discussing the need to talk to children, adolescents, and young adults about the nature of their health in compassionate but truthful terms for 40 years. About 10 years ago, a broader movement started taking shape regarding how to take the adult concept of advance care planning and customize it for young patients. Although it sounds like a good thing to do in theory, there are logistical challenges to overcome, such as where to record these directives and how to cope with the emotional challenges of having

these conversations. Even if it is ethically the right thing to do, these conversations are emotionally difficult for physicians. Many physicians think of these conversations as depressing and disturbing, but they can have good outcomes for both adolescents and young adults, who are given an opportunity to have this important discussion, and their family members, because their loved ones also benefit from learning about patients’ wishes for end-of-life care.

A Matter of Control Is one of the main benefits of including adolescents and young adults in discussions about their end-of-life care that it gives them back some sense of control over their life? That is one important aspect of advance care planning discussions. Adolescents and young adults often report that they feel these conversations give them a voice and some control. They feel empowered to be who they are and also to express the reality of the situation; and given that reality, they have the opportunity to express what they care about. This is their experience; they are the ones who are most intimately involved with the situation, and this gives them an avenue to talk about it. So, yes, it’s a control issue, but it also gives young patients the ability to be who they are and provides them the chance to leave a written legacy of their life, how they want to be remembered, and their hopes for their loved ones.

When to Talk: Sooner Than Later How can oncologists start this difficult dialogue with their patients, and when should these conversations begin? Some physicians are reluctant to initiate advance care planning conversations because they think the timing is not right, or maybe it is going to be too upsetting for patients and their family members. We all should look at this as an area of medical care that can be improved and search for ways to get better at having these conversations. For example, physicians can introduce the topic by saying: “I promised you I’d always be straightforward. While there is nothing new that we

GUEST EDITOR

Brandon Hayes-Lattin, MD, FACP

dolescent and Young Adult Oncology explores the unique physical, psychosocial, social, emotional, sexual, and financial challenges adolescents and young adults with cancer face. The column is guest edited by Brandon HayesLattin, MD, FACP, Associate Professor of Medicine and Medical Director of the Adolescent and Young Adult Oncology Program at the Knight Cancer Institute at Oregon Health and Science University in Portland, Oregon; Senior Medical Advisor to the LIVESTRONG Foundation; and Chief Medical Officer of Critical Mass: The Young Cancer Alliance.

need to worry about, I feel that I owe it to you to have a ‘just in case’ discussion about how you would want me to take care of you if you were to get really sick and were unable to tell me what you wanted.” Physicians can also say, “Many patients with cancer appreciate having the chance to talk about what matters most to them in case some day they get really sick and can’t tell people what they want in terms of their care.” They can also use some of the tools available in Voicing My Choices to help guide these conversations. If a physician does not personally feel comfortable facilitating this type of discussion, he should enlist the help of someone on the interdisciplinary clinical team who does, because the comfort level of the facilitator will have a big impact on how comfortable the adolescents and young adults feel about engaging in the discussion. In terms of when to start the talk continued on page 64

The ASCO Post | AUGUST 10, 2015

PAGE 64

Adolescent and Young Adult Oncology Chris Feudtner, MD, PhD, MPH continued from page 63

about death and dying, the answer is we don’t know for sure. There is no evidence to show that there is a “best time.” What I can say is that when adolescents and young adults are given an opportunity to think about advance care planning while they are still fairly healthy, they do not object to it. They seem gratified to be given the chance to talk about something they know is a scary possibility and don’t slip into magical thinking that because they are talking about death when they are still healthy, it inevitably means they are not going to survive. In addition, they also may not be depressed by the c onversation. I don’t know that we will ever be able to say with certainty what the best timing is for such a conversation, but the feeling among many physicians that having these discussions too early is somehow a bad thing does not seem to be true. The conversation should be offered as an option sooner rather than later because it does not appear to be harmful. But you must keep in mind that adolescents and young adults are individuals, and they should have a say in when this conversation would make sense and be meaningful to them.

The Ethics of Patient Autonomy If a patient is under the age of 18, do you need permission from the parents before these discussions can begin? This question addresses the ethics of autonomy of the patient, specifically for a child or adolescent who over time has an emerging capacity for autonomy, and how to respect this emerging autonomy while at the same time also respecting the responsibility and authority of parents to safeguard the well-being of their child. At both a conceptual and a practical level, it does not make sense to disregard parents by not involving them in the timing of these conversations. So one wants to approach parents with deep respect for their commitment to their children and their authority to make treatment decisions until their children are 18 or emancipated. At the same time, you want be aware this is a very stressful situation for parents, and the conversation is going to be difficult not just potentially for the adolescent and young adult, but also for the parents. So what we want to do is support all of them in having this conversation and help them to realize that although the conversation will be challenging, it is something they may have already been thinking and worry-

ing about. If they can hear each other talk through the issues they are confronting, it allows them the opportunity to join together and support each other, rather than be opposed or apart from each other. What are some other ethical issues physicians may confront as a result of initiating end-of-life discussions with their young patients? There are basically two issues. One is how to navigate the space between a child’s emerging autonomy of adolescence and not just respect that autonomy but enable it to develop. If you don’t engage younger adolescents in discussions about what they are going through and the treatments they are going to receive—and elicit their input— it is going to be difficult later on as their cancer progresses to transition them suddenly to the point where they have to cope with the inevitability of what is happening and make all of their decisions on their own. It is better for younger patients to acquire the ability to make good choices for their own health by giving them the chance to have real informed input about what types of choices will be made on their behalf and that informed input might actually shift from decisions that are made for them to decisions that are made by them. There is more of a role over time for informed input in medical decisions. Some people call it “informed assent,” but I would broaden that concept beyond informed assent. It is rather “informed input,” which means that rather than giving someone an option either to assent or not, the patient can talk about what matters to him (or her) in terms of treatment or end-of-life care, is informed about the process of figuring out what is the right thing to do, and is given the opportunity to be involved in care decisions. In other words, before children or adolescents are developmentally ready to assent or dissent to a particular treatment course, they may be developmentally ready and eager to be given the chance to provide input regarding how they want to be treated. The second ethical consideration is to be honest with them about the degree to which they are going to be able to craft the treatment to fit their preference. We have to be sure not to overpromise or misrepresent our commitment to honor their preferences. If we are going to seek patients’ assent, we also need to honor their “dissent” about what they do not want at the end of life. And since we often are

not willing to honor patients’ dissent, we have to be careful not to make promises we are not willing to keep. The bottom line is if we are going to involve adolescents in decisions about what the best thing is to do for them, we have to involve them with the utmost integrity, assuring them that we will honor our commitments to the promises we made about their preferences and their views. It is better to be straightforward about our lack of commitment to honor our young patients’ preferences than to make a promise and not live up to it.

A Sense of Connectedness Does including adolescents and young adults in the decision-making of their endof-life care help them accept death? I don’t use the phrase “accept death.” I don’t believe we fully understand what goes on in the minds of people as they actively start to die. In my practice, I have observed that sometimes when patients decline, they often become isolated and lonely. Having a conversation about what might happen once this process begins and asking patients how they want to be cared for allow them to have a stronger connectedness with their loved ones, and then they don’t feel as isolated.

And because of that connectedness, I have observed that patients are calmer and more comforted. I think people want to believe their loved one accepted death, because it is easier to cope with the loss of that person, but I don’t know that it is true. Our goal is to figure out whether we can help people feel connected vs separate and calm vs panicky as they are dying. We have no scientific evidence that having these conversations results in end-of-life care that helps patients feel more connected and calmer, but we have reason to believe that it is true. What scientific data do show is that having these conversations does not appear to upset people and that there is a general sense of appreciation for having had the conversation. n

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

References 1. Wiener L, Zadeh S, Battles H, et al: Allowing adolescents and young adults to plan their end-of-life care. Pediatrics 130:897-905, 2012. 2. National Cancer Institute: A snapshot of adolescent and young adult cancers. Available at http://www.cancer.gov/ research/progress/snapshots/adolescentyoung-adult. Accessed July 14, 2014.

San Jacinto Park, Palm Springs

San Jacinto Park, Palm Springs, California. The Palm Springs Aerial Tramway ascends 8,000 feet high above the desert to a beautiful forest with hiking trails that stretch for miles. Photo courtesy of Chase Doyle, Copyright 2015. ChaseDoyle.com

ASCOPost.com | AUGUST 10, 2015

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Announcements

AACR Launches New Funding Initiative to Promote Innovative Research From Young Investigators

he American Association for Cancer Research (AACR) is pleased to announce the launch of the AACR NextGen Grants for Transformative Cancer Research, a new funding initia-

tive to stimulate highly innovative research from young investigators. This new grant mechanism is intended to promote and support creative, paradigm-shifting cancer research

that, because of its very nature, may not otherwise be funded through existing channels. “The AACR NextGen Grants for Transformative Cancer Research rep-

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resent an exciting new initiative to provide funding to young investigators who are working on projects that have the potential to lead to major breakthroughs in the field of cancer research,” said Carlos L. Arteaga, MD, AACR Immediate Past-President, and the Donna S. Hall Vhair in Breast Cancer Research and Director of the Center for Cancer Targeted Therapies at Vanderbilt-Ingram Cancer Center. “Young investigators are vital to our future progress against cancer because they are the source of many of the most novel, ambitious, and transformative ideas in cancer research. We at the AACR are proud to be able to offer them this mechanism of support.”

Carlos Arteaga, MD

Grant Requirements Eligibility will be limited to junior faculty who, at the start of the grant term, have held a full-time, tenure-track appointment as an assistant professor for no more than 3 years. The proposed research must represent a highly innovative approach to a major contemporary challenge in cancer research. The funded projects must have the potential to lead to groundbreaking discoveries in the field, and transform our understanding of the tumorigenesis process and/or our ability to treat, detect, or prevent cancer. The research can be in any area of basic, translational, or clinical science. The grants will provide a total of $450,000 over a period of 3 years, beginning July 1, 2016. The recipients will formally accept the grants at the AACR Annual Meeting 2016, to be held April 16–20, in New Orleans. Letters of intent must be submitted by noon Eastern Time, August 10, 2015, using the proposalCENTRAL website (https://proposalcentral.altum.com). Additional inquiries may be directed to Ashley Jones at grants@aacr.org. Further details are available at http://www.aacr.org/Funding/Pages/ Funding-Detail.aspx?ItemID=48#. VY2XV84ii-I. n

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Perspective

Cost vs Our Values in Cancer Care By Richard J. Boxer, MD, FACS ditional 4 months of life is rational given our nation’s fiscal constraints? Does it make sense to prolong a life (or prolong the onset of death) by a few months with such a hefty price

tag when the money might be better spent to address the desperate needs of many others in the country? The cost of cancer care as measured by the value in increased life,

especially quality of life, has commonly been a discussion about the impact on the individual, and there is great reason for that. However, there should be room for the cost

n 80-year-old patient with metastatic prostate cancer asked me to discontinue his treatments, which were costing him more than $1,000 every 3 months. Although he had Medicare, he did not have secondary insurance. I told him that I would seek compassionatecare payment from the pharmaceutical company, but he insisted. I was perfectly willing to accept Medicare as the only

Science always races ahead of our moral, philosophical, and ethical understanding. —Richard J. Boxer, MD, FACS

payment, but in the perverse rules of the Centers for Medicare and Medicaid Services, it is a crime to accept Medicare as payment in full because then I am “overcharging” Medicare. A colleague tells me that being compassionate by not charging the patient the co-pay is a crime in Nebraska. This is the best definition of “No good deed goes unpunished.” The gentleman knew he was going to die soon and that the money expended now for a few more months of life would be essential for his wife after he was gone. He died later that year, without receiving any more treatment.

Societal Costs of Cancer Care Science always races ahead of our moral, philosophical, and ethical understanding. Can we honestly say that the present or future $100,000/year miracle medication that gives an adDr. Boxer is Voluntary 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.

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Perspective

to society in that discussion. Science creates targeted therapies, but should there be a targeted future with a rationale? Cost-effectiveness analysis, intensely discussed 7 years ago, provoked our understanding of the issue of value (of care) and values (of humanity).1 Studying the effect of

new treatments on quality-adjusted life-years brings some measure of rationale to the discussion. However, as Douglas Owens said in his editorial, “Cost-effectiveness analysis is a tool that cannot substitute for value judgments. We must still decide how much money we are willing to spend to improve our health.”1

So where does this leave our cancer care community? We must continue to push the envelope in basic and clinical research to find the next discovery that will lead to improved treatments, prevention of disease, cures, and quality-adjusted life-years but should never forget that we live in a complex society, where the value placed on life should

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not prolong inevitable death at the expense of society as a whole. n

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

Reference 1. Owens DK: Interpretation of costeffectiveness analyses. J Gen Intern Med 13:716-717, 1998.

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Announcements

Daratumumab Expanded Access Program Open to Eligible U.S. Patients With Heavily Pretreated Multiple Myeloma

anssen Biotech, Inc, announced the opening of a daratumumab expanded access program for eligible patients in the United States. Daratumumab is an investigational human anti-CD38

monoclonal antibody being evaluated in clinical trials as a treatment for patients with multiple myeloma. The multicenter, open-label expanded access program is available to multiple

myeloma patients who are refractory to both a proteasome inhibitor and an immunomodulatory drug, or who have received three or more prior lines of therapy, including a protea-

some inhibitor and an immunomodulatory drug.

Urgent Need “We understand that heavily pre-

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Announcements

treated or double-refractory patients are in immediate need of new treatment options,” said Craig Tendler, MD, Vice President of Late Development and Global Medical Affairs, Oncology at Janssen. “Through a research collaboration with the Multiple Myeloma Research Foundation (MMRF), we have broadened our

network of sites and sped site activation. Our goal is to provide timely access to daratumumab for multiple myeloma patients who may benefit while its application is under review with the U.S. Food and Drug Administration (FDA). MMRF’s significant experience in multiple myeloma research and innovation has helped to

accelerate our efforts to meet this urgent patient need.” “While we work urgently each day to find solutions for all who are fighting multiple myeloma, our most critical focus is for those individuals whose multiple myeloma has relapsed and often have few or no active treatment options,” commented Walter

M. Capone, Chief Executive Officer and President of the MMRF. In the United States, expanded access programs are conducted as clinical trials and designed to make investigational medicines available for patients with serious or life-threatening illnesses who are ineligible for ongoing interventional trials and have exhausted currently available treatment options. Up to 40 medical centers in the United States will enroll patients in the daratumumab expanded access program. The MMRF played a key role in identifying sites geographically distributed across the country and opening sites for enrollment.

Regulatory History

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On May 1, 2013, daratumumab received Breakthrough Therapy designation from the FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory drug, the current standards of care, or who are doublerefractory to a proteasome inhibitor and an immunomodulatory drug. On June 5, 2015, Janssen announced it had initiated the rolling submission of its biologics license application for daratumumab to the FDA for the treatment of this set of multiple myeloma patients. A rolling submission allows the company to submit portions of the regulatory application to the FDA as they are completed. The regulatory submission for daratumumab will be primarily supported by data from the phase II MMY2002 (SIRIUS) monotherapy study announced in May 2015 at the 2015 ASCO Annual Meeting, along with additional data from four other studies, including the phase I/II GEN501 monotherapy study. The expanded access protocol has specific inclusion and exclusion criteria for patients to be considered for enrollment in the program, and patients must not be eligible for another daratumumab study. Interested patients should contact their physician to discuss whether they may be a candidate for daratumumab through the expanded access protocol. Additional information about the expanded access protocol can be found on the National Institutes of Health website ClinicalTrials.gov (search with identifier NCT02477891). n

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2015-2016 2015 Oncology Oncology Meetings Meetings August 6th Annual Pain Management Symposium: From Evidence to Clinical Practice August 20-21 • Pasadena, California For more information: http://boa.asco.org/ World Congress on Cancer and Prevention Methods August 27-29 • Dubai, United Arab Emirates For more information: http:// scientificfuture.com/oncology-2015/ 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

International Palliative Care Workshop September 3-5 • Fez, Morocco For more information: www.asco.org/ international-programs/internationalpalliative-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 The International Liver Cancer Association’s 9th Annual Conference September 4-6 • Paris, France For more information: www.ilca2015.org

European Society for Medical Oncology Academy 2015 August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

24th Annual Symposium on Molecular Pathology: Clinical Applications of Genomic Medicine September 16-17 • Troy, Michigan For more information: http://cmetracker.net/BEAUMONT/ The Inaugural International Cancer Immunotherapy Conference: Translating Science Into Survival September 16-19 • New York, New York For more information: http://www.aacr.org/Meetings/ Pages/MeetingDetail.aspx?Even tItemID=54&DetailItemID=309#. VXcJKVXtmko

29th Annual Canadian Association of Radiation Oncology (CARO) Annual Scientific Meeting September 9-12 • Kelowna, Canada For more information: www.caro-acro.ca

September

American Society of Head and Neck Radiology (ASHNR) Annual Meeting September 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ ashnr-annual-meeting/

2015 World Molecular Imaging Congress September 2-5 • Honolulu, Hawaii For more information: www.wmis.org/meetings/

Perspectives in Melanoma XIX September 11-12 • Cleveland, Ohio For more information: http://imedex.com/perspectivesmelanoma-conference/index.asp

The Annapolis Breast Cancer Genomics Conference September 18 • Annapolis, Maryland For more information: http://www.eventbrite.com/e/theannapolis-breast-cancer-genomicsconference-cme-7-cme-creditsregistration-16864239394 3rd Annual Hematology/Oncology Pharmacy Association (HOPA) Oncology Pharmacy Practice Management Program September 18-19 • Chicago, Illinois For more information: www.hoparx. org/education/2015-PracticeManagement-Program/2015-practicemanagement-program-welcome.html 2nd International Symposium of the Cancer Research Center of Lyon September 21-23 • Lyon, France For more information: www.crclsymposium2015.fr

16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org 25th World Congress of Lymphology September 7-11 • San Francisco, CA For more information: www.lymphology2015.com

August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/

2015-2016 2015

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

4th Annual Conference on Immunotherapy in Pediatric Oncology (CIPO2015) September 25-26 • Seattle, Washington 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 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, Maryland For more information: http://medschool.umaryland.edu/ ihvmeeting/default.html continued on page 72

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The ASCO Post | AUGUST 10, 2015

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2015

2015 Oncology Meetings continued from page 70

5th World Congress on Cancer Therapy September 28-30 • Atlanta, Georgia For more information: http://cancer.global-summit.com/ americ

October Advances in Cancer ImmunotherapyTM October 2 • Nashville, Tennessee For more information: www.sitcancer.org/sitc-meetings/ aci2015/tn Institute for Clinical ImmunoOncology (ICLIO) 1st Annual National Conference October 2 • Philadelphia, Pennsylvania For more information: http://accc-iclio.org/events/iclio-1stannual-national-conference/ 5th International Breast Cancer Prevention Symposium October 2-3 • Le Gosier, Guadeloupe, French West Indies For more information: www.purdue.edu/breastcancer/

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

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 Anniversary Annual Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis, and Immunology October 5-8 • Cambridge, MA For more information: http://cmeregistration.hms.harvard. edu/events/30th-anniversaryannual-critical-issues-in-tumormicroenvironment-angiogenesismetastasis-and-immuno/ event-summary-567a0dd5664947b09 6f8a5fd33946e52.aspx

ASTRO’s 57th Annual Meeting October 18-21 • San Antonio, Texas For more information: www.astro.org/Meetings-andEvents/2015-Annual-Meeting/Index. 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

Lymphoma & Myeloma 2015: An International Congress on Hematologic Malignancies October 22-24 • New York, New York For more information: http://www.imedex.com/lymphomamyeloma-conference/index.asp

Society for Immunotherapy of Cancer 30th Anniversary Annual Meeting November 4-8 • National Harbor, Maryland For more information: www.sitcancer.org/2015

13th Annual West Coast Colorectal Cancer Symposium October 23 • Seattle, Washington http://www.swedish.org/for-healthprofessionals/cme/conferences/ colorectal-cancer-symposium

JADPRO Live at APSHO for Advanced Practitioners in Oncology November 5-8, 2015 • Phoenix, Arizona JW Marriott Desert Ridge For more information: jadprolive.com

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 Caring for the Caregivers X October 30 • Waltham, Massachusetts For more information: http://www.massmed.org Continuing-Education-and-Events/ Event-Information/?code=CFC2015

November NRCI Cancer Conference November 1-4 • Liverpool, United Kingdom For more information: http://conference.ncri.org.uk 33rd Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® November 4-6 • New York, New York For more information: http://www.chemotherapyfoundationsymposium.org/CMS/

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 10th Annual New York Lung Cancer Symposium November 7 • New York, New York For more information: http://www.gotoper.com/ conferences/nyl/meetings/10thAnnual-New-York-Lung-CancerSymposium Best of ASTRO November 13-14 • San Diego, California For more information: www.astro. org/Meetings-and-Events/2015-Bestof-ASTRO/Index.aspx 12th International Conference of the Society for Integrative Oncology November 15-16 • Boston, MA For more information: www. integrativeonc.org/index.php/events

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Announcements

Mount Sinai Honors James F. Holland, MD, FASCO, on the Occasion of His 90th Birthday By Jo Cavallo

n May 14, 2015, over 160 colleagues, family members, friends, and patients of James F. H olland, MD, FASCO, gathered in the Goldwurm Auditorium in the Icahn School of Medicine at Mount Sinai Hospital in New York to honor Dr. Holland for the contributions he has made during his remarkable career in oncology and to celebrate his 90th birthday. Born on May 25, 1925, in Morristown, New Jersey, Dr. Holland’s medical career spans nearly 7 decades, including a pivotal year from 1953 to 1954 spent at the National Cancer Institute, where he and colleagues began the first combination chemotherapy program in acute leukemia. Dr. Holland’s work with other early pioneers in oncology, including Emil Frei, MD, Emil J Freireich, MD, DSc, and Jean Bernard, MD, among others,

exactly that. And I know that there are trainees here who are here specifically because [of his emphasis on knowing] how to interact with patients.” He continued, “The big question I think he has been focused on—the big question that all of us deal with day-today—is how do we go from genotype to phenotype? What I think my Dad has taught me and all of you whom I’ve heard from is [to ask] how do we go from patients to principles, how do we take individual observations and generalize them to make sure that tomorrow is, in fact, a better day?”

A Lucky Man Left to right: Steven M. Holland, MD, James F. Holland, MD, FASCO, and Steven Burakoff, MD.

can women’s breast cancers), which is 90% to 95% homologous to the mouse mammary tumor virus.

I hope that in the course of time, we can leave a legacy of having found the cause of human breast cancer, which will make a difference for women around the world. —James F. Holland, MD

as well as members of the Acute Leukemia Group B, transformed childhood acute lymphoblastic leukemia from an incurable disease into one with an over 80% survival rate and helped usher in the modern era of chemotherapy. Dr. Holland, along with his colleagues at Roswell Park Memorial Institute in Buffalo, New York, developed the “7 + 3” regimen of three daily injections of daunorubicin and 7 days of intravenous cytarabine in the treatment of acute myelocytic leukemia, which is now used worldwide. He also was the first to identify cisplatin as an effective treatment in testicular cancer and doxorubicin as a therapy for osteosarcoma. In the early 1970s, Dr. Holland established the Department of Neoplastic Diseases at The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, later serving as its Chairman, and is currently the Institute’s Distinguished Professor of Neoplastic Diseases in the Department of Medicine. Dr. Holland splits his time between seeing patients several days a week and pursuing research he began 20 years ago in the human mammary tumor virus (present in 40% of Ameri-

A Lasting Legacy During the 4-hour symposium honoring Dr. Holland, his colleagues and former students, including Larry Norton, MD, Deputy Physician-inChief for Breast Cancer Programs and Medical Director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center, and Elizabeth J. Shpall, MD, Professor and Howard and Lee Smith Chair in Cancer Research and Deputy Chair in the Department of Stem Cell Transplantation at The University of Texas MD Anderson Cancer Center, spoke about the impact Dr. Holland has had on their careers. Dr. Holland’s son, Steven M. Holland, MD, Chief, Laboratory of Clinical Infectious Diseases and Chief, Immunopathogenesis Section at the National Institutes of Health, reminisced about his father’s career accomplishments. He cited the number of research papers he has published—605, with his first published when he was just 23 and another coming out in June—and the textbook Cancer Medicine, which Dr. Holland coauthored with Emil Frei in

1973 and which is now in its eighth edition.1 He praised his father’s dedication to his patients and to the advancement of oncology care. “There are a lot of buzzwords in medicine, and you hear them in government and in academic environments: evidence-based, personalized, scientific,” said Dr. Steven Holland. “But I like to think that what my Dad has been practicing all these years is really patient-based medicine…. I know that there are patients here today because of

In his remarks to the audience (see sidebar), Dr. Holland expressed his gratitude for having such a long and meaningful career and for the extraordinary people in his life, especially his wife Jimmie C. Holland, MD, Wayne E. Chapman Chair in Psychiatric Oncology at Memorial Sloan Kettering Cancer Center. n Reference 1. Hong WK, Bast RC Jr, Hait WN, et al (eds): Holland-Frei Cancer Medicine, ed 8. Shelton, Connecticut; People’s Medical Publishing House-USA; 2010.

Reflections By James F. Holland, MD, FASCO

t is a humbling experience to reach 90 and to have a party and to have friends of the caliber I have. I think what keeps me going is the pleasant activities I have with Drs. Beatriz Pogo [MD, DMSc, Professor of Medicine, Hematology and Medical Oncology at Mount Sinai] and Stella Melana [PhD, Assistant Professor of Medicine, Hematology and Medical Oncology at Mount Sinai] trying to find and prove that a virus is a factor in human breast cancer. I have no doubt about it, but I’ve got to prove it to others. But what makes my life really important to me is my wife, because we have 58 years and 10 months of marriage together. And out of that [union] has come five wonderful children, and I have a daughter who

came before, and as a happy family, we are indeed joyous. I’m a very lucky man. I’m lucky to have friends like you. Mount Sinai has treated me well, and I hope that in the course of time, we can leave a legacy of having found the cause of human breast cancer, which will make a difference for women around the world. n

Drs. Jimmie and James Holland, May 14, 2015.

The ASCO Post | AUGUST 10, 2015

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Announcements

Charles Roberts, MD, PhD, Named Director of St. Jude Comprehensive Cancer Center

t. Jude Children’s Research Hospital has named Charles W.M. Roberts, MD, PhD, Executive Vice President and Director of the St. Jude Comprehensive Cancer Center in

Memphis, the first and only National Cancer Institute (NCI)-designated Comprehensive Cancer Center devoted solely to children. Dr. Roberts will also serve as a full member in

the Department of Oncology, and hold the Lillian R. Cannon Comprehensive Cancer Center Director Endowed Chair. “As a world-class investigator,

compassionate physician and experienced leader, Dr. Roberts is well suited to guide the Cancer Center, which connects scientists and clinicians to drive advances in research and treatment,” said James R. Downing, MD, St. Jude President and CEO.

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Dr. Roberts will assume his new role September 1. He joins St. Jude from Dana-Farber Cancer Institute, Boston, where he served as Deputy Chief Scientific Officer. An international leader in cancer epigenetics, his research has provided new insights into the central role of chromatin remodeling in germline and sporadic cancers. Dr. Roberts has also co-led an initiative on DNA sequencing of pediatric solid tumors at the Broad Institute. Beyond scientific accomplishments, he is a noted pediatric oncologist at Boston Children’s Hospital. He chaired the Pediatric Institutional Review Board for Dana-Farber Cancer Institute and Boston Children’s Hospital, and coled the Pediatric Solid Tumor Disease Program. “The St. Jude Cancer Center reflects leading excellence in research, patient care, education, and community outreach,” Dr. Roberts said. “It’s an honor to join the St. Jude faculty, and I look forward to continuing the advancement of scientific research to find cures for pediatric cancers.” Dr. Roberts received his medical and doctoral degrees from Washington University School of Medicine in St. Louis, Missouri. He completed his pediatric residency and pediatric hematology/ oncology fellowship at Boston Children’s Hospital. n

Visit The ASCO Post website at ASCOPost.com

This program is approved for AMA PRA Category 1 Credit™ and is also certified for nurses and pharmacists.

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ASCOPost.com | AUGUST 10, 2015

PAGE 75

Issues in Oncology Health-Care Policy

Medicare to Reimburse Doctors for End-of-Life Counseling By Ronald Piana

n a breakthrough proposal announced on July 8, the Centers for Medicare & Medicaid Services (CMS) plans to reimburse physicians for end-of-life counseling, a move that the oncology community has long been lobbying for. Arriving just as the presidential election cycle begins to heat up, the CMS proposal will ostensibly settle the infamous “death panel” debate that raged before the passage of the Affordable Care Act. A final decision will be made on November 1, and the proposal—if passed as expected—will take effect on January 1, 2016. Although the CMS proposal was the result of exhaustive lobbying by major health-care organizations, it needed the imprimatur of policymakers, which came by way of a bill called the Care Planning Act of 2015, S. 1549, sponsored by U.S. Senators Johnny Isakson (R-GA) and Mark R. Warner (D-VA). The bill creates a Medicare benefit for patient-centered care planning for people with serious illnesses such as cancer. Medicare will reimburse healthcare professionals for providing voluntary, structured discussions about the patient’s goals, illness, and treatment options.

Respecting Patient Preferences

and supporting health professionals in having end-of-life conversations with patients and their families is crucial if we are to respect patients’ goals and preferences for end-of-life care. This includes helping patients and their families to think about their preferences, complete advance directives, and be comforted knowing that their health-care providers understand their wishes. It also will help the health professionals to better understand and advocate for the patient’s preferences.”

Billing Concerns To enable billing for these services, CMS has suggested the use of two new American Medical Association (AMA)generated CPT codes (99479 and 99498), which allow providers to be reimbursed for their consultation in end-of-life conversations and also to encourage conversations prior to their being clinically necessary. The AMA codes are structured to cover substantive discussions about goals of care, treatment options, values, and preferences when it comes to end-of-life planning. While feeling this is a step in the right direction, Dr. Mason noted, “I’m concerned that the conversation may have to

What Will the Care Planning Act Do? ■■ Establish Medicare reimbursement for health-care professionals to provide voluntary discussions about the goals and treatment options for individuals with serious illness ■■ Test new models for more intensive services for those with advanced illness and provides funding to support the development of a public information campaign to encourage effective care planning ■■ Put structures in place to focus providers on evidence of patient preferences, such as directives from other states or past discussions about treatment goals ■■ Direct the U.S. Department of Health and Human Services to develop quality metrics that will measure synchronicity among the individual’s stated goals, values, and preferences with documented care plans ■■ Prohibit the use of funds in violation of the Assisted Suicide Funding Restriction Act of 1997 and require that all services be free from discrimination based on age, disability status, or the presence of advanced illness

“I applaud CMS for this change. End-oflife counseling is a difficult task—it takes time, emotional involvement, and courage for the patient and the physician. It’s only fair to compensate a physician for the hardest clinical encounter of his/her day. I don’t consider this payment as a mandate for end-of-life counseling, but it does remove one of the significant barriers preventing those discussions.” Proponents of end-of-life counsel-

Regarding the heated controversy over the so-called death panels and other fierce rhetoric that had long stalled this initiative, one of the bill’s authors, Senator Warner commented during a press conference: In the past several years, some have deliberately chosen to misrepresent the purpose of care planning services to frighten people and to score cheap political points. It’s about making sure that your doctors, your hospital, and your family know what choices you have made about your care. If a patient prefers to explore every possible treatment option, that choice will be respected. And if an individual prefers a different approach after informed consultations with their health team, their family, and others, those choices should be documented and honored too. The important thing is being able to make that decision and trust that it will be respected.

Speaking with The ASCO Post, nationally regarded health-care expert Diana Mason, PhD, RN, FAAN, President of the American Academy of Nursing, said: The proposed changes to the Medicare physician payment policy that would provide reimbursement for advance care planning services are important to improving end-of-life care. Encouraging

Diana Mason, PhD, RN, FAAN

Lee N. Newcomer, MD, MHA

be linked to a terminal diagnosis. The proposed rule says that the two CPT codes for advance planning services can be used ‘when the described service is reasonable and necessary for the diagnosis or treatment of illness or injury.’ We don’t always know when death is around the corner. These conversations should be part of an initial or periodic visit to a qualified health professional and all professionals should encourage and help patients to complete and properly file advance directives.” Prior to the CMS proposal, certain private insurers had offered reimbursement. However, about three-quarters of the people who die each year in the United States are 65 and older, making Medicare the largest insurer at the end of life. Speaking from the perspective of a private payer, Lee N. Newcomer, MD, MHA, Senior Vice President, Oncology, Genetics and Women’s Health, UnitedHealthcare, said,

Eduardo Bruera, MD, FAAHPM

ing have contended that the focus on person-centered care and the longitudinal view of the care chain logically should include professional counseling and discussions on end-of-life options, which could lead to better informed choices by the dying, as well as lessened anxieties for families and caregivers.

Central to Quality Care According to nationally regarded palliative care expert Eduardo Bruera, MD, FAAHPM, of The University of Texas MD Anderson Cancer Center, reimbursement for cognitive services such as end-of-life counseling is central to quality care. “ It is very important for CMS and all other payers to reimburse physicians for delivering end-of-life counseling. This is a medical procedure not different from a biopsy or a prescription for chemotherapy. It requires an appropriate physical setting,

time, and a trained physician to conduct this medical procedure successfully.” Moreover, Dr. Bruera sees the move by CMS as part of an important change in the medical culture. “It is very important that all graduate clinical programs in oncology conduct formal clinical training on how to safely conduct these interventions. Mandatory rotations in supportive and palliative care for all trainees will empower future oncologists to be successful at end-of-life counseling as well as multiple other interventions capable of reducing physical and psychosocial distress among advanced cancer patients.” He added, “This training will also reduce distress that can lead to burnout among cancer specialists.” The oncology community has roundly approved this long-awaited move by CMS. Many view the proposed change as one more step in recognizing the difficult cognitive services that oncologists have been performing for decades without being reimbursed. As Dr. Bruera pointed out, cognitive services are medical services. And the evidence has been there for a long time. For instance, a 2010 Journal of Clinical Oncology study1 concluded, “Patients with cancer are more likely to receive [end-of-life] care that is consistent with their preferences when they have had the opportunity to discuss their wishes for [end-of-life] care with a physician.” n Disclosure: Drs. Mason and Bruera reported no potential conflicts of interest. Dr. Newcomer is an employee and shareholder of UnitedHealthcare.

Reference 1. Mack JW, Weeks JC, Wright AA, et al: End-of-life discussions, goal attainment, and distress at the end of life. J Clin Oncol 28:1203-1208, 2010.

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In the Literature

Emerging Clinical Data on Cancer Management COLORECTAL CANCER Collaboration Between Surgeons and Medical Oncologists Improves Outcomes for Patients With Stage III Colon Cancer Collaboration between surgeons and medical oncologists “is associated with lower mortality without increased cost among patients with stage III colon cancer,” according to a study by T anvir Hussain, MD, MSc, and colleagues from Johns Hopkins University School of Medicine, Baltimore, and the University of Michigan Health System, Ann Arbor. “We operationalized collaboration between surgeons and oncologists as the number of patients they shared (ie, when both providers bill for medical services for the same patient), because this has been shown to reflect advice-seeking and referral relationships between physicians,” the authors explained. An increase in the number of patients receiving shared care from a surgeon and medical oncologist was associated with improved survival benefits,” the researchers reported the Journal of Oncology Practice.

Study Details Coordination of cancer care has been identified as a “priority area for improvement” by the National Institutes of Medicine, investigators noted. Explaining their focus on stage III colon cancer, they wrote: “Stage III colon cancer requires timely surgery and adjuvant chemotherapy to improve survival. Because this involves coordination between specialists, patients with stage III colon cancer are vulnerable to

poor coordination; many patients do not receive guideline-concordant care, and disparities exist.” The retrospective cohort study looked at patients with stage III colon cancer identified using Surveillance, Epidemiology, and End Results (SEER)Medicare data and diagnosed between 2000 and 2009. All patients were over age 65, slightly more than 57% were female, and close to 86% were white. Overall, 5,160 patients (55.3%) died during the 12-year observation period, which extended until December 31, 2011. The median survival time was 5.3 years. “A total of 9,329 patients received care from 3,623 different surgeons and 2,319 medical oncologists, representing 6,827 unique surgeon–medical oncologist pairs,” the investigators reported. The median number of shared patients was three. “As the number of patients shared between specialists increased from one to five (25th to 75th percentile), patients experienced an approximately 20% improved survival benefit from allcause and colon cancer–specific mortalities. Specifically, for each additional patient shared between oncologist and surgeon, all-cause mortality improved by 5% (hazard ratio = 0.95; 95% confidence interval [CI], 0.92–0.97), and colon cancer–specific mortality improved by 5% (subhazard ratio = 0.95; 95% CI, 0.91–0.97),” the researchers reported. They found no association between collaboration and cost of care. “Even after accounting for whether specialists worked in the same or different hospitals, patient sharing remained associated with lower mortality, which may suggest that additional informal

mechanisms are important,” the investigators pointed out. “Facilitating formal and informal collaboration between specialists may be an important strategy for improving the care of patients with complex cancers.” Hussain T, et al: J Oncol Pract 11:e388-e397, 2015.

HEPATOCELLULAR CARCINOMA More Than One-Third of Those Diagnosed With Hepatocellular Carcinoma as Outpatients Have Diagnostic Delays of 3 or More Months Nearly 20% of patients with hepatocellular carcinoma “wait more than 3 months from presentation to diagnosis, which can contribute to interval tumor growth,” Nishant Patel, MD, and colleagues concluded in the Journal of the National Comprehensive Cancer Network. They based their conclusions on a review of records of consecutive patients with cirrhosis and hepatocellular carcinoma at Parkland Memorial Health and Hospital System, a large urban safety net hospital in Dallas, between January 2005 and July 2012. “Diagnostic delays are particularly common among outpatients, occurring in more than one-third,” the researchers found. “These delays may be related to several potential issues, including providers failing to recognize positive surveillance tests, patients missing radiology appointments, and insensitive diagnostic tests. Although we did not find any difference in receipt of hepatocellular carcinoma–directed treatment, diagnostic delays were associated with potential interval tumor growth in nearly one-fifth of patients.”

Study Details

Among 457 patients with cirrhosis and hepatocellular carcinoma, 231 were inpatients, and 226 (49.5%) were diagnosed as outpatients. Although the time from presentation to diagnosis was less than 1 week for more than 90% of inpatients, the median time to diagnosis was 2.2 months for outpatients, with 87 patients (38.5%) experiencing a diagnostic delay, defined as a time to diagnosis exceeding 3 months. Higher rates of diagnostic delays were observed among those diagnosed as outpatients who had hepatic encephalopathy (56% vs 35%). “Among

49 patients with mass-forming hepatocellular carcinoma and diagnostic delay, 18% had interval tumor growth of 2 cm or greater,” the investigators stated. The median age of the patients was 56 years, and more than 75% were men. “Our population was racially diverse, with 36% African Americans, 30% Hispanic Caucasians, and 26% non-Hispanic Caucasians,” the researchers noted.

Impact of Electronic Medical Record System Lower rates of diagnostic delays were observed in patients diagnosed as outpatients who presented after implementation of a comprehensive electronic medical record system, 26% vs 60% for those presenting before electronic medical records. The authors noted, “diagnostic delays may be more common in hospital systems without an electronic medical record, because of higher rates of unrecognized positive surveillance tests.” Patients presenting with an abnormal ultrasound, with or without an elevated alpha-fetoprotein level, also had lower rates of diagnostic delay, 27% vs 50%.

Contributing to Outcome Disparities The investigators noted that the incidence of hepatocellular carcinoma is increasing because of a growing number of cases of nonalcoholic fatty liver disease and hepatitis C virus. Curative options are “only available for those diagnosed at an early stage. Patients with early hepatocellular carcinoma achieve 5-year survival rates near 70% with resection or liver transplantation, whereas those with advanced hepatocellular carcinoma have a median survival of less than 1 year,” the authors added. “Despite the availability of efficacious surveillance tests, only 40% of hepatocellular carcinoma cases are diagnosed at an early stage nationally,” the researchers wrote. “Tumor stage at diagnosis can be impacted by several factors in clinical practice, including low surveillance rates and delays in follow-up of abnormal screening tests. These issues may be particularly prevalent among racial minorities and socioeconomically disadvantaged patients, potentially contributing to racial and socioeconomic disparities in cancer outcomes.” n Patel N, Yopp AC, Singal AG: J Natl Compr Canc Netw 13:543-549, 2015.

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Perspective John F. Smyth, MD continued from page 1

Defining Benefit

In the dictionary in my office, value is defined as “the relationship between something that is useful and its exchangeability.” These interesting words are worth pondering. In oncology, we recognize usefulness as benefit, but not everyone agrees as to what benefit really means in any given setting. In an education session on lung cancer, Rogerio Lilenbaum, MD, from Yale, described the difficulty of agreeing on “clinical benefit” and referred to ASCO’s initiative in encouraging a new focus on “clinically meaningful” goals in the design of clinical trials.1 Many of us have argued that overall survival is not necessarily the best measure of clinical benefit, and certainly in my own experience, progression-free survival is a much more important factor for the majority of patients. Of course, these considerations are disease-specific, but for treatable but incurable cancers—the situation for the majority of solid tumors—relapse represents the lowest point emotionally for patients, even when there are two, three, or more subsequent treatments possible. Quality of life is not easy to determine meaningfully, and in all the considerations of defining benefit, opinions differ considerably in different parts of the world. Nevertheless, I believe that collectively we are aware of the multitude of factors that contribute to “clinical benefit,” and we have the tools to address and discuss this side of the value argument. I suggest that the other side—cost—is much more problematic. The expression “exchangeability” in health economic parlance means “opportunity cost”—ie, if you spend on plan A, you cannot spend the same on plan B or C; you have to choose, and this is the hub of the problem. Leaving aside political arguments that health-care budgets should be enhanced at the expense of other areas of government spending, I believe that whatever sum is available for spending on health, the demand is always going to exceed the monies available.

Unstoppable Research, Limited Resources Scientific research is unstoppable, and as we saw so excitingly illustrated at this year’s ASCO meeting, science is being realistically translated into meaningful progress in programs of prevention, screening, diagnosis, and management. The incidence of cancer is increasing and we are living longer, thereby not only requiring more cancer care, but also stretching demands on

other health areas, including cardiology, orthopedics, and geriatrics. There will never be enough resources, and this problem is especially obvious in countries such as the United Kingdom, where we still try to offer health care free at the point of delivery. In the UK and many European countries, the patient does not have to pay

directly, but increasingly, government funds cannot make available all the interventions that we would wish. All too often, people debate this issue around the cost of drugs, especially the introduction of new drugs, but it is important to remember that opportunity cost refers to all aspects of cancer care—surgery, radiation, etc—and it is

not only the cost of goods and services but the availability of staff, time in operating rooms and on machines, and so on.

Who Decides? The challenge facing us over the next 5 to 10 years is to decide which sectors in society should contribute to the very continued on page 78

CALL FOR ABSTRACTS

Cancer Survivorship Symposium: Advancing Care and Research

A Primary Care and Oncology Collaboration JANUARY 15-16, 2016

SAN FRANCISCO MARRIOTT MARQUIS, SAN FRANCISCO, CA

SUBMIT BY SEMPTEMBER 1, 2015

Submit an abstract for presentation at the inaugural Cancer Survivorship Symposium: Advancing Care and Research. This innovative educational event will feature research presentations, educational sessions, keynote lectures, and networking events to address the needs of clinicians, researchers, and health professionals who are interested in cancer survivorship care.

ABSTRACT SUBMISSION DEADLINE: SEPTEMBER 1, 2015, AT 11:59 PM (EDT) The Program Committee seeks abstracts on the following topic areas: CARE COORDINATION AND FINANCIAL IMPLICATIONS

LATE-AND LONG-TERM EFFECTS/ COMORBIDITIES

• Chronic Care Management • Cost of Care • Educational Curriculum • Financial Toxicity • Hospice • Issues, Trends, and Statistics in Health Care Access and Survivorship • Models of Care/Medical Homes • Payment/Reimbursement Models • Quality Assurance • Survivorship Care Plans

• Fertility Preservation • Long-term Complications/Sequelae of Treatment (Noncancer) • Onco-cardiology • Rehabilitation Services and Function • Screening for Late-/Long-term Effects • Short-term Complications • Symptom Management

COMMUNICATION • Communicating About Advanced Care Planning and End-of-Life Decisions • Communicating with Patients/Families/ Caregivers • Oncology/Primary Care Communication Coordination

HEALTH PROMOTION • Complementary Therapy, Vitamins, NSAIDs, etc. in Cancer Survivors • Energy Balance: Diet, Exercise, and Metabolic Syndrome • Smoking Cessation

PSYCHOSOCIAL ISSUES • Addressing the Emotional Needs of Families and Caregivers • Psychological and Social Well-being • Quality-of-Life Issues • Spirituality

RECURRENCE AND SECONDARY MALIGNANCIES • Detection of Recurrence and Secondary Malignancies • Genetic Risk Assessment for Prevention of Second Primaries and Cancer Recurrence • Prevention of Secondary Cancers • Treatment of Recurrent Cancer

survivorsym.org

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Perspective John F. Smyth, MD continued from page 77

difficult decisions on what we do or do not fund—these are real choices that have to be faced. As discussed at this year’s ASCO meeting, in the United States, patients and their physicians often have a primary role in these choices, especially, for example, in the use of new, expensive drugs. Even for an individual family, opportunity costs have to be considered, particularly in situations where life expectancy is short. However, in assessing the overall value of a medical intervention, we can argue that while patients and their advocates are an essential component, they are by definition biased and not well positioned to contribute to the overall opportunity discussion. In my opinion, politicians are the least suited to make these decisions due to their short termism and the need to appeal to the popular vote. The pharmaceutical industry is pivotal and frequently challenged about the costs of new drugs but, of course, members of this sector argue in defense of their research and development costs and responsibility to shareholders. Regulators, for example, with the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), have a role in the value equation. When I served on the EMA’s Scientific Advisory Group for Oncology, I argued (often unsuccessfully) that although we were not involved in pricing issues per say, we nevertheless had a responsibility to avoid granting

licenses for drugs with very marginal benefit. If a drug is not licensed, it cannot add to the complexity of the value discussion, but of course there is a constant clamour to make new drugs available as long as they have some proven efficacy.

for Health and Care Excellence (NICE) is responsible for recommendations after a medicine is licensed by the EMA. The National Health Service is under incredible cost pressures, and I do not envy the brave people who sit on NICE committees in having to reach their

It is unlikely that health care can ever become cheaper, and scientific progress can only add to the burden of the opportunity cost debate—a good problem to have but one of the great contemporary challenges for society as a whole. —John F. Smyth, MD

Drug Licensing and Availability The hardest problem in opportunity costing lies with health technology assessment programs. I greatly admire the progress made in recent years by both the FDA and EMA to speed up the process of licensing decisions by opening up discussion with drug developers throughout the clinical trial period and adapting their procedures accordingly. In Europe, however, there are also people who decide whether a newly licensed medicine should be made available to the public. Moreover, there are considerable variations in the decisions reached by different health technology assessment programs in different European countries. In England, the National Institute

very difficult decisions. The criteria by which they reach these decisions can be challenged. For example, just recently NICE surprisingly (and controversially) rejected olaparib (Lynparza) for women with ovarian cancer and a BRCA1 or BRCA2 mutation, citing the drug’s high cost and the availability of other treatment options that offer comparable benefits. Even within the UK, there are different criteria for value decisions, with Scotland having its own counterpart to NICE (ie, the Scottish Medicines Consortium, which also advised against the use of olaparib). In Austria, by contrast, health technology assessment is not such an obstacle, and any newly licensed drug is immediately available to be prescribed.

Finding the Right Mix So who should decide how we spend limited health budgets—patients, physicians, providers, insurance companies, health technology assessment programs, regulators, industry, or another stakeholder? All have a part to play, but we have yet to get the right mix involved, and we lack criteria for determining an agreed-upon value for any new intervention. I believe that we need to create new platforms accepting different attitudes and ambitions from the public and physicians in different parts of the world, but these issues need to be debated so that we can better attribute value to new or established interventions and decide on the best opportunity cost. Maybe ASCO, with its global, independent, and comprehensive understanding of cancer, could be the host for discussing the optimum forum where these very pressing issues can be debated. This problem will not go away. It is unlikely that health care can ever become cheaper, and scientific progress can only add to the burden of the opportunity cost debate—a good problem to have but one of the great contemporary challenges for society as a whole. n

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

Reference 1. Lilenbaum R: Statistical and clinical significance in lung cancer trials. 2015 ASCO Annual Meeting. Education Session. Presented May 30, 2015.

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References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol. 2004;172:6074-6079. © 2014 Amgen Inc. All rights reserved. 8/14 USA-678-100568