TAP Vol 5 Issue 15

Gynecologic Oncology 12, 29, 30 | Metastatic Prostate Cancer

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| National Clinical Trials Network

VOLUME 5, ISSUE 15

86

SEPTEMBER 15, 2014

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

International Lung Cancer Congress

Will Oncologists Be the First to Cure Heart Disease?

Can Metastatic Lung Cancer Be Cured?

By Caroline Helwick

D

on’t expect metastatic lung cancer to be cured any time soon, says Paul A. Bunn, Jr, MD, Professor and James Dudley Chair in Cancer Research at the University of Colorado School of Medicine, Denver.

“You have to be diseasefree for some length of time in order to be cured, which is our goal,” he said. Unfortunately, by 2 years, the majority of patients with stage IV lung cancer show disease progression, in spite of whatever promising experimental agent they may have received.

“Molecular therapies have improved the quality and quantity of life, but they are unlikely to cure non–small cell lung cancer patients when used in any stage of disease,” Dr. Bunn said in a keynote lecture during the 15th Annual International Lung Cancer Congress in Huntington Beach, California.

By Robert Peter Gale, MD, PhD, DSc(hc), FACP

Molecular therapies have improved the quality and quantity of life, but they are unlikely to cure non–small cell lung cancer patients when used in any stage of disease.

—Paul A. Bunn, Jr, MD

Nevertheless, he acknowledged that the identification of driver mutations is a step in the right direction.

Sequential tyrosine kinase inhibitors and novel combinations appear to be keeping patients alive longer, and immunotherapy is promising, albeit unproven, he said.

Phase III Trials of Targeted Agents Dr. Bunn ran through a list of molecularly targeted agents and their outcomes in unselected continued on page 8

Issues in Oncology

9/11 and Cancer: What Do We Know?

O

Media Attention That said, regarding cancers, well-intended sentiment is running ahead of the scientific process. For September Is Childhood Cancer Awareness Month

continued on page 56

Dr. Gale is Visiting Professor of Haematology, Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London.

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

MORE IN THIS ISSUE

By Ronald Piana n September 11, 2001, the devastating terrorist attack that destroyed the World Trade Center left in its wake a unique toxic site in both mass and quantity of hazardous materials. It took 9 months to remove approximately 2 million tons of wreckage from Ground Zero, during which thousands of emergency personnel and inhabitants of the area were exposed to a dizzying array of toxins, some of which were known carcinogens.

Now, more than a decade later, 9/11-related diseases, including cancers, are being reported and studied to better understand the effects of this noxious exposure on health. Helping those who were made sick by their service at Ground Zero is a national imperative. Yet, determining the etiology of diseases related to environmental exposure is also a public health issue, and must be handled and reported with exacting scientific rigor.

O

ncologists love jargon—a language peculiar to a particular trade, profession, or group that facilitates communication among members. Our day-to-day communications, medical notes, and journal reports are filled with this type of jargon. Other definitions of jargon are less flattering, including unintelligible or meaningless talk or writing (ie, gibberish), talk or writing one does not understand, or language characterized by uncommon or pretentious vocabulary and convoluted syntax, often vague in meaning (like this sentence). And although using jargon usually serves us well, it is this last definition—uncommon or pretentious

instance, a New York Post article reported that the number of cancer cases among 9/11 responders had more than doubled in the past year.1 The piece cited a 63-year-old retired New York City Fire Department captain who Donald A. Berry, PhD worked at Ground Zero; he received a $1.5 million award from the federal 9/11 Victim Compensation Fund for lung disease and pancreatic cancer. But since more than 80% of pancreatic cancers are diagnosed between the ages of 60 and 80,2 linking a 63-year-old’s pancreatic cancer to 9/11 exposures is risky science, at best.

Donald A. Berry, PhD, Professor of Biostatistics at The University of Texas MD Anderson Cancer Center, Houston, told The ASCO Post, “The reaction of pa-

Oncology Meetings Coverage International Lung Cancer Congress �������������������������������������� 3–5, 8–9 Breast Cancer Symposium ������������������������ 10 Best of ASCO ���������������������������� 12–16, 19 Inside the Black Box: Patient-Reported Outcomes �����������������������45 Judy E. Garber, MD, MPH, on Breast Cancer Risk ��������������������������������������52 Direct From ASCO ��������������������������� 74–77 Mary F. Mulcahy, MD, on Do-Not-Resuscitate Orders ����������������������� 80

continued on page 64

A Harborside Press® Publication

The ASCO Post | SEPTEMBER 15, 2014

PAGE 2

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PAGE 3

International Lung Cancer Congress Thoracic Oncology

In Advanced Lung Cancer, Targeted Combinations Are Still Works in Progress

By Caroline Helwick

F

or the treatment of advanced non– small cell lung cancer (NSCLC), combinations of targeted agents are of great research interest but have not yet been shown to improve outcomes.

Single-agent treatment with tyrosine kinase inhibitors, therefore, remains the standard of care for patients with specific mutations, according to James CH Yang, MD, PhD, Professor of the Graduate Institute of Oncology and Di-

“On the other hand, targeted therapy combinations are also intensively evaluated in patients who have progression of their tumor after [tyrosine kinase inhibitor] treatment. Acquired resistance to EGFR tyrosine kinase inhibitors is an important issue for patients with EGFR mutations, and novel salvage treatments are much needed in this population. Since different resistant mechanisms may emerge after

In EGFR mutation–positive patients resistant to [tyrosine kinase inhibitors], we need good methods to quantitate resistant biomarkers and conquer heterogeneity.… We must be smarter in designing biomarker-driven trials.

—James CH Yang, MD, PhD

rector of the Cancer Research Center at National Taiwan University College of Medicine in Taipei.

High Benchmark “Though tyrosine kinase inhibitor combinations are under active investigation as front-line therapy, tyrosine kinase inhibitor monotherapy is still the standard treatment for patients with specific driver mutations such as EGFR or ALK fusion,” Dr. Yang noted at the 15th Annual International Lung Cancer Congress in Huntington Beach, California.

Single-agent tyrosine kinase inhibitors—gefitinib (Iressa), erlotinib, and afatinib (Gilotrif) for patients with EGFR-mutated disease, and crizotinib (Xalkori) and ceritinib (Zykadia) in patients with ALK fusions—produce high response rates (60%–70%) and very high disease control rates (85%–95%).

Compared to the standard median 5 to 7 months of progression-free survival for platinum-based chemotherapy, these tyrosine kinase inhibitors provided a progression-free survival of 9 to 14 months, he noted.

“If we want to combine any drugs with these agents and beat these outcomes, it will be difficult. The long progression-free survival associated with currently available [tyrosine kinase inhibitor] treatment in patients with specific mutations is a very high benchmark,” according to Dr. Yang.

acquiring resistance to [tyrosine kinase inhibitors], combination therapy would be better tested using molecularly characterized rebiopsy samples,” he said.

Combinations With Chemotherapy Summarizing the data on the combination of chemotherapy plus an EGFR tyrosine kinase inhibitor, Dr. Yang noted that no benefit was shown for adding gefitinib or erlotinib to chemotherapy in the INTACT-1,1 INTACT-2,2 ­TRIBUTE,3 and TALENT4 trials, nor was there benefit in adding paclitaxel and carboplatin to erlotinib in neversmokers in the CALGB 30406 study.

However, benefit was shown in progression-free and overall survival for adding intercalated erlotinib to gemcitabine plus cisplatin or carboplatin in FASTACT 15 and FASTACT 2,6 in an EGFR mutation–positive subgroup.

Progression-free survival advantage was shown when afatinib was added to paclitaxel in the fourth- or fifth-line setting in LUX-Lung-5 study, but there was no difference in overall survival outcome.7 He commented, “We saw differences in important outcomes using a strategy of intercalating erlotinib to chemotherapy in the FASTACT 2 study in patients with EGFR mutations.” In that subset, progression was reduced by 75% (P < .0001) with the combination,

and deaths were reduced by 52% (P = .0092). “However, we have to compare intercalating therapy to EGFR [tyrosine kinase inhibitor] monotherapy in EGFR muation–positive patients in order to show that this strategy is successful,” he said.

Regarding the Lux-LUNG-5 trial, Dr. Yang suggested that a population of patients who had benefit from prior gefitinib or erlotinib and again received benefit of afatinib and managed to receive at least four lines of treatment may be quite different from the average NSCLC patient.

These mixed results led Dr. Yang and his colleagues to revisit the results of the INTACT, TRIBUTE, and T ­ALENT studies, according to EGFR mutation status, in a meta-analysis of 23 trials that evaluated EGFR inhibitors as monotherapy or in combination with chemotherapy.8 In the four above-mentioned trials, which initially were negative, EGFR mutation–positive patients did derive a progression-free survival benefit (hazard ratio [HR] = 0.54). In the mutation-negative group, the effect was less pronounced, though still present (HR = 0.82).

“It seems that if we separate patients according to EGFR mutation status, there could be added benefit for combining an EGFR inhibitor with chemotherapy. This was not seen originally because we lumped these groups together,” he said.

“Adding chemotherapy to an EGFR [tyrosine kinase inhibitor] was shown at least in some studies to be effective in terms of progression-free survival.”

Combinations With Antiangiogenesis Agents Activity has recently been shown for a tyrosine kinase inhibitor plus an antiangiogensis agent, but requires confirmation, Dr. Yang said.

The Japanese JO25567 trial randomly assigned 150 chemotherapy-naive EGFRmutation-positive patients to erlotinib alone or with bevacizumab, demonstrating a 6.3-month difference in progression-free survival with the combination (P = .0015; HR = 0.54).9 The phase III BeTa trial of erlotinib vs erlotinib plus bevacizumab in 636 unselected chemotherapy-treated patients showed no difference in progressionfree survival, although the hazard ratios were impressive in Asians (HR = 0.26) and nonsmokers (HR = 0.39).10 “I think we need to examine these trial data seriously and confirm them in a large randomized study,” Dr. Yang suggested. “The important question, however, still remains: is overall survival also improved?”

Combinations With Novel Targeted Agents Many randomized trials of an EGFR tyrosine kinase inhibitor with or without a drug targeting another pathway have been negative (Table 1). “Unselected populations may be the key failure factor. And even in the right population, it’s not only about the right mutations—the associated targeted molecules will be important as well,” Dr. Yang suggested.

For example, targeting cMET is thought to be of importance. However, the global phase III MetLung trial of onartuzumab plus erlotinib was disappointing.11 Dr. Yang

Table 1: Randomized Trials of Targeted Agents With or Without an EGFR Tyrosine Kinase Inhibitor Target

Agent

Result

Possibly MET?

Tivantinib

Negative

MET

Onartuzumab

Negative

HER3

MM121

Negative

IGFR

Figitumumab

Negative

HGF

Vandetanib

Negative

VEGFR

Ficlatuzumab

Negative

HER3 = human epidermal growth factor receptor 3; HGF = hepatocyte growth factor; IGFR = insulinlike growth factor receptor; VEGFR = vascular endothelial growth factor receptor. Courtesy of James CH Yang, MD, PhD.

Findings from the IMPRESS trial, expected soon, will indicate whether patients for whom gefitinib fails will benefit from gefitinib plus pemetrexed/ platinum, vs chemotherapy alone.

suggested that the negative results might be a reflection of the method for measuring cMET for patient selection.

“There are many tests for cMET— continued on page 4

The ASCO Post | SEPTEMBER 15, 2014

PAGE 4

International Lung Cancer Congress Thoracic Oncology

Hsp90 Inhibitors May Soon Transition Into Clinic

By Caroline Helwick

I

nhibitors of heat shock protein 90 (Hsp90) look promising for the treatment of advanced non–small cell lung cancer (NSCLC) and have the advantage of not needing a specific mutation to target, said Suresh S.

Underlying Mechanism Hsp90s are important “chaperone proteins” to a number of oncoproteins. More than 200 Hsp90 “client proteins” have been described, many of which are relevant to NSCLC, such as the epidermal growth

A number of key oncoprotein targets in lung cancer are activated in an Hsp90-dependent manner, and that’s why blocking Hsp90 is a rational therapeutic strategy.

— Suresh S. Ramalingam, MD

Ramalingam, MD, Professor and Chief of Medical Oncology at the Winship Cancer Institute of Emory University, Atlanta, during the 15th Annual International Lung Cancer Congress in Huntington Beach, California.

factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR).

When Hsp90 binds to an inactive client protein, the protein then becomes activated and is able to perform its biologic functions. Hsp90 inhibition prevents

Targeted Therapies for Lung Cancer

That aside, he added that AZD9291 monotherapy is an effective treatment for patients who fail to benefit from EGFR tyrosine kinase inhibitor therapy and who harbor the T790M mutation. At this year’s ASCO Annual Meeting, Jänne et al reported a response rate of 64% and disease control rate of 94% with this approach.12 “Though we know there will be some cMET mutation–positive patients in there, we still see very good responses,” he said.

“In EGFR mutation–positive patients resistant to tyrosine kinase inhibitors, we need good methods to quantitate resistant biomarkers and conquer heterogeneity. If we want to add targeted agents,

continued from page 3

fluorescence in situ hybridization (FISH) for cMET DNA amplification, quantitative reverse transcription polymerase chain reaction (PCR) for mRNA amount, or immunohistochemistry for protein expression—and we don’t know which is best and what is the cutoff point for cMET to be important in driving tumor cells to grow,” he indicated.

In addition, the level of extracellular hepatocyte growth factor (the ligand of cMET) could be a confounder, as production of this growth factor is a resistance mechanism in EGFR-mutant NSCLC. It is also difficult to draw conclusions, he added, from recent studies showing activity for the cMET inhibitor INC280 in combination with gefitinib, since it is unclear whether the responses are to both agents or to either agent alone. He added that much work needs to be done to understand acquired resistance, and how to test for and target the relevant and sometimes overlapping mutations.

For example, by testing only for the EGFR mutation T790M or the cMET mutation, patients harboring both abnormalities could be undertreated. Some, though clearly not all, would require a T790M mutation–specific drug such as AZD9291 and also a cMET inhibitor such as crizotinib or any new cMET inhibitors that are in development.

Hsp90 binding to the client, and the inactive client protein is instead degraded.

“Hsp90 inhibition is an indirect way of inhibiting oncoproteins, as compared to direct targeting,” Dr. Ramalingam noted.

“A number of key targets in lung cancer are activated in an Hsp90-dependent manner, and that’s why blocking Hsp90 is a rational therapeutic strategy.”

Heat shock proteins have been recognized as cancer targets for decades, but only recently have inhibitors been developed that are safe and active. The first-generation Hsp90 inhibitors—which were 17-AAG derivatives—had issues with formulation, limited clinical activity, and undue toxicity, especially hepatotoxicity. The second-generation compounds, such as ganetespib, are structurally unrelated to 17-AAG, have higher potency, and are safer.

Indirect Targeting According to Dr. Ramalingam, indirect targeting via Hsp90 inhibition we need to know how to measure resistant pathways in tumor cells to predict that a corresponding agent will be effective. We must be smarter in designing biomarker-driven trials,” Dr. Yang said. n

Disclosure: Dr. Yang has received honoraria from AstraZeneca, Roche/Genentech, Pfizer, Novartis, Merck Serono, MSD, Bayer, Clovis Oncology, and Boehringer Ingelheim for an advisory role or as a speaker.

References 1. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine plus cisplatin in advanced non-small –cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22:777-784, 2004.

Targeting Lung Cancer ■■ Single targeted agents remain the standard of care for advanced non–small cell lung cancer with driver mutations.

■■ The combination of an EGFR inhibitor and chemotherapy may improve progression-free survival in patients with EGFR mutation, though the data have been conflicting.

■■ An EGFR tyrosine kinase inhibitor plus an antiangiogenesis agent (bevacizumab) has shown activity, improving progression-free survival in EGFR mutation–positive patients, but this needs confirmation.

■■ Randomized trials of EGFR inhibitors plus novel targeted agents have been negative ■■ Clinical trial results need to be correlated with novel biomarkers such as cMET, but the best way to test for biomarkers remains unclear in most instances.

■■ New methods are needed to quantitate biomarkers and conquer heterogeneity in patients with acquired resistance to EGFR and ALK inhibitors.

may be preferable to direct molecular targeting in certain situations. For example, patients with ALK-positive tumors exposed to crizotinib (Xalkori) will develop resistance, often by mechanisms that are dependent on alterations to the receptor binding site. Since Hsp90 inhibition affects downstream proteins without binding to the receptors themselves, “no matter what the mechanism of resistance, ganetespib can inhibit the activation of the pathway,” he pointed out.

Dr. Ramalingam and his colleagues at Emory have also shown the drug’s effect on hypoxia-inducible factor-1 (HIF-1) alpha subunit, an important client protein that is involved in angiogenesis and that helps drive tumor aggressiveness. In rectal tumor biopsies, HIF-1 alpha was inhibited by ganetespib, leading to a reduction in VEGF. “HIF-1 alpha can affect important continued on page 5

2. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel plus carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. J Clin Oncol 22:785-794, 2004.

3. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892-5899, 2005.

4. Gatzemeier U, Pluzanska A, Szczesna A, et al: Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non–small-cell lung cancer: The Tarceva Lung Cancer Investigation Trial. J Clin Oncol 25:1545-1552, 2007.

5. Mok TS, Wu YL, Yu CJ, et al: Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 27:5080-5087, 2009.

6. Wu Y-L, Lee JS, Thongprasert S, et al: Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small cell lung cancer (FASTACT-2): A randomized, doubleblind trial. Lancet Oncol 14:777-786, 2013.

7. Schuler MH, Yang J C-H, Park K, et al: Continuation of afatinib beyond progression: Results of a randomized, open-label, phase III trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy in patients with metastatic non-small cell lung cancer procontinued on page 5

ASCOPost.com | SEPTEMBER 15, 2014

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International Lung Cancer Congress Hsp90 Inhibitors in NSCLC continued from page 4

pathways that are hallmarks of cancer,” he said. “This is another mechanism by which we can affect tumor growth and metastasis with Hsp90 inhibition.”

Clinical Data As single agents, second-generation Hsp90 inhibitors such as ganetespib produce responses in 5% to 13% of unselected NSCLC populations, including ALKpositive and EGFR-mutated patients. This single-agent activity has been considered notable enough to explore combinations of Hsp90 inhibitors with other agents.

Synergy has been observed preclinically for the combination of ganetespib and docetaxel. The compounds have synergistic effects on the cell cycle, microtubules, and resistance pathways, and complementary effects on tumor biology. A phase I study proved the activity and tolerability of this duet, and led to the phase II GALAXY-1 trial, in which 241 patients with advanced adenocarcinoma and one prior regimen were randomly assigned to docetaxel alone (75 mg/m2 every 3 weeks) or with ganetespib (150 mg/m2 on days 1 and 15 every 3 weeks).1 One of the stratification factors was time since diagnosis of advanced dis-

Targeted Therapies for Lung Cancer continued from page 4

gressed on erlotinib/gefitinib and afatinib— LUX-Lung 5. ASCO Annual Meeting. Abstract 8019. Presented June 3, 2014.

8. Lee CK, Brown C, Gralla RJ, et al: Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: A meta-analysis. J Natl

ease (≤ 6 months vs > 6 months).

Time > 6 months was suggestive of response to first-line therapy, and this constituted the chemosensitive subset.

“We found the regimen was tolerated well, and there was [essentially] no ocular toxicity, which we have seen with other second-generation compounds,” he reported. Two patients on the combination had grade 1 visual impairment.

The most common adverse events of all grades for the combination vs docetaxel alone were neutropenia (44% vs 45%), diarrhea (49% vs 16%), and fatigue (34% vs 24%). The most common grade 3 or 4 adverse events were neutropenia (38% vs 42%), febrile neutropenia (9% vs 4%), and anemia (8% vs 2%). The proportion of patients with adverse events leading to death were 15% vs 12%, and to treatment discontinuation were 7% vs 6% for the combination vs docetaxel, respectively.

Hsp90 Inhibitors in Non–Small Cell Lung Cancer ■■ Second-generation inhibitors of heat shock protein-90 (Hsp90) are showing single-agent activity and tolerability in advanced non–small cell lung cancer.

■■ They work indirectly by inhibiting the chaperone rather than the oncoprotein.

■■ Ganetespib in combination with docetaxel yielded benefits in progressionfree and overall survival in chemosensitive patients.

The best activity was observed in patients who were chemosensitive and in those with elevated lactate dehydrogenase (LDH), which may be a marker for upregulated HIF-1 alpha. Among patients with elevated LDH, median

progression-free survival was 3.4 months with the combination vs 1.9 months with docetaxel alone, and median overall survival was 5.2 vs 4.3 months, respectively.

Somewhat surprisingly, patients with mutated KRAS derived no additional benefit from adding ganetespib, he reported.

Among the subset of 178 chemosensitive patients, the benefit was quite robust: median progression-free survival was 5.3 months with ganetespib/ docetaxel vs 3.4 months with docetaxel (adjusted hazard ratio [HR] = 0.72; P = .030), and median overall survival was 10.7 vs 7.4 months, respectively (adjusted HR = 0.72; P = .040).

“Based on these findings, we are now conducting the phase III GALAXY-2 trial, evaluating this combination secondline in advanced adenocarcinoma patients who [had disease progression] more than 6 months from diagnosis [ie, are chemo-

Cancer Inst 105:585-605, 2013.

9. Kato T, Seto T, Nishio M, et al: Erlotinib plus bevacizumab versus erlotinib alone as first-line treatment for advanced EGFR mutation-positive nonsquamous non-small cell lung cancer: An open-label randomized trial. ASCO Annual Meeting.

Abstract 8005. Presented June 2, 2014.

10. Herbst RS, Ansari R, Bustin F, et al: Efficacy of bevacizumab plus erlotinib ver-

sus erlotinib alone in advanced non-smallcell lung cancer after failure of standard first-line chemotherapy (BeTa): A doubleblind, placebo-controlled, phase 3 trial.

Lancet 377:1846-1854, 2011.

11. Spigel DR, Edelman MJ, O’Byrne K, et al: Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb or IV NSCLC: Results from the pivotal phase III randomized, multicenter, placebo-con-

Benefit in Chemosensitive Population

sensitive], with overall survival as the primary endpoint,” he said. This study is now enrolling.

Ganetespib is joined in the oncology pipeline by several other Hsp90 inhibitors. In ALK-positive NSCLC alone, there are six trials underway involving ganetespib, AUY922, and AT13387. Studies in breast cancer, prostate cancer, and other malignancies are also underway, he said.

Disclosure: Dr. Ramalingam has served on advisory boards for Amgen, Aveo, Ariad, AstraZeneca, Biodesix, Boehringer Ingelheim, Celgene, Lilly, Gilead, Genentech, and Novartis.

Reference 1. Ramalingam S, Shapiro G, Hirsh V, et al: GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients. World Conference on Lung Cancer.

Abstract 003.01. Presented October 28, 2013.

trolled METLung (OAM4971g) global trial.

ASCO Annual Meeting. Abstract 8000. Presented June 2, 2014.

12. Jänne PA, Ramalingam SS, Yang JC, et al: Clinical activity of the mutantselective EGFR inhibitor AZD9291 in patients with EGFR inhibitor-resistant non-small cell lung cancer. ASCO Annual Meeting. Abstract 8009. Presented May 31, 2014.

SEPTEMBER IS

Childhood Cancer Awareness Month

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

GRANIX is another option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines.

The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40138 January 2014.

The ASCO Post | SEPTEMBER 15, 2014

PAGE 8

International Lung Cancer Congress Metastatic Lung Cancer continued from page 1

phase III trial populations: • Necitumumab plus gemcitabine/ cisplatin in squamous cell non–small cell lung cancer: median overall survival improvement of 1.6 months (hazard ratio [HR] = 0.84) but no improvement in non–squamous cell

subsets.1 Necitumumab is an antibody against the epidermal growth factor receptor (EGFR).

• Ramucirumab (Cyramza) plus docetaxel, in the second line: median overall survival improvement of 1.4 months (HR = 0.86).2 Ramucirumab is an antibody against vascular endothelial growth factor

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease.

Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

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

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

(VEGF) receptor 2.

• Nintedanib plus docetaxel: median overall survival improvement of 2.3 months in patients with non–squamous cell histology (HR = 0.83) but no improvement in the overall population.3 Nintedanib is a small-molecule multi–tyrosine kinase inhibitor.

Discussing these studies, Dr. Bunn

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

made the following points: (1) it is necessary to determine in which subsets the biologic effect of these agents is seen, (2) evaluating drugs in the second-line setting in combination with docetaxel is not the best measure of their worth, (3) at around 18 months, few patients remain diseasefree, regardless of statistically significant benefits that emerge in trials, and (4) about 20% of patients are still alive at 2 years.

“It doesn’t take a genius to know that after many randomized trials in unselected patients, which show only tiny advantages or negative outcomes, we are not going to cure patients by conducting this type of trial,” he said.

“Not that they should not be done, but we won’t cure anyone.”

Targeting Driver Mutations The Lung Cancer Mutation Consortium recently identified driver mutations in 64% of 1,007 patients with advanced adenocarcinoma.4 These were primarily in KRAS (25%), EGFR (sensitizing, 17%), and ALK (8%). By matching the individual genotype with a targeted treatment, outcomes were improved (Fig. 1).

Median overall survival was 3.5 years for the 260 patients with an oncogenic driver and genotype-directed therapy, compared with 2.4 years for the 318 patients with a driver mutation but no targeted therapy, and approximately 2 years for patients lacking a driver mutation.

“A median overall survival of 3.5 years in stage IV disease, with drugs that are better tolerated than chemotherapy—one could say this is a shift in the treatment paradigm,” Dr. Bunn said.

“Clearly, this approach has had a major impact for patients with a driver mutation,” he noted. “On the other hand, the survival curves are still heading toward zero.”

The study also showed that some genes can be more effectively targeted than others. Patients with multiple oncogenic drivers, and those with HER2 and KRAS mutations, had worse outcomes than patient with abnormalities of ALK, BRAF, and EGFR. Numerous randomized trials have confirmed that when patients with mutations receive the appropriate EGFR tyrosine kinase inhibitor, response rates are higher and progression-free survival is better than with chemotherapy. In terms of overall survival, however, the order in which they receive these drugs vs chemotherapy is inconsequential. From the patient’s perspective, the oral tyrosine kinase inhibitor is preferred, he said.

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 9

International Lung Cancer Congress sion, by 2 years—once again—the majority of patients have had disease progression, he noted.

Immunotherapy With Checkpoint Inhibitors Could immunotherapy be the answer? Approximately 20% of patients with advanced disease respond to the immune checkpoint inhibitors, and response is not histology-dependent.

Some responses are quite durable, and this has generated tremendous excitement in the lung cancer field.

This exuberance may be premature, Dr. Bunn maintained. “There’s a phase III randomized trial comparing nivolumab to docetaxel. The media are treating this as if the trial has been completed and the

results are positive,” he said.

He pointed out that the survival curves for nivolumab are virtually the same as for ramucirumab and nintedanib. “Just because 20% of patients are alive at 2 years, to me, does not mean that without patient selection immune checkpoint inhibition will be a winner,” he commented. “Like everything else, selection with a biomarker, in the long run, will be the answer— not just giving these agents to all patients who come through the door.”

Currently, the optimal biomarker is not clear. PD-L1 expression is the best candidate so far, he said, but there are issues in measuring it, determining thresholds, dealing with variability in testing and reproducibility, and so forth. “At least it’s a start,” Dr. Bunn ­acknowledged.

1.0

0.8

Survival Probability

Unfortunately, resistance to targeted agents is universal. Tumor cells escape from the initial tyrosine kinase inhibitor through a secondary gatekeeper mutation or through activation of another signaling pathway. Third-generation tyrosine kinase inhibitors may help in this regard: those that do not bind to the wild-type receptor do bind to the EGFR T790M receptor gatekeeping mutation.

“With these agents, such as AZD9291, we have seen very high response rates and very long durations of response, with median progression-free survival exceeding 2 years,” he indicated. “Nonetheless, every patient in these studies is still relapsing.”

Dr. Bunn maintained that using tyrosine kinase inhibitors as adjuvant treatment would probably have little effect on long-term outcomes. When this has been tried, patients have disease progression once the drug is stopped, and none are cured.

“In my opinion, there’s not a whit of evidence that adjuvant treatment is better than waiting until the disease recurs, and then putting the patient on the [tyrosine kinase inhibitor],” he said.

“Keeping patients on these drugs for 10 years is not a real treat for them.”

He added, “I don’t think we can cure patients with molecular therapy at the moment, even in the early stage of their disease.”

The same pattern holds for patients with the ALK translocation. While third-generation ALK inhibitors do provide a “reasonable” time to progres-

No targeted therapy

0.6

Targeted therapy

0.4 No driver

0.2 Log-rank P < .001 0

0

1

2

3

4

5

Years Fig. 1: Lung Cancer Mutation Consortium Survival by Group. Patients with an oncogenic driver mutation who did and did not receive targeted therapy, and patients without an ocogenic driver.

Adapted, with permission, from Kris M, et al.4 © 2014, American Medical Association.

“With immunotherapy, time will tell,” he concluded. “Let’s not yet assume these agents have the ability to cure. We just hope they will.” n Disclosure: Dr. Bunn has consulted for Amgen, AstraZeneca, Bayer, Biodesix, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi-Sankyo, Eli Lilly, GSK, Merck, Novartis, OSI/Genentech/Roche, and Sanofi-Aventis.

References 1. Thatcher N, Hirsch FR, Szczesna A, et al: A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin chemotherapy plus necitumumab versus GC alone in the first-line treatment of patients with stage IV squamous non-small cell lung cancer. ASCO Annual Meeting.

Abstract 8008. Presented June 2, 2014.

2. Garon EB, Ciuleanu TE, Arrieta O, et al: Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): A multicentre, doubleblind, randomised phase 3 trial. Lancet.

June 2, 2014 (early release online).

3. Reck M, Kaiser R, Mellemgaard A, et al: Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): A phase 3, doubleblind, randomised controlled trial. Lancet Oncol 15:143-155, 2014.

4. Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998-2006, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post

Bradley J. Monk, MD, and Michael A. Bookman, MD, on recurrent epithelial ovarian cancer see page 30

Brigid K. Killelea, MD, MPH, FACS, and Karla Kerlikowske, MD, on breast cancer screening costs in Medicare population see page 92 and 95

Mary F. Mulcahy, MD, on do-not-resuscitate orders see page 80

James P. Allison, PhD, on immunotherapy research see page 96

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | SEPTEMBER 15, 2014

PAGE 10

Breast Cancer Symposium Disparities Persist in Early-Stage Breast Cancer Treatment, MD Anderson Study Finds

D

espite its acceptance as standard of care for early-stage breast cancer almost 25 years ago, barriers still exist that preclude patients from receiving breast-conserving therapy, with some patients still opting for a mastectomy, according to research from The University of Texas MD Anderson Cancer Center and presented recently at the 2014 Breast Cancer Symposium in San Francisco.

The study found the barriers that exist are socioeconomic, rather than medically-influenced. Meeghan Lautner, MD, formerly a Fellow at MD Anderson Cancer Center and now at The University of Texas San Antonio presented the group’s findings.1 Breast-conserving therapy for early-stage breast cancer includes surgery, followed by 6 weeks of radiation. It has been the accepted standard of care for early-stage breast cancer since 1990 when randomized, prospective clinical trials confirmed its efficacy, leading to the National Institute of Health issuing a consensus statement. Yet, a number of patients still opt for a mastectomy.

In hopes of ultimately democratizing care, it was important to look at surgical choices made by women and their association with disparities, said Isabelle Bedrosian, MD, Associate Professor, Surgical Oncology at MD Anderson.

Isabelle Bedrosian, MD

“What’s particularly novel and most meaningful about our study is that we looked at how the landscape has changed over time,” said Dr. Bedrosian, the study’s senior author. “We hope this will help us understand where we are and are not making progress, as well as identify the barriers we need to overcome to create equity in the delivery of care for our patients.”

National Cancer Database Used in Study For the retrospective, populationbased study, the MD Anderson team used the National Cancer Database,

a nationwide outcomes registry of the American College of Surgeons, the American Cancer Society, and the Commission on Cancer that captures approximately 70% of newly di-

agnosed cases of cancer in the country. They identified 727,927 women with early-stage breast cancer, all of whom were diagnosed between 1998 and 2011 and had undergone either

breast-conserving therapy or a mastectomy.

Overall, the researchers found that breast-conserving therapy rates increased from 54% in 1998 to 59%

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 11

Breast Cancer Symposium in 2006, and stabilized since then.

Adjusting for demographic and clinical characteristics, breast-conserving therapy use was more common in women aged 52 to 61 compared to younger or older patients, those with a higher education level and median income, those with private insurance, compared to those uninsured, and

in those who were treated at an academic medical center vs a community medical center.

Geographically, breast-conserving therapy rates were higher in the Northeast than in the South, and in those women who lived within 17 miles of a treatment facility compared to those who lived further away.

How Have Barriers Changed With Time?

An important question to then ask, said Dr. Bedrosian, was to compare barriers for women receiving breast-conserving therapy in 1998 to 2011 and understand how have those barriers changed. The researchers found that, overall, usage of breast-

conserving therapy has dramatically increased across all demographic and clinical characteristics, however, significant disparities related to insurance, income, and distance to a treatment facility still exist.

Dr. Bedrosian was gratified to see that in the areas where physicians and the medical field can make a direct impact, such as geographic distribution and practice type, disparities have equalized over time. However, she noted that factors outside the influence of the medical field, such as insurance type, income, and education, still remain. Of great interest is the insurance disparity, said Dr. Bedrosian.

“Now with health-care exchanges providing new insurance coverage options, will we rectify the disparity and overall increase breast-conserving therapy use? We will have wait to see,” she says.

Dr. Bedrosian hopes that health policymakers will take note of the findings and barriers related to women receiving breast-conserving therapy and make appropriate changes to democratize care. n

Isn’t it time therapy evolved?

Disclosure: The study was institutionally funded. Drs. Lautner and Bedrosian reported no potential conflicts of interest.

Unchanged for decades, standard regimens for relapsed or refractory acute myeloid leukemia (AML) seem almost prehistoric.1-3 And while the wait for an epigenetic breakthrough continues, the question is still what to do for patients with relapsed or refractory disease, whose only real hope for survival is a successful transition to transplant.4-6

In addition to Drs. Bedrosian and Lautner, other MD Anderson authors on the study included Heather Y. Lin, PhD, and Yu Shen, PhD, both Biostatistics; Henry Kuerer, MD, PhD, and Gildy Babiera, MD, both Surgical Oncology; and Simona Flora Shaitelman, MD, Radiation Oncology. Catherine Parker, MD, formerly a Fellow at MD Anderson, also contributed to the findings.

Developing novel technological approaches that may enable more patients to pursue the option of

transplant is an exciting prospect.

Complete remission (CR) is one thing, but the quality of those CRs is what ultimately matters.3 At Sunesis, we are committed to enabling the broadest constituency of patients to cross the bridge to transplant by striving to evolve better options for induction therapy.

Survival data from the largest industrysponsored multinational study on relapsed and refractory AML are expected later this year.

The ASCO Post

Driving induction forward References: 1. Yates JW, Wallace HJ Jr, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973;57(4):485-488. 2. Herzig RH, Lazarus HM, Wolff SN, Phillips GL, Herzig GP. High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia. J Clin Oncol.

1985;3(7):992-997. 3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Acute Myeloid Leukemia (Version 2.2014). © 2014 National Comprehensive Cancer Network, Inc. Available at NCCN.org. 4. Armistead PM, de Lima M, Pierce S, et al. Quantifying the survival benefit for allogeneic hematopoietic stem cell transplantation in relapsed acute myelogenous leukemia. Biol Blood Marrow Transplant. 2009;15(11):1431-1438.

5. Fung HC, Stein A, Slovak MI, et al. A long-term follow-up report on allogeneic stem cell transplantation for patients with primary refractory acute myelogenous leukemia: impact of cytogenetic characteristics on transplantation outcome. Biol Blood Marrow Transplant. 2003;9(12):766-771.

6. Biggs JC, Horowitz MM, Gale RP, et al. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood. 1992;80(4):1090-1093.

SUNESIS and the related logo are trademarks of Sunesis Pharmaceuticals, Inc. © 2014 Sunesis Pharmaceuticals, Inc., South San Francisco, CA 94080. All Rights Reserved. Printed in USA S-14-001

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Best of ASCO® Gynecologic Oncology

In Managing Ovarian Cancer, Precision Medicine Is a Work in Progress

By Charlotte Bath

P

recision medicine in the management of ovarian cancer “is a work in progress, to be sure,” Steven B. Newman, MD, noted in wrapping up the session on gynecologic cancer at the recent Best of ASCO meeting in Chicago. “A list of different histologic types of ovarian cancer and potential targets are currently being looked at,” he said, but much work needs to be done in matching specific genetic sequences, defects, and therapeutic agents. Dr. Newman is Associate Professor of Clinical Medicine-Hematology/Oncology at Northwestern University, Feinberg School of Medicine, Chicago.

“Progress in extending the lives of women with recurrent ovarian cancer has hit a therapeutic ceiling. A lot of that has to do with the fact that the best therapy, which is given upfront, is really the only good therapy we have. While these molecular targets may in fact have added value going forward, the targets are going to have to be considerably more precise than they are now,” Dr. Newman continued.

“The biology of these tumors is different enough that any one compound for any one target is probably going to be limited in scope. At the end of the day, this is going to lead to a cavalcade of drugs that may be useful in a specific tumor, but not overall, the way paclitaxel and carboplatin are,” he added.

MUC1 Dendritic Cell Vaccine Immunotherapy Targets Mucin The phase II open-label CAN-003 trial of, a targeted therapy known as CVac (made by culturing autologous dendritic cells with a mucin 1 fusion protein), was among the gynecologic cancer studies summarized at Best of ASCO. An autologous cellular therapy intended to elicit a killer T-cell response specific to mucin 1–overexpressing ovarian cancer cells, CVac produced a significant improvement in progression-free survival over observational standard of care in patients with epithelial ovarian cancer who had obtained a complete response after second-line chemotherapy.1 Mucin 1 is overexpressed in several cancers, including 83% of ovarian cancers, and “should in theory be a reasonable target,” Dr. Newman observed.

Among the 56 patients in the intentto-treat population, 29 were randomly assigned to 10 doses of CVac over 56 weeks and 27 to observational standard

of care. All patients had stage III or IV epithelial ovarian cancer, and 42 had achieved a complete response to standard first-line chemotherapy, while 21 had achieved a complete response to second-line chemotherapy.

Progression-free survival was significantly improved in 20 patients in second-line complete response receiving CVac compared to standard of care. In the second-line complete responders, the median progression-free survival was 4.94 months for patients receiving observational standard of care, but for patients receiving CVac, the median progression-free survival was not reached but greater than 12.91 months (P = .04). Progression-free survival was not improved among patients with a complete response to first-line chemo-

angiogenesis-related gene expression, these patients would benefit less from bevacizumab (Avastin). A 63-gene expression signature was generated to prospectively identify this subgroup and validated as prognostic for overall survival.

The gene signature was then applied to translational research samples from the ICON 7 study of paclitaxel/ carboplatin with and without concomitant and maintenance bevacizumab for first-line treatment of ovarian cancer. The assay showed that for patients in the immune molecular subgroup (41% of cases), the addition of bevacizumab resulted in worse progressionfree survival (HR = 1.73, 95% confidence interval [CI] = 1.12–2.68) and overall survival (HR = 2.00, 95% CI =

The biology of these tumors is different enough that any one [targeted agent] for any one target is probably going to be limited in scope.

At the end of the day, this is going to lead to a cavalcade of drugs that may be useful in a specific tumor, but not overall, the way paclitaxel and carboplatin are?

—Steven B. Newman, MD

therapy receiving CVac (hazard ratio [HR] = 1.8; P = .69). The overall median progression-free survival was 8.64 months with observational standard of care and 12.89 with CVac. Nine serious adverse events occurred. None were unexpected, and only one (small bowel obstruction) was classified as “unlikely–related to CVac,” the researchers reported.

CVac therapy is “feasible and doable,” Dr. Newman said. Many questions remain about overall survival, but “I think the important thing to take home here is that there is a target,” he added.

Predicting Benefit From Bevacizumab Following the identification of an immune molecular subgroup of highgrade serous ovarian cancer with superior survival, researchers from the United Kingdom hypothesized that since this subgroup had repressed

1.11–3.61) compared to chemotherapy alone.

Two other subgroups identified had angiogenic gene upregulation, and among patients in the proangiogenic subgroups, there was a nonsignificant trend to improved progression-free survival with the addition of bevacizumab (median, 17.4 vs 12.3 months), the researchers noted in their ASCO Annual Meeting abstract.2 “These data suggest a mechanism for stratification of [bevacizumab] therapy and should be validated in additional datasets,” the authors concluded.

“This is a really important paper,” Dr. Newman commented. “We’re talking about the administration of an extremely expensive compound” that in many cases has, at best, only marginal survival benefit to patients. “There does appear to be a group of patients for which the addition of bevacizumab not only doesn’t help,” Dr. Newman said, but can actually be associated with less favor-

able outcomes. By identifying patients most likely to benefit from a drug, studies such as this may drive discussions about the value of a specific drug, Dr. Newman noted.

First-Line Standard of Care A Japanese Gynecologic Oncology Group ( JGOG)/Gynecologic Cancer Intergroup (GCIG) phase III trial compared paclitaxel/carboplatin to cisplatin/irinotecan as first-line chemotherapy in patients with clear cell carcinoma of the ovary. A histologic subtype of epithelial ovarian cancer, clear cell carcinoma represents 19% of ovarian cancers in Japan, but only 6% in the United States. “[Clear cell carcinoma] has become well known for its resistance to current standard chemotherapy [paclitaxel/ carboplatin]. Our previous trial demonstrated the potential benefit of [cisplatin/irinotecan] regimen on [clear cell carcinoma],” wrote the Japanese researchers in their ASCO abstract.3 In the current trial, however, progressionfree survival, the primary endpoint, was not significantly different between the two study arms.

“Sometimes good intentions go unrewarded, and this is one of those situations,” Dr. Newman said. “Carboplatin/ paclitaxel remains the standard of care.”

He noted that over the years, “there has certainly been no shortage of randomized trials comparing other agents to carboplatin/paclitaxel.”

At 44.3 months’ median follow-up, 2-year progression-free survival among the 314 evaluable patients in the cisplatin/irinotecan arm was 73.0% (95% CI = 67.7–77.5) vs 77.6% (95% CI = 72.4– 81.9) among the 305 evaluable patients in the paclitaxel/carboplatin arm (HR = 1.171, 95% CI = 0.867–1.581, P = .303). The 2-year overall survival rates were 85.5% in the cisplatin/irinotecan arm (95% CI = 81.1–89.0) and 87.4% in the paclitaxel/carboplatin arm (95% CI = 83.1–90.7; HR = 1.133, 95% CI = 0.796–1.613, P = .486).

“In the early stage of the disease, there is absolutely no difference whatsoever,” Dr. Newman said. “In the later stages, there is some difference. It does not approach statistical significance, but there appears to be some advantage to the [cisplatin/irinotecan] regimen.”

Grade 3/4 leukopenia, neutropenia, thrombocytopenia, peripheral sensory neuropathy, and joint pain occurred

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 13

Best of ASCO® more frequently in the paclitaxel/carboplatin arm (P < .05), whereas grade 3/4 anorexia, diarrhea, nausea, vomiting, and febrile neutropenia occurred more frequently in the cisplatin/irinotecan arm (P < .05).

“Since both regimens were well tolerated and the toxicity profiles were different, CPT-P can be an alternative regimen for [clear cell carcinoma],” the study’s authors stated.

serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab.

ASCO Annual Meeting. Abstract 5502.

Presented May 31, 2014.

3. Okamoto A, Sugiyama T, Hamano T, et al: Randomized phase III trial of paclitaxel/carboplatin (PC) versus cisplatin/irinotecan (CPT-P) as first line chemotherapy in patient with clear cell carcinoma (CCC) of

the ovary. ASCO Annual Meeting. Abstract 5507. Presented May 31, 2014.

4. Liu J, Barry WT, Birrer, MJ, et al: A randomized phase 2 trial comparing efficacy of the combination of the PARP-inhibitor olaparib and the anti-angiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. ASCO Annual Meeting. Abstract 5500. Presented

May 31, 2014.

5. Onda T, Yoshikawa H, Shibata T, et al: Comparison of treatment invasiveness between upfront debulking surgery versus neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in phase III randomized trial. ASCO Annual Meeting. Abstract 5508. Presented May 31, 2014.

Previously Reported Studies Dr. Newman also reviewed two other ovarian cancer studies presented at the 2014 ASCO Annual Meeting.

A phase II trial, reported in detail in the June 25, 2014, issue of The ASCO Post, found that the oral investigational agents olaparib and cediranib nearly doubled progression-free survival in women with platinum-sensitive recurrent ovarian cancer.4 A phase III trial, described in the same issue of The ASCO Post, suggested that neoadjuvant chemotherapy followed by interval debulking surgery may be a better strategy for the initial treatment of advanced ovarian cancer.5 n Disclosure: Dr. Newman reported no potential conflicts of interest.

References 1. Gray HJ, Gargosky SE: Progressionfree survival in ovarian cancer patients in second remission with mucin-1 autologous dendritic cell therapy. ASCO Annual Meeting. Abstract 5504. Presented May 31, 2014.

2. Gourley C, McCavigan A, Perren T, et al: Molecular subgroup of high-grade

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The ASCO Post | SEPTEMBER 15, 2014

PAGE 14

Best of ASCO® Genitourinary Oncology

Studies Help Refine Management of Prostate Cancer

By Susan London

S

everal studies reported at this year’s ASCO Annual Meeting address gray areas in the management of prostate cancer, according to Evan Y. Yu, MD, Associate Professor at the University of Washington and the Seattle Cancer Care Alliance. “In prostate cancer, probably the most excitement has happened within the last 4 years. We have really made a lot of great changes, and I feel fortunate to be in this field,” he commented at the Best of ASCO meeting held in Seattle, where he recapped some of the key abstracts and shared his own perspectives.

Deferring Androgen Deprivation After Relapse After treatment of clinically localized prostate cancer, management of biochemical recurrence, indicated by

rising prostate-specific antigen (PSA), remains one such gray area, generating anxiety for patients and clinicians alike, according to Dr. Yu. In an analysis of data from CaPSURE, investigators compared immediate initiation of androgen-deprivation therapy vs deferred initiation—defined as waiting 2 years or until symptomatic, imaging, or PSA doubling evidence of metastases—in men who had a PSA-only relapse.1 Results showed statistically indistinguishable 5- and 10-year rates of all-cause mortality and prostate cancer–specific mortality between the two strategies.

“The key here is this probably doesn’t change standard of care, whatever standard of care is. And in the United States, we probably tend to get a little nervous when the PSA rises high or is rising fast, and start [androgen-deprivation ther-

When Should Chemotherapy Be Used in Metastatic Prostate Cancer?

Q

uestions abound when it comes to the optimal timing and sequencing of chemotherapy in metastatic prostate cancer, according to Dr. Yu. For example, arguments could be made both for using it earlier, while disease is still hormone-sensitive, or later, after hormonal resistance emerges.

“For quality-of-life reasons, many patients don’t want chemotherapy. So this is something that is probably individually based. I think it’s a worthwhile discussion with the patient,” he recommended.

Additionally, if patients are given docetaxel up front, as in the CHAARTED trial, in new metastatic hormone-sensitive prostate cancer, what is the best course of action when the disease becomes castrationresistant? “Do you go back to docetaxel for retreatment? Move on to cabazitaxel [ Jevtana]? That’s not clear either,” Dr. Yu said. “There are cost considerations though. Docetaxel is off patent, so it’s certainly much more affordable than cabazitaxel.”

Castration-Resistant Disease Another question is, what is the appropriate niche for chemotherapy in metastatic castration-resistant prostate cancer? Here, arguments could be made for using it in patients with visceral disease, given their much more aggressive course and much worse prognosis; for patients with rapidly progressive disease, as signaled by prostate-specific antigen; for patients who have primary resistance to abiraterone (Zytiga) or enzalutamide (Xtandi); or for patients with acquired resistance to either of those agents.

“None of this is clear in the field. So we really have an embarrassment of riches right now—this huge smorgasbord of options. How to choose, how to sequence, it’s very unclear in our field right now,” he commented.

Forthcoming results of a phase II trial called PRIMCAB may offer some guidance, according to Dr. Yu. Patients with primary hormonal resistance, defined as progressive disease within 6 months of receiving either abiraterone or enzalutamide, are randomly assigned to either the alternate hormonal agent or cabazitaxel.

“This is an interesting study, and it really addresses an unanswered question in the field, which is should we be moving chemotherapy earlier, especially if you have already started to show disease progression on one of these novel hormonal therapy agents,” he said. n

apy] before the patient has metastatic disease,” Dr. Yu commented. However, he added, most of the patients studied had low-risk disease; at 10 years, only 30% had died and merely 10% had died of prostate cancer.

“I’m not sure what intervention might improve upon whatever other

if moved earlier (see sidebar, “Pros and Cons of Early Chemohormonal Therapy” on page 15).

Patients with radiographically detectable metastases were randomized to continuous androgen-deprivation therapy plus docetaxel or androgen ablation alone. The primary end-

For metastatic hormone-sensitive prostate cancer, six cycles of docetaxel in addition to androgen deprivation is a new acceptable standard of care.

—Evan Y. Yu, MD

intervention we use when most of your patients don’t die of the disease. They are going to live a long time and die of other causes,” he said.

An ongoing collaborative phase III trial in Australia2 exploring the optimal timing of androgen-deprivation therapy initiation in this context may help provide more guidance in this area. However, “my concern even with this phase III trial is that the eligibility criteria are loose. It’s not picking the highest-, highest-risk patients. I think to make an impact here, you have to pick those patients,” Dr. Yu said.

Chemohormonal Therapy for Newly Metastatic Disease The randomized phase III CHAARTED trial compared chemohormonal therapy with hormonal therapy in men with hormone-sensitive newly metastatic prostate cancer.3 The rationale came in part from the observation that adding chemotherapy had a benefit in castration-resistant metastatic disease, so it might be similarly efficacious

point of overall survival was significantly better with chemohormonal therapy, with a median 13-month gain (hazard ratio [HR] = 0.61); subgroup analyses suggested benefit was restricted to patients with highvolume disease, defined as presence of visceral metastases or four bone lesions, at least one of them outside the axial skeleton, with a median 17-month gain in overall survival in this subset (HR = 0.60).

Dr. Yu concurred with the authors that these data are practice-changing.

“For metastatic hormone-sensitive prostate cancer, six cycles of docetaxel in addition to androgen deprivation is a new acceptable standard of care,” he stated.

And cost analyses are also favorable for this chemohormonal combination, given that docetaxel has come off patent.

At the same time, Dr. Yu noted that patients with low-volume disease have had shorter follow-up, and the definition of high-volume disease is somewhat arbitrary (see sidebar, “What Constitutes High-Volume, Extensive

Important New Data in Prostate Cancer ■■ Men with a PSA-only relapse have similar all-cause and prostate cancer– specific mortality whether androgen-deprivation therapy is initiated immediately or deferred for up to 2 years.

■■ Chemohormonal therapy has an overall survival benefit relative to hormonal therapy in men with hormone-sensitive newly metastatic prostate cancer.

■■ Orteronel plus prednisone improves radiographic progression-free survival but not overall survival in men with chemotherapy-naive metastatic castration-resistant disease.

■■ Men with metastatic prostate cancer who are positive for AR-V7 are less likely to have a response to abiraterone or enzalutamide.

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 15

Best of ASCO® Disease?” on page 16). He also questioned the emphasis placed on the negative subgroup finding in patients with low-volume disease, given that conventional wisdom is to deemphasize positive subgroup findings in negative trials.

“We obviously need to see the qualityof-life data, and we anticipate there will be toxicities from the docetaxel, but it is only six cycles,” he said.

subsequent therapies that prolong survival in prostate cancer, that they would have been positive,” he noted. But given the data, “orteronel development has basically ceased.”

That said, orteronel trials being conducted by cooperative groups like SWOG and the Radiation Therapy Oncology Group are still ongoing.

Biomarkers are an area of intensive research in metastatic prostate cancer, according to Dr. Yu. “We definitely need predictive biomarkers in prostate cancer—we need our EGFRs, our HER2s, our KRASs. And variant 7 of the androgen receptor (AR-V7) is potentially a very promising biomarker,” he commented. This splice variant al-

lows the internal domain of the receptor to be constitutively active, even without a ligand, making it a possible resistance mechanism.

In a study reported at the Annual Meeting, investigators assessed the presence of AR-V7 in circulating tumor cells from patients with metastatic continued on page 16

New Data on CastrationResistant Prostate Cancer A randomized phase III trial of o­rteronel (formerly TAK-700) plus prednisone in chemotherapy-naive patients with metastatic castrationresistant disease yielded disappointing results.4 There was a 5.1-month radiographic progression-free survival benefit (HR = 0.71) but no significant overall survival benefit.

“Many people have noted that if these [orteronel] trials were done a year, a year and a half earlier, without so much confounding from all the other

Pros and Cons of Early Chemohormonal Therapy

T

here is considerable debate about moving chemohormonal therapy to an earlier point in the treatment of prostate cancer, at the time of initial diagnosis of metastases, according to Dr. Yu. In the pro column, “You might hit those de novo testosterone-independent clones if they exist.” Additionally, if one waits until the time of progression, some patients may be too frail to receive chemotherapy.

“The cons: a lot of people, admittedly like myself, thought there was potential for failure because when you give people [androgen-depriation therapy], it takes the cells out of the cell cycle. You get cell-cycle arrest, and your chemotherapy doesn’t do anything except add toxicity. In addition, we have data in breast cancer that shows we don’t do them together.” Furthermore, “some patients respond for a long period of time with initial [androgen-deprivation therapy] and may die of other causes and don’t even need chemotherapy.

So why introduce that toxicity?

That’s the debate.” n

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The ASCO Post | SEPTEMBER 15, 2014

PAGE 16

Best of ASCO® Prostate Cancer Management continued from page 15

castration-resistant prostate cancer.5 Compared with counterparts who were negative for this variant, patients who were positive had a dramatically higher risk of progression or death if treated with abiraterone (Zytiga; HR = 16.5) or enzalutamide (Xtandi; HR = 8.5).

Additionally, prevalence of AR-V7 appeared to increase with the extent of exposure to hormonal agents. It was 11.6% in patients who had received neither drug, 25.0% in those who had received only enzalutamide, 51.2% in those who had received only abiraterone, and 66.7% in those who had received both.

“AR-V7 warrants further evaluation as a potential predictive biomarker. A randomized controlled study to determine predictive value may show AR-V7 to be a negative predictor of response to these therapies,” Dr. Yu commented. “The bar is probably lower for getting this biomarker approved, more like a KRAS, because it’s not selecting you for therapy, it is selecting you away from certain therapy.” These data could also help inform development of inhibitors of the intracellular N-terminal domain of the androgen receptor, he added. n

Disclosure: Dr. Yu has received research funding from Bristol-Myers Squibb, Dendreon, Janssen, and OncoGeneX and consulting honoraria from Bayer, Dendreon, Janssen, Medivation/Astellas, and Sanofi-Aventis.

References 1. Garcia-Albeniz X, Chan JM, Paciorek AT, et al: Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. ASCO Annual Meeting. Abstract 5003. Presented June 1, 2014.

2. Androgen deprivation therapy in treating patients with prostate cancer.

Available at clinicaltrials.gov, identifier NCT00110162, last updated August 6, 2013.

3. Sweeney C, Chen Y-H, Carducci MA, et al: Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOGled phase III randomized trial. ASCO Annual Meeting. Abstract LBA2. Presented June 1, 2014.

4. De Wit R, Fizazi K, Jinga V, et al: Phase 3, randomized, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients (pts) with chemotherapynaïve metastatic castration-resistant prostate cancer (mCRPC) (ELM-PC 4 trial).

ASCO Annual Meeting. Abstract 5008.

Presented June 1, 2014.

5. Antonarakis ES, Lu C, Wang H, et al:

What Constitutes High-Volume/Extensive Disease?

“I

’m not sure what extensive disease really is, but in some patients, when you see it, you really recognize it. In other patients, it’s not 100% clear,” Dr. Yu commented (Fig. 1). Some patients with multiple medium or large lesions in bone would clearly meet the definition used in the CHAARTED trial (left). Others with widespread but tiny lesions would fulfill the criteria as well (middle). However, a patient whose entire hemipelvis is involved by tumor but who has no other bony metastases would be classified as having low-volume disease (right). “So I think there is controversy and potential problems with this classification of low-volume vs high-volume disease,” Dr. Yu maintained. n

Fig. 1: What Is Extensive Disease? Courtesy of Michael Morris, ASCO 2014.

Androgen receptor splice variant, AR-V7, and resistance to enzalutamide and abiraterone in men with metastatic castration-

resistant prostate cancer (mCRPC). ASCO Annual Meeting. Abstract 5001. Presented June 1, 2014.

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PAGE 19

Best of ASCO® Hematology

‘Paradigm-Shifting’ Results in Treatment of Hematologic Disorders

By Charlotte Bath

T

he three leukemia/lymphoma studies selected from the many 2014 ASCO Annual Meeting abstracts for presentation at the recent Best of ASCO meeting in Chicago “are really paradigm-shifting,” noted Lucy A. Godley, MD, PhD, of the University of Chicago. These studies, she said, “give great promise for new therapies” for patients with acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and polycythemia vera.

Blinatumomab Activity Confirmed A large phase II trial confirmed the antileukemia activity of single-agent blinatumomab among difficult-totreat patients with relapsed/refractory B-precursor acute lymphoblastic leukemia. Within the first two cycles of treatment (continuous intravenous infusion, 4 weeks on 2 weeks off), 43% of patients achieved complete remission or complete remission with partial hematologic recovery. “For treating patients who had refractory ALL, this is a remarkable percentage,” Dr. Godley commented.

“Blinatumomab, an investigational bispecific T-cell engaging (BiTE) antibody that directs cytotoxic T cells to CD19-expressing target cells, has shown antileukemia activity in an exploratory study in adult relapsed/refractory B-precursor ALL,” according to the ASCO abstract.1 Blinatumomab “brings cytotoxic T cells into physical proximity and really to touching B cells,” Dr. Godley explained. “And these cytotoxic T cell use perforin [a cytolytic protein] and other enzymes to kill that B cell within minutes, at least when that has been measured in vitro. It’s a very novel mechanism of action and really brings great promise to our ALL patients.”

Bridge to Stem Cell Transplant The study was open to adults (≥ 18 years old) with Philadelphia chromosome–negative B-precursor ALL who had primary refractory disease, early relapse (duration of first remission ≤ 12 months), relapse within 12 months of allogeneic hematopoietic stem cell transplantation, or any relapse or refractory disease after first salvage therapy.

“Importantly here, patients had to have more than 10% bone marrow blasts at the time of going on the study and had

to be well-performing patients,” Dr. Godley said.

The median age of the 189 study participants was 39 years (range, 18–79), and 63% were male. A total of 39% had received two or more salvage therapies, and 34% had undergone prior allogeneic stem cell transplant.

“One of the critical elements of this abstract,” Dr. Godley stated, is where the responses were seen. “These responses were seen largely in patients who had lower disease burden—less than 15% bone marrow blasts at the time of enrollment in the study. Patients who had greater than 75% bone marrow blasts really did not do well. So this generates ideas of how blinatumumab will be most effective moving forward.”

The most effective way to use blinatumumab may be “to bridge patients to first or potentially second allogeneic

( Jakafi) was shown to be superior to best supportive therapy in controlling hematocrit without phlebotomy and reducing spleen volume in the phase III RESPONSE trial. “RESPONSE is the first phase III study to evaluate a JAK inhibitor in treating [polycythemia vera],” according to the Annual Meeting abstract.2 Ruxolitinib is a JAK1/ JAK2 inhibitor approved by the U.S. Food and Drug Administration for patients with intermediate- or high-risk myelofibrosis.

Phlebotomy-dependent patients with splenomegaly (≥ 450 cm3) who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to ruxolitinib at 10 mg twice a day or investigator-selected best available therapy (eg, interferon, anagrelide, pipobroman [Vercyte], an immunomodulatory drug, or observation). The

Ruxolitinib may be a valuable new treatment option in patients with polycythemia vera. This is just the first-in-class for JAK inhibitors; it will be very exciting to see the development of other JAK inhibitors.

—Lucy A. Godley, MD, PhD

stem cell transplant,” she noted.

The most frequently reported adverse events were pyrexia (59%), headache (35%), and febrile neutropenia (29%). The most frequent grade ≥ 3 adverse events were febrile neutropenia (26%), anemia (15%), and neutropenia. The most common grade ≥ 3 nervous system disorders were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients had grade 5 adverse events that were considered treatment-related, two with sepsis and one with Candida infection.

“A randomized, open-label phase III study of blinatumomab in this patient population is currently underway,” Dr. Godley said. “Some larger questions that arise from this work come when we think about how can we move the drug from a relapse setting into the front-line setting.”

Ruxolitinib for Hematocrit Control Maintaining hematocrit control is a key therapeutic goal in patients with polycythemia vera, and ruxolitinib

initial randomization assigned 110 patients to treatment with ruxolitinib and 112 to best available therapy, but 108 best available therapy patients (96%) discontinued randomized treatment and 96 crossed over to ruxolitinib. By contrast, 17 ruxolitinib patients (15%) discontinued treatment.

‘Hands-Down Winner’ The primary endpoint was the proportion of patients who achieved both hematocrit control without phlebotomy from week 8 to week 32 (with ≤ 1 phlebotomy from week 0 to week 8) and a ≥ 35% reduction in spleen volume at week 32. “The primary response was the ability of patients to not need transfusions any more. The primary endpoint was achieved in 21% of ruxolitinib patients compared to only 1% of patients receiving best available therapy,” Dr. Godley stated (P < .0001).

At least one component of the primary endpoint was achieved by 77% of patients assigned to ruxolitinib.

The duration of response “was offthe-scale positive,” Dr. Godley added.

At week 48, 91% of ruxolitinib patients maintained their response.

Complete hematologic response was achieved in 23.5% of ruxolitinib patients vs 9% of the best available therapy group (P = .003). Among the 26 patients who achieved a complete hematologic response, 23 (88.5%) maintained it at week 48. In addition, ≥ 50% improvement in a 14-item myeloproliferative neoplasm symptom score was achieved by 49% of patients receiving ruxolitinib at week 32 vs 5% of best available therapy recipients. “Treatment with ruxolitinib wins hands-down over best available therapy,” Dr. Godley declared.

Ruxolitinib was generally well tolerated. “Most adverse events were grade 1/2, and few patients developed grade 3/4 cytopenias,” Dr. Godley reported.

She pointed out that “a few more events of nonmelanoma skin cancer” occurred among patients receiving ruxolitinib.

Four patients receiving ruxolitinib had nonmelanoma skin cancer (grade 3/4 in 3), vs two patients receiving best available therapy (grade 3/4 in 1).

Seven patients in the ruxolitinib group developed herpes zoster infections (no grade 3/4), whereas none of the patients in the best available therapy group did.

In conclusion, Dr. Godley said that the “data demonstrate that ruxolitinib may be a valuable new treatment option in this population of patients with polycythemia vera. This is just the first-inclass for JAK inhibitors,” she noted. “It will be very exciting to see the development of other JAK inhibitors.”

Ibrutinib for Second-Line CLL/SLL The 391-patient RESONATE study found that ibrutinib (Imbruvica) significantly improved response, progression-free survival, and overall survival compared to ofatumumab (Arzerra) in second-line chronic lymphocytic leukemia/small lymphocytic leukemia.3 (The study was reported in detail in the June 25 issue of The ASCO Post.)

“This study establishes ibrutinib as an effective, new single-agent therapy” for patients with CLL/SLL “and the new standard of care,” Dr. Godley stated. She noted that mutations have been identified in all six study patients who were resistant to ibrutinib, along with two different mechanisms of recontinued on page 20

The ASCO Post | SEPTEMBER 15, 2014

PAGE 20

FDA Update

FDA Approves Pembrolizumab for Advanced Melanoma

T

he U.S. Food and Drug Administration (FDA) today granted accelerated approval to the anti–PD-1 antibody pembrolizumab (Keytruda) for the treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs.

Pembrolizumab is intended for use following treatment with ipilimumab (Yervoy). For melanoma patients with

BRAF V600–positive tumors, pembrolizumab is intended for use after treatment with ipilimumab and a BRAF ­inhibitor. “[Pembrolizumab] is the sixth new melanoma treatment approved since 2011, a result of promising ad-

vances in melanoma research,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

“Many of these treatments have dif-

ferent mechanisms of action and bring new options to patients with melanoma.”

The FDA action was taken under the agency’s accelerated approval program, which allows approval of a drug to treat

Hematologic Disorders continued from page 19

sistance. “It will be very interesting to see, as so many more patients are going to be treated now, if these two mechanisms of resistance persist,” Dr. Godley remarked. n Disclosure: Dr. Godley reported no potential conflicts of interest.

References 1. Topp MS, Goekbuget N, Stein AS, et al: Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r/ ALL). ASCO Annual Meeting. Abstract 7005. Presented June 3, 2014.

2. Verstovek S, Kiladjian J-J, Greisshammer M, et al: Results of a prospective, randomized, open-label phase 3 study of ruxolitinib (RUX) in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU): The RESPONSE trial ASCO Annual Meeting. Abstract 7026.

Presented June 3, 2014.

3. Byrd JC, Brown JR, O’Brien SM, et al: Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic lymphoma: Results from the phase III RESONATE trial. ASCO Annual Meeting. Abstract LBA7008. Presented June 3, 2014.

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

All submissions will be considered for publication

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PAGE 21

FDA Update

a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

Clinical Trial Results Pembrolizumab’s efficacy was established in 173 clinical trial par-

ticipants with advanced melanoma whose disease progressed after prior treatment. All study participants were treated with pembrolizumab, either at the recommended dose of 2 mg/kg or at a higher dose of 10 mg/kg.

In the half of the participants who received pembrolizumab at the rec-

ommended dose of 2 mg/kg, approximately 24% had their tumors shrink.

A similar percentage of patients had their tumor shrink at the 10-mg/kg dose.

Pembrolizumab’s safety was established in the trial population of 411 participants with advanced melanoma. The most common side ef-

fects of the drug were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.

Severe immune-mediated side effects involving healthy organs, including the lung, colon, hormoneproducing glands, and liver, were uncommon. n

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The ASCO Post | SEPTEMBER 15, 2014

PAGE 22

FDA Update

Novel Immunotherapy for Ovarian Cancer Receives Fast Track Designation

T

he U.S. Food and Drug Administration (FDA) has granted fast track designation to the investigation of motolimod (VTX-2337) when administered in combination with pegylated liposomal doxorubicin for the treatment of

women with ovarian cancer whose disease has progressed on or recurred after platinum-based chemotherapy.

Motolimid is a novel Toll-like Receptor 8 (TLR8) immunotherapy currently being evaluated in two randomized, pla-

cebo-controlled phase II trials. The agent directly activates multiple components of the innate immune system, including human myeloid dendritic cells, monocytes, and natural killer cells, which results in the production of high levels of

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PAGE 23

FDA Update

mediators known to orchestrate the integration of innate and adaptive antitumor responses.

Clinical Trials Underway Results from preclinical models suggest that combining motolimod with pegylated liposomal doxorubicin may provide a synergistic effect in stimulating

a variety of immune pathways associated with antitumor activity. A recently completed phase I trial in this same study population demonstrated that the combination was safe and well-tolerated.

VentiRx has completed enrollment of over 290 patients in the GOG-3003 randomized, placebo-controlled phase II trial of motolimod in combination

with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer for whom prior platinum-based chemotherapy has failed. The primary endpoint of the study is overall survival. In April 2014, the FDA granted Orphan Drug designation to motolimod for the treatment

of ovarian cancer.

GOG-3003 is one of two phase II clinical trials of motolimod currently underway. The second trial, called Active8, is a company-sponsored, randomized, phase II placebo-controlled trial in patients with locally advanced and metastatic squamous cell carcinoma of the head and neck. n

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The ASCO Post | SEPTEMBER 15, 2014

PAGE 24

FDA Update

FDA Grants Fast Tract Designation to Investigational Combination Therapy In Metastatic Pancreatic Cancer

T

he U.S. Food and Drug Administration (FDA) has granted Fast Track designation for Halozyme Therapeutics’ program investigating pegylated recombinant human hyaluronidase

(PEGPH20) in combination with gemcitabine and albumin-bound paclitaxel (nab-paclitaxel [Abraxane]) for the treatment of patients with metastatic pancreatic cancer to demonstrate an

improvement in overall survival.

“The FDA’s Fast Track designation for our PEGPH20 program in pancreatic cancer underscores the significant need for new treatment options for pan-

creatic cancer patients with advanced disease,” stated Helen Torley, MD, President and Chief Executive Officer of Halozyme. “We look forward to continuing to work with the FDA on this program to explore whether patients with metastatic pancreatic cancer can benefit from this therapy.”

The Fast Track designation process was developed by the FDA to facilitate the development, and expedite the review of drugs to treat serious or lifethreatening diseases and address unmet medical needs. n

Save the Date

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13th International Conference on Malignant Lymphoma (ICML) June 17–20, 2015 Lugano, Switzerland The 13-ICML will bring 3,000 physicians to Lugano from all over the world: hematologists, clinical oncologists, radiation oncologists, pediatricians, pathologists, and leading researchers involved in the study and treatment of lymphoid neoplasms.

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ASCOPost.com | SEPTEMBER 15, 2014

PAGE 25

Journal Spotlight Genitourinary Oncology

European Researchers at 13-Year Follow-up: Increased Absolute Benefit of PSA Screening in Prostate Cancer Mortality, but ‘Time for Population-Based Screening Has Not Arrived’

By Matthew Stenger

T

he 13-year follow-up of the European Randomized Study of Screening for Prostate Cancer (ERSPC), reported by Fritz H. ­ Schröder, MD, PhD, Professor Emeritus of Urology at Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues in The Lancet, showed that prostate-specific antigen (PSA) screening in men aged 55 to 69 years is associated with a 21% reduction in risk of prostate cancer mortality and with an increase in absolute benefit since the 9- and 11-year follow-ups.1 Nevertheless, given the potential harms associated with overdiagnosis in screening (estimated by the authors to include 40% to 50% of screen-detected cases) and resultant overtreatment, the authors concluded that populationbased screening could not yet be recommended.

Study Details In the ERSPC, men aged 50 to74 years identified from population registries in eight European countries (the Netherlands, Belgium, Sweden, Finland, Italy, Spain, Switzerland, and France) were randomized to PSA screening or no intervention.

The screening interval was 4 years (2 years in Sweden). Screening was discontinued after 2 rounds in France and 3 rounds in Belgium, Finland, and Spain, and continued for up to 5 rounds in the Netherlands and 10 in Sweden.

The primary endpoint of the study was prostate cancer mortality in the core age group of 55 to 69 years on an intent-to-treat basis. A secondary analysis of mortality in screened men was performed to correct for selection bias due to nonparticipation.

Data from France are included in

the assessment of 9-year prostate cancer incidence but not in assessment of mortality, due to incomplete follow-up through 2010. The analysis of mortality in the core age group includes 162,388

1,000 men randomized, which is equivalent to 1 prostate cancer death prevented per 781 (95% CI = 490–1,929) men invited for screening (number needed to invite) or 1 per 27 (95% CI = 17–66)

Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening.

—Fritz H. Schröder, MD, PhD, and colleagues

randomly assigned men and the analysis in the entire cohort includes 181,999 randomly assigned men.

Incidence in Core Age Group In the core age group (excluding France), 7,408 prostate cancer cases were diagnosed in the screening group and 6,107 were diagnosed in the control group. The rate ratio of prostate cancer incidence for the screening vs control groups was 1.91 (95% confidence interval [CI] = 1.83–1.99) after 9 years (1.64, 95% CI = 1.58–1.69, including France), 1.66 (95% CI = 1.60– 1.73) after 11 years, and 1.57 (95% CI = 1.51–1.62) after 13 years.

Risk Reduction The rate ratio of prostate cancer mortality for the core intervention vs control groups was 0.85 (95% CI = 0.70–1.03) after 9 years, 0.78 (95% CI = 0.66–0.91) after 11 years, and 0.79 (95% CI = 0.69– 0.91, P = .001) after 13 years.

The absolute risk reduction at 13 years (after adjustment for a randomization ratio of 1:1.5 in Finland) was 0.11 per 1,000 person-years or 1.28 per

PSA Screening in Prostate Cancer ■■ Screening was associated with a 21% reduction in risk for prostate cancer mortality and a 27% reduction after adjustment for nonparticipation.

■■ The number needed to invite (NNI) of 781 and number needed to detect (NND) of 27 to prevent 1 prostate cancer death represent a greater absolute benefit of screening than the NNI of 1,410 and NND of 48 after 9 years of follow-up and the NNI of 979 and NND of 35 at 11 years.

additional prostate cancers detected (number needed to detect). These figures represent improvements from the number needed to invite of 1,410 and number needed to detect of 48 (risk reduction of 0.10/1,000 person-years and 1.02/1,000 men) observed after 9 years of follow-up and the number needed to invite of 979 and number needed to detect of 35 (risk reduction of 0.06/1,000 person-years and 0.46/1,000 men) observed after 11 years.

After adjustment for nonparticipation, the rate ratio of prostate cancer mortality in the screening vs control groups was 0.73 (95% CI = 0.61–0.88).

Additional Findings Screening was also associated with reduced risk of prostate cancer mortality in the entire cohort of men aged 50 to 74 years (excluding France), with a rate ratio for screening vs control of 0.83 (95% CI = 0.73–0.94, P = .004).

Analysis of prostate cancer death in the core age group at individual centers showed significantly reduced risk only in Sweden (rate ratio =0.62, 95% CI = 0.41–0.92) and the Netherlands (rate ratio = 0.67, 95% CI = 0.51–0.88). The authors noted that a more extensive analysis of effects at individual centers that includes adjustment for noncompliance is to be performed.

There was no difference between the screening and control groups in allcause mortality in the core age group (rate/1,000 person-years = 18.6 vs 18.9, rate ratio = 1.00, P = .82) or in the entre

cohort (rate/1,000 person-years = 19.5 vs 19.6, rate ratio = 1.00, P = .98).

Conclusions The investigators concluded, “In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening.”

They added: Our data show a significant relative reduction in prostate cancer mortality when comparing the screening group and control group of 21% and 27% in men who participated in the study. The main weakness of screening is a high rate of overdiagnosis and overtreatment. We conclude that the time for population-based screening has not arrived. In the present situation, early diagnosis cannot be refused to men who are well informed and request to be tested. Information must concentrate on the occurrence of overdiagnosis, which is also the main target of future research. Multiparametric MRI [magnetic resonance imaging] and the developments of new markers are the hope for the future. In the meantime available instruments with multivariate risk stratification must be applied. n Disclosure: Each center had its own funding responsibility. Most funding was provided by national cancer research funding agencies, European funding through Framework programs, some private sponsors, and a grant from the former Beckman/Hybritech company.

For full disclosures of the study authors visit www.thelancet.com.

Reference 1. Schröder FH, Hugosson J, Roobol MJ, et al: Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet.

August 6, 2014 (early release online).

See a commentary on this study by Anthony V. D’Amico, MD, PhD, on ­ page 26.

The ASCO Post | SEPTEMBER 15, 2014

PAGE 26

Perspective

PSA—It Just Keeps Getting Better, So Why Should It Stand Alone?

By Anthony V. D’Amico, MD, PhD

T

he updated results of the European Randomised Study of Screening for Prostate Cancer (ERSPC)—reported in The Lancet by Fritz H. Schröder, MD, of Erasmus University Medical Center, and colleagues1 and reviewed in this issue of The ASCO Post—show a continued decline, as predicted,2 in the number invited to prostate-specific antigen (PSA) screening and the additional number needed to treat to prevent one death from prostate cancer.

These estimates have now declined to 781 and 27, respectively. Prostate cancer–specific mortality curves begin to separate 7 years after randomization and continue to diverge at the latest observed time point of 13 years, representing a 21% risk reduction in death from prostate cancer attributable to PSA screening.

Important Considerations A few important considerations deserve further discussion. First, these results substantiate that PSA screening with further follow-up continues to reduce mortality from prostate cancer by 21% in an average-risk population, with fewer men after 13 vs 9 years of follow-up invited to be screened (1,410 vs 781) and treated (48 vs 27) to avoid one prostate cancer death. Therefore, based on the model2 that predicted these declines in the number needed to screen and number needed to treat, by 25 years of follow-up, the number needed to screen would be expected to be 262, and only 9 additional men would need to be treated to prevent one prostate cancer death. These observed and predicted results have significant lifesaving implications for healthy men in their 50s whose remaining life expectancy exceeds 25 years.

Second, these improved results with longer follow-up speak to the concerns regarding the early reporting at a median follow-up of only 10 years of the Prostate Cancer Intervention vs Observation Trial (PIVOT) study,3 which reported a near significant benDr. D’Amico is Department of Radiation Oncology, Harvard Medical School, Chief of Genitourinary Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

efit in reduction in the risk of death from prostate cancer (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.36–1.09, P = .09] for men screened in a Veterans Administration population in the United States.

Further, it should be noted that this hazard ratio is similar to that observed in the Swedish randomized study of radical prostatectomy vs observation4 (HR = 0.56, 95% CI = 0.41–0.77, P = .001)—a trial performed in healthier (by 15 years, 50% vs only 30% of men were alive) and younger (median age, 64.7 vs 67 years at randomization) men with

cancer in men with intermediate- or high-risk disease in a postrandomization subgroup analysis.

Moreover, even in the event that prostate cancer of questionable clinical significance is diagnosed (ie, very low- or low-risk disease), active surveillance protocols now exist that evaluate such men with tools such as 3 Tesla multiparametric magnetic resonance imaging (MRI) to identify occult high-grade prostate cancer (ie, Gleason score 7–10) prior to initiating active surveillance and then follow them with annual image-guided targeted transrectal ultrasound–mag-

If costs for this imaging technology can be moderated, such data hold promise for a future in which a PSA level alone will not be used to determine who to biopsy, but will rather be part of a firststep multimodality screening … to determine if risk of having clinically significant disease is high enough to obtain a multiparametric MRI. —Anthony V. D’Amico, MD, PhD

more-advanced disease (T1c = 12% vs 50%; median PSA = 13.0 vs 7.8 ng/mL) that showed a significant reduction in prostate cancer–specific mortality with a number needed to treat of only 8.

Thus, there is considerable evidence to support the concept that treatment of clinically significant prostate cancer in healthy men can save lives and in relatively short order.

Multimodality Screening Using tools5 that incorporate not only the PSA level but also age, race, and digital rectal examination findings can optimize the diagnosis of prostate cancer that is clinically significant (intermediate- or highrisk). Despite enrolling less healthy men then those of average health in the United States based on Surveillance, Epidemiology, and End Results (SEER)-Medicare data,6 the PIVOT trial3 demonstrated a reduction in the risk of dying from prostate

netic resonance fusion biopsy of suspicious intraprostatic lesions on multiparametric MRI.7 With this approach, treatment is offered only when a clinically significant prostate cancer is found.

Such an approach coupled with multimodality screening allows men at high risk for developing clinically significant disease to be diagnosed, offered treatment, and educated about potential toxicities, thereby reducing overtreatment and the understandable concerns associated with this issue.

Role of Multiparametric MRI Based on promising results of a prospective study8 comparing detection of intermediate- and high- vs low-risk prostate cancer using transrectal ultrasound–guided vs MRIguided biopsy techniques, a new approach as to when to recommend a prostate biopsy may be on the horizon. Specifically, following the determination of elevated risk (perhaps

15%) of having a clinically significant prostate cancer using multimodality screening,5 a patient is referred for a multiparametric MRI and a biopsy is recommended only if clinically significant disease as assessed anatomically (ie, by evidence of extraprostatic or seminal vesicle or neurovascular bundle invasion) and/or diffusion-weighted imaging evidence of restricted diffusion (ie, Gleason score 7 or higher) is present.

In the recent study, the investigators found that by using multiparametric MRI as compared to transrectal ultrasound assessment and guidance for biopsy, the recommendation for biopsy was reduced by 51% and low-risk prostate cancer diagnoses declined by 89.4% while intermediate- and high- risk diagnoses increased by 17.7%.

Looking Ahead If costs for this imaging technology can be moderated, such data hold promise for a future in which a PSA level alone will not be used to determine who to biopsy, but will rather be part of a first-step multimodality screening using PSA level, age, digital rectal exam findings, race, and family history to determine if risk of having clinically significant disease is high enough (eg, > 15%) to obtain a multiparametric MRI. Then, a prostate biopsy would be recommended only if the index of suspicion for clinically significant disease is high enough based on the multiparametric MRI findings using the scoring system based on the Prostate Imaging and Reporting Archiving Data System (PI-RADS).9 Indeed, promising PI-RADS data regarding the high specificity of this approach to identify clinically significant disease are becoming available.8 By including these additional parameters in the biopsy decision-making process, we can achieve the longterm benefits of PSA screening in reducing death from prostate cancer through early detection while minimizing the diagnosis of disease—at any given point in time—that is unlikely to progress to metastatic disease if left untreated. In this way, overdiagnosis and overtreatment will become significantly less likely. n

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 27

Perspective

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

References 1. Schröder FH, Hugosson J, Roobol MJ, et al: Screening and prostate cancer mortality: results of the European Randomised

Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. August 6, 2014 (early release online).

2. Gulati R, Mariotto AB, Chen S, et al: Long-term projections of the harmbenefit trade-off in prostate cancer screening are more favorable than previ-

ous short-term estimates. J Clin Epidemiol 64:1412-1417, 2011.

3. Wilt TJ, Brawer MK, Jones KM, et al, the Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group: Radical prostatectomy versus observation for localized prostate cancer.

Erbitux® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WArNiNG: SEriOuS iNFuSiON rEACtiONS and CArDiOPuLMONArY ArrESt infusion reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000.

[See Warnings and Precautions, Adverse Reactions.] immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4) in Full Prescribing information, Warnings and Precautions.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European union (Eu)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-Fu) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing information.] iNDiCAtiONS AND uSAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

K-Ras Mutation-negative, EGFr-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information] • in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.]

Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information].

CONtrAiNDiCAtiONS None WArNiNGS AND PrECAutiONS infusion reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.]

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.]

Pulmonary toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients.

Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] use of Erbitux in Combination With radiation and Cisplatin: In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%.

In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

N Engl J Med 367:203-213, 2012.

4. Bill-Axelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in early prostate cancer.

N Engl J Med 370:932-942, 2014.

5. Ankerst DP, Hoefler J, Bock S, et continued on page 28

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

K-Ras testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information].

Perform the assessment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results.

Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux.

Epidermal Growth Factor receptor (EGFr) Expression and response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADvErSE rEACtiONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.]

• Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.]

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

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

The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). table 1:

incidence of Selected Adverse reactions (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus radiation radiation therapy Alone (n=208) (n=212) body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 15 3 2 0 Infusion Reactionb Infection 13 1 9 1 16 0 5 0 Chillsa Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, highc 38 1 24 1 Aspartate Transaminase, highc Alkaline Phosphatase, highc 33 <1 24 0 respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

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Perspective

Prostate Cancer Screening continued from page 27

al: Prostate Cancer Prevention Trial risk calculator 2.0 for the prediction of lowvs high-grade prostate cancer. Urology 83:1362-1367, 2014.

6. Aizer AA, Chen MH, Hattangadi J,

et al: Initial management of prostate-specific antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer. BJU Int 113:43-50, 2014.

7. Verma S, Bhavsar AS, Donovan J: MR imaging-guided prostate biopsy techniques. Magn Reson Imaging Clin

N Am 22:135-144, 2014.

8. Pokorny MR, de Rooij M, Duncan E, et al: Prospective study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasound-guided biopsy versus magnetic resonance (MR) imaging with subsequent MR-guided bi-

Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux (cetuximab) provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Table 2 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89). table 2:

incidence of Selected Adverse reactions (≥10%) in Patients with recurrent Locoregional Disease or Metastatic SCCHN Eu-Approved Cetuximab Platinum-based plus Platinum-based therapy with therapy with 5-Fu 5-Fu Alone (n=219) (n=215) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona infections and infestations 44 11 27 8 Infectionb Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous tissue Disorders 70 9 2 0 Acneiform Rashc Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm.

Colorectal Cancer Study 4: EU-Approved Cetuximab in Combination with FOLFIRI — Study 4 used EU-approved cetuximab.

U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Table 3 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224). table 3:

incidence of Selected Adverse reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFr-expressing, Metastatic Colorectal Cancera Eu-Approved Cetuximab plus FOLFiri FOLFiri Alone (n=317) (n=350) Grades Grades Grades body System Grades b 1–4 3 and 4 1–4 3 and 4 Preferred Term % of Patients blood and Lymphatic System Disorders Neutropenia 49 31 42 24 Eye Disorders Conjunctivitis 18 <1 3 0 Gastrointestinal Disorders Diarrhea 66 16 60 10 Stomatitis 31 3 19 1 Dyspepsia 16 0 9 0 General Disorders and Administration Site Conditions 14 2 <1 0 Infusion-related Reactionc Pyrexia 26 1 14 1 infections and infestations Paronychia 20 4 <1 0 investigations Weight Decreased 15 1 9 1 Metabolism and Nutrition Disorders Anorexia 30 3 23 2 (Continued)

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opsy in men without previous prostate biopsies. Eur Urol 66:22-29, 2014.

9. Barentsz JO, Richenberg J, Clements R, et al: European Society of Urogenital Radiology. ESUR prostate MR guidelines 2012. Eur Radiol 22:746757, 2012.

table 3: (Continued)

incidence of Selected Adverse reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFr-expressing, Metastatic Colorectal Cancera Eu-Approved Cetuximab plus FOLFiri FOLFiri Alone (n=317) (n=350) Grades Grades Grades body System Grades b 1–4 3 and 4 1–4 3 and 4 Preferred Term % of Patients Skin and Subcutaneous tissue Disorders 86 18 13 <1 Acne-like Rashd Rash 44 9 4 0 Dermatitis Acneiform 26 5 <1 0 Dry Skin 22 0 4 0 Acne 14 2 0 0 Pruritus 14 0 3 0 Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1 Skin Fissures 19 2 1 0 a Adverse reactions occurring in at least 10% of Erbitux (cetuximab) combination arm with a frequency at least 5% greater than that seen in the FOLFIRI arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. d Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”.

Erbitux Monotherapy — Table 4 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions]. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1–51). table 4:

incidence of Selected Adverse reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFr-expressing, Metastatic Colorectal Cancer treated with Erbitux Monotherapya Erbitux plus bSC bSC alone (n=118) (n=124) Grades Grades Grades body System Grades b 3 and 4 1–4 3 and 4 Preferred Term 1–4 % of Patients Dermatology/Skin Rash/Desquamation 95 16 21 1 Dry Skin 57 0 15 0 Pruritus 47 2 11 0 Other-Dermatology 35 0 7 2 Nail Changes 31 0 4 0 Constitutional Symptoms Fatigue 91 31 79 29 Fever 25 3 16 0 18 3 0 0 Infusion Reactionsc Rigors, Chills 16 1 3 0 Pain Pain-Other 59 18 37 10 Headache 38 2 11 0 Bone Pain 15 4 8 2 Pulmonary Dyspnea 49 16 44 13 Cough 30 2 19 2 Gastrointestinal Nausea 64 6 50 6 Constipation 53 3 38 3 Diarrhea 42 2 23 2 Vomiting 40 5 26 5 Stomatitis 32 1 10 0 Other-Gastrointestinal 22 12 16 5 Dehydration 13 5 3 0 Mouth Dryness 12 0 6 0 Taste Disturbance 10 0 5 0 infection Infection without neutropenia 38 11 19 5 Musculoskeletal Arthralgia 14 3 6 0 Neurology Neuropathy-sensory 45 1 38 2 Insomnia 27 0 13 0 Confusion 18 6 10 2 Anxiety 14 1 5 1 Depression 14 0 5 0 a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related.

Erbitux in Combination with Irinotecan — The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay.

Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

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News Gynecologic Oncology

Early Study Finds Olaparib Tablet Safe in Pretreated Ovarian Cancer Patients; More Effective in Those With BRCA Mutations

A

n oral tablet form of a poly-ADP ribose polymerase (PARP) inhibitor, olaparib, given in combination with chemotherapy, was safe in heavily pretreated patients with

ovarian cancer, and patients with BRCA mutations may have a better response compared with those without a BRCA mutation, according to phase Ib clinical trial data pre-

The incidence 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 Erbitux (cetuximab) 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 Erbitux. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Aseptic meningitis • Mucosal inflammation DruG iNtErACtiONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. uSE iN SPECiFiC POPuLAtiONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of 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, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49.

No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, 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 cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric use: The safety and effectiveness of Erbitux in pediatric patients have not been established.

The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients.

The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

sented at the Marsha Rivkin Center for Ovarian Cancer Research-AACR 10th Biennial Ovarian Cancer Research Symposium, held earlier this month in Seattle.1

Geriatric use: Of the 1662 patients who received Erbitux (cetuximab) with irinotecan, FOLFIRI or Erbitux monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects.

OvErDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLiNiCAL tOxiCOLOGY Carcinogenesis, Mutagenesis, impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys.

It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument.

At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PAtiENt COuNSELiNG iNFOrMAtiON Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2013 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886B3

Rev August 2013 693US13PBS02201

Tablets, Not Capsules, Used in Study “This study is one of the first studies to use olaparib tablets instead of olaparib capsules,” said Saul Rivkin, MD, Founder and Chairman of the Marsha Rivkin Center for Ovarian Cancer Research, and a Research Scientist at the Swedish Cancer Institute, both in Seattle. “The goal was to find the maximum tolerated dose of olaparib tablets plus weekly metronomic carboplatin and paclitaxel in patients with relapsed ovarian cancer.

“This treatment regimen provided a response rate of 66% in heavily pretreated ovarian cancer patients,” said Dr. Rivkin.

Study Details Dr. Rivkin and colleagues enrolled 14 heavily pretreated ovarian cancer patients (from three to eight prior therapies), ages 42 to 77. Patients received paclitaxel and carboplatin weekly for 3 out of 4 weeks, with increasing doses of olaparib. The maximum tolerated dose of olaparib was found to be 150 mg twice daily for 3 consecutive days of each week of each cycle.

Of the 12 evaluable patients, four had a complete response (33%), four had a partial response (33%), two had stable disease (16%), and two had disease progression (16%).

BRCA mutations were detected in the tumors of three patients with a complete response, three with a partial response, one with stable disease, and one with disease progression .

The most common grade 3 toxicities included neutropenia, leukopenia, lymphopenia, and anemia. There was no evidence of gastrointestinal, renal, cardiac, hepatic, pulmonary, or dermatologic toxicities in any of the patients with a toxicity grade greater than 2.

The investigators plan to recruit up to 40 additional patients in the phase II extension of this protocol. n

Disclosure: This study was funded by the Dulien Fund and AstraZeneca. Dr. Rivkin reported no potential conflicts of interest.

Reference 1. Rivkin S: Phase Ib/II with expansion of patients at the MTD study of olaparib plus weekly (metronomic) carboplatin and paclitaxel in relapsed ovarian cancer.

Marsha Rivkin Center for Ovarian Cancer Research-AACR 10th Biennial Ovarian Cancer Research Symposium. Presented September 9, 2014.

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Journal Spotlight Gynecologic Oncology

Adding Antiangiopoietin Agent Trebananib to Paclitaxel Improves Progression-Free Survival in Recurrent Epithelial Ovarian Cancer

By Matthew Stenger

T

rebananib inhibits angiogenesis by blocking the binding of angiopoietins 1 and 2 to the Tie2 receptor expressed on endothelial cells, a mechanism that differs from vascular endothelial growth factor (VEGF) inhibitors and that involves a different signaling pathway. In the phase III TRINOVA-1 trial reported in Lancet Oncology, Bradley J. Monk, MD, of the University of Arizona Cancer Center, Phoenix, and colleagues found that adding trebananib to paclitaxel significantly prolonged progression-free survival in patients with recurrent epithelial ovarian cancer.1 The toxicity profile of trebananib did not include an excess frequency of adverse events typically associated with VEGF inhibitors.

Study Details In this double-blind trial, 919 patients from 32 countries were randomly assigned between November 2010 and November 2012 to receive weekly paclitaxel at 80 mg/m2 plus weekly IV placebo (n = 458) or trebananib at 15 mg/kg (n = 461). Patients had to have received one platinum-based regimen for primary disease and no more than

two additional cytotoxic regimens for recurrent or persistent disease, had to have a platinum-free interval of ≤ 12 months, and could not have received maintenance or consolidation with single-agent paclitaxel. Previous antiangiogenic therapy was permitted.

Patients were stratified according to platinum-free interval (≤ 6 months vs > 6–12 months), measurable disease, and region (North America, western Europe and Australia, or rest of world). The primary endpoint was progression-free survival in the intention-to-treat population.

The trebananib and placebo groups were generally balanced for age (median, 60 and 59 years), race (84% and 79% white, 13% and 18% Asian), Gynecologic Oncology Group performance status (0 in 56% and 55%, 1 in 43% and 45%), primary tumor (ovarian in 92%

This non-VEGF antiangiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents.

—Bradley J. Monk, MD, and colleagues

and 91%, primary peritoneal carcinoma in 5% in both, fallopian tube in 3% in both), histology (serous in 84% and 85%), and histologic grade (eg, poorly differentiated in 59% and 56%, moderately differentiated in 15% and 18%).

The two groups were also balanced for previous lines of treatment (3 in 20% and 25%, 2 in 38% in both, 1 in 41% and

Trebananib in Ovarian Cancer ■■ Adding trebananib to paclitaxel significantly prolonged progression-free survival, but not overall survival, with the effect being consistent across patient subgroups.

■■ Trebananib was not associated with obviously increased rates of anti-VEGF class-specific adverse events.

38%), platinum-free interval (≤ 6 months in 51% and 53%, > 6–12 months in 48% and 46%), previous antiangiogenic treatment (8% in both), measurable disease (94% and 95%), and region (North America for 20% in both, western Europe and Australia for 42% and 41%, and rest of world for 38% and 39%).

Prolonged Progression-Free Survival After a median follow-up of 10.1 months, median progression-free survival was 7.2 months in the trebananib group vs 5.4 months in the placebo group (hazard ratio [HR] = 0.66, P < .0001). Hazard ratios favored trecontinued on page 31

Angiogenesis in Ovarian Cancer: Are We Missing the Clinical Target?

By Michael A. Bookman, MD

P

roduction of vascular endothelial growth factor (VEGF) is increased during normal ovulation, and can account for much of the reversible toxicity associated with ovarian hyperstimulation.1,2 We also have compelling data from multiple clinical trials to validate the importance of tumor-associated angiogenesis in the growth of ovarian cancer, including the effects of agents that sequester VEGF (with an emphasis on bevacizumab [Avastin]), small-molecule tyrosine kinase inhibitors that inhibit VEGF receptor signaling, antibodies that can prevent VEGF receptor activation, and a synthetic binding protein (trebananib) that sequesters angiopoietin-1 and angiopoietin-2.

Dr. Bookman is Professor of Medicine, Division of Hematology-Oncology, University of Arizona Cancer Center, Tucson.

While there are additional “upstream” drivers and “downstream” signals, this commentary will focus on VEGF and angiopoietin-1/2.

Important Data After more than 10 years of investigation of bevacizumab, it is instructive to consider a few key points: • Two single-agent nonrandomized phase II trials documented impressive tumor and ascites response in approximately 20% of patients with recurrent disease, regardless of prior chemotherapy history or platinum resistance.3,4 A number of responses were sustained > 1 year and associated with control of disease-related symptoms.

• Randomized phase III trials in the front-line setting with concurrent chemotherapy followed by extended monotherapy (as maintenance)

have documented modest, statistically significant, improvements in progression-free survival, but without an impact on overall survival, and without convincing evidence of clinical benefit.5,6 Of note, the majority of patients in these trials underwent primary cytoreductive surgery, achieving optimal (smallvolume) residual disease at study entry, without disease-related symptoms.

• In a retrospective analysis of one study (ICON7),6 a subset of patients with more-advanced or bulky disease showed modest improvement in overall survival, but this has generally been attributed to infrequent postprogression crossover, compared to similar studies with a 30% rate of ­crossover.

• Randomized studies in combination with chemotherapy in the

setting of platinum-sensitive and platinum-resistant recurrent disease have documented significant and more sustained improvements in progression-free survival, with strong hazard ratios, but generally without improved overall ­survival.7,8 • Two studies of recurrent disease have documented improved overall survival, including chemotherapy with cediranib (VEGF receptor tyrosine kinase inhibitor) in ICON6 and a subset analysis of bevacizumab with weekly paclitaxel in ­AURELIA (but without an overall survival benefit in combination with polyethylene-glycosylated liposomal doxorubicin or topotecan). The significance of these findings is unclear, and lack of crossover or access to subcontinued on page 32

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Journal Spotlight

bananib treatment in all prespecified subgroups and significantly favored trebananib for subgroups with no previous angiogenic therapy (0.67), white (0.65) and Asian (0.62) ethnicity, 1 (0.75) and 2 (0.54) previous lines of therapy, platinum-free interval of ≤ 6 (0.65) and > 6 to 12 (0.66) months, no bulky disease (0.66), and age < 70 years (0.65). Trebananib was associated with nonsignificantly prolonged progression-free survival in patients with prior antiangiogenic therapy (HR = 0.69, 95% confidence interval = 0.41–1.17).

Objective response occurred in 39% of trebananib recipients and 30% of placebo recipients, including complete response in 4% and 5%. An interim overall survival analysis showed no significant difference between groups (median, 19.0 vs 17.3 months, HR = 0.86, P = .19).

subscale and assessment of health utility with the EuroQol EQ-5D suggested no differences between the trebananib and placebo groups.

The investigators concluded: Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF antiangio-

genesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents.

Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. n Disclosure: The study was funded by Amgen. For full disclosures of the study

authors, visit www.thelancet.com.

Reference 1. Monk BJ, Poveda A, Vergote I, et al: Antiangiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): A randomised, multicentre, doubleblind, placebo-controlled phase 3 trial. Lancet Oncol 15:799-808, 2014.

For HR+, early-stage invasive breast cancer

Confidence begins with a highly accurate risk assessment

Toxicity The incidence of grade ≥ 3 adverse events was 56% in the trebananib group and 54% in the placebo group, with the most common in trebananib-treated patients being ascites (11% vs 8%), neutropenia (6% vs 9%), abdominal pain (5% vs 5%), localized edema (5% vs 1%), and hypokalemia (5% vs 3%). Serious adverse events occurred in 34% vs 28%, and adverse events led to discontinuation of treatment in 17% vs 6%.

Edema of any grade occurred in 64% vs 28% (grade 3 in 5% vs 1%). Other adverse events of any grade occurring in ≥ 10% of patients in either group and in ≥ 5% more patients in the trebananib group were ascites (20% vs 12%), pleural effusion (14% vs 4%), nasopharyngitis (12% vs 6%), and generalized edema (11% vs 3%), whereas those occurring in ≥ 5% more patients in the placebo group were neutropenia (28% vs 22%) and anemia (20% vs 10%).

Anti-VEGF Toxicities Adverse events of interest on the basis of their association with anti-VEGF therapy did not appear to occur with markedly greater frequency in the trebananib group, including hypertension (6% vs 4%), bleeding (10% vs 17%), pulmonary embolism (1% vs 2%), arterial thrombotic events (1% vs 1%), proteinuria (3% vs 3%), impaired wound healing (< 1% vs < 1%), gastrointestinal perforation (2% vs < 1%), and venous thromboembolic events (6% vs 4%).

Assessment of patient-reported outcomes with the Functional Assessment of Cancer Therapy–Ovary questionnaire and its ovarian cancer–specific

Introducing Prosigna™: Guide your decisions with the power of PAM50-based molecular profiles1 • Prosigna translates a patient’s underlying tumor biology into an individualized risk assessment

• Prosigna is the only genomic assay for breast cancer that is FDA 510(k) cleared for use in local qualified laboratories

• Prosigna’s PAM50-based genomic assay quickly and accurately provides prognostic information you need

• Obtain precise, reproducible results from formalin-fixed paraffin-embedded (FFPE) tissue in as few as 3 days

To find a Prosigna provider and for a copy of the Package Insert, visit Prosigna.com today.

Reference: 1. Prosigna [Package Insert]. Seattle, WA: NanoString Technologies, Inc; 2013.

Prosigna is indicated for use in postmenopausal women with hormone receptor–positive, node-negative or node-positive early-stage (stages I and II) breast cancer to be treated with adjuvant endocrine therapy.

Special conditions for use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients. © 2014 NanoString Technologies, Inc. All rights reserved. NanoString, the NanoString Technologies logo, Prosigna and the Prosigna logo are trademarks and/or registered trademarks of NanoString Technologies, Inc. in various jurisdictions. USPS_PM0006 04/14

Proceed with confidence

The ASCO Post | SEPTEMBER 15, 2014

PAGE 32

Perspective

Angiogenesis in Ovarian Cancer continued from page 30

sequent therapy could have influenced overall survival.

• We do not yet have any reliable biomarkers to predict who is most likely to benefit, or not benefit, from antiangiogenic therapy, although certain clinical parameters, such as bulky disease and tumor-associated ascites or pleural effusions, may identify patients more likely to benefit from bevacizumab.9 • Several antiangiogenic agents have successfully met predesigned primary study objectives for progression-free survival in large placebocontrolled randomized trials, but have not yet achieved U.S. Food and Drug Administration (FDA) regulatory approval in ovarian ­cancer.

• In spite of the lack of FDA regulatory approval in the United States, the majority of patients now receive bevacizumab at some point during their treatment, often in the setting of recurrent disease, and it is generally covered by insurance, based on compendia listings and published studies.

Regulatory Approval We do not yet have a standardized approach for determination of clinical benefit based on progression-free survival. Small, but statistically significant improvements in progression-free survival (eg, < 3 months) are clearly not sufficient and are unlikely to drive regulatory approval. Prolonged progression-free survival benefit, perhaps >12 months, would likely be viewed as clinically significant, but this is an infrequent occurence. Progressionfree survival integrated with clinical outcomes, such as delay in subsequent therapy, quality adjustments, or sustained management of disease-related symptoms, might be viewed as clinically significant, but this is currently considered on a case-by-case basis.

In December 2011, bevacizumab received marketing approval through the European Medicines Agency for patients with newly diagnosed ovarian cancer (based on ICON7 and GOG0218). This was followed by European approvals for bevacizumab in combination with chemotherapy for platinum-sensitive recurrent disease (based on OCEANS) in October 2012 and with chemotherapy for

platinum-resistant recurrent disease (based on AURELIA) in August 2014. Bevacizumab has not yet received FDA regulatory approval in the United States for any setting in ovarian cancer, but it is undergoing priority review for platinum-resistant disease as of July 2014.

Clinical Impact Against this background, we have the well-designed, 919-patient, placebo-controlled, randomized phase III trial of the angiopoietin-1/2 inhibitor trebananib reported by Monk et al in The Lancet Oncology and reviewed in this issue of The ASCO Post.10 Trebananib provided a modest (< 2 month) improvement in progression-free survival with a hazard ratio of 0.66 in the setting of platinum-resistant recurrent

with the timing of cross-sectional imaging. Of note, the reported benefit in progression-free survival is very close to one cross-sectional imaging time interval (8 weeks).

Our continued emphasis on measuring small changes in cross-sectional imaging makes it more difficult to determine if the investigational regimen might have delayed tumor progression and initiation of subsequent therapy or contributed to improved patient outcomes, even if the estimated progression-free survival based on cross-sectional imaging was similar.

Next Steps Where do we go from here? Robert Fulghum has suggested that “All I Really Need to Know I Learned in Kindergarten.”12 Without being overly

It is now clear that angiopoietin-1/2 has been validated as an important component of tumor angiogenesis, together with VEGF, and we await smaller innovative trials to bring true clinical benefit to our patients in the best clinical context.

—Michael A. Bookman, MD

disease, confirming earlier data from a randomized phase II trial reported by Karlan et al.11 While the primary endpoint for this trial was met on statistical terms, the clinical impact of these findings needs to be considered in the context of treatment-related toxicity (particularly edema), as well as the results previously reported with bevacizumab in a similar patient population (­AURELIA). The authors state that, in combination with weekly paclitaxel, “trebananib provided a clinically meaningful prolongation in progression-free survival,” but they do not convincingly state how this conclusion would be substantiated.

As in other trials, the study required prescheduled cross-sectional imaging to monitor tumor response, and the vast majority of patients had disease progression declared based on asymptomatic changes in crosssectional imaging, as evidenced by the stepwise decrements in actuarial progression-free survival that correlate

simplistic, it is conceivable that most of what we really needed to know we learned from two small single-arm phase II trials in the setting of recurrent disease.

These studies educated us about the importance of tumor-associated angiogenesis, targeted therapeutics, toxicity, safety, efficacy, and clinical principles of patient selection (favoring large-volume disease, often with ascites or pleural effusion, and without regard to prior platinum exposure or chemotherapy resistance). The fact that nearly 20% of patients had objective evidence of tumor response, often sustained, and associated with improvement in disease-related symptoms, was consistent and astounding.

Taken together, publication of these trials has guided the use of antiangiogenic treatment in a large proportion of women with recurrent ovarian cancer, in spite of the lack of FDA regulatory approval.

Our subsequent randomized trials have been informative, and we

are grateful for the infrastructure that made these studies possible, as well as the enthusiastic participation of so many women with ovarian cancer. However, after this extraordinary commitment of time, clinical resources, finances, and laboratory expertise, we have made only incremental progress. It is now clear that angiopoietin-1/2 has been validated as an important component of tumor angiogenesis, together with VEGF, and we await smaller innovative trials to bring true clinical benefit to our patients in the best clinical context. n

Disclosure: Dr. Bookman has received compensation for participation in independent data monitoring committees for phase III trials with antiangiogenic agents from GenentechRoche and Boehringer Ingelheim, and he has also received travel support and compensation for participation in multiple ad hoc advisory boards related to the development of clinical trials in ovarian cancer with nonmarketed investigational drugs, including from Amgen, Boehringer Ingelheim, and GenentechRoche. He has no financial holdings in the pharmaceutical industry.

References 1. Ferrara N, Chen H, Davis-Smythe T, et al: Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med 4:336-340, 1998.

2. Giles J, Requena A, García-Velasco JA, et al: GnRH analogue for the prevention of ovarian hyperstimulation syndrome: A pilot study. Fertil Steril 91(4 suppl):1366-1369, 2009.

3. Cannistra SA, Matulonis UA, Penson RT, et al: Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25:5180-5186, 2007.

4. Burger RA, Sill MW, Monk BJ, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group Study. J Clin Oncol 25:5165-5171, 2007.

5. Burger RA, Brady MF, Bookman MA, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473-2483, 2011.

6. Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:2484-2496, 2011.

7. Pujade-Lauraine E, Hilpert F, Weber B, et al: Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 32:1302-1308, 2014.

8. Aghajanian C, Blank SV, Goff BA, et al: OCEANS: A randomized, double-

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 33

Perspective

2014 Lasker Award

T

he Albert and Mary Lasker Foundation has announced Mary-Claire King, PhD, of the University of Washington, Seattle, will receive the 2014 Lasker~Koshland Special Achievement Award for her contributions to medical science and human rights.

Dr. King’s demonstration of the existence of familial susceptibility to breast cancer and her discovery of the BRCA1

Ascites predicts degree of treatment benefit of bevacizumab in front-line therapy of advanced epithelial ovarian, fallopian tube, and peritoneal cancers. Society of Gynecologic Oncology Annual Meeting.

Abstract 62. Presented March 23, 2014.

10. Monk BJ, Poveda A, Vergote I, et

al: Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): A randomised, multicentre, BLEED:8.375” double-blind, placebo-controlled phase 3 TRIM:7.875” trial. Lancet Oncol 15:799-808, 2014.

11. Karlan BY, OzaSAFETY:7” AM, Richardson GE, et al: Randomized, double-blind, pla-

Now enrolling for alectinib

NCT 02075840 BO28984

A Randomized, Phase III Study Comparing Alectinib With Crizotinib in Treatment-Naïve Anaplastic Lymphoma Kinase (ALK)-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

Patients (N=286) • Advanced, recurrent, or metastatic ALK-positive NSCLC

Mary-Claire King, PhD

gene locus took place in the era before high-speed sequencing technology and at a time when few scientists believed that susceptibility to a complex disease such as breast cancer could be linked to a single mutated gene.

Dr. King began her search for the putative gene in 1974. The hunt took her through meticulous analysis and mathematical modeling of more than 1,500 families of women with breast cancer, from which she concluded that a single gene was indeed responsible for breast cancers in some families. In 1990, Dr. King reported that a section of chromosome 17 was responsible for early-onset breast and/or ovarian cancer in some of the families she analyzed. She named the gene locus BRCA1. Dr. King’s approach has since become a model for the identification of genes that cause complex diseases.

Dr. King also developed DNA-based analysis to help families prove genetic relationships and find the “lost children” of Argentina who had been kidnapped as infants or born while their mothers were in prison during the military regime of the late 1970s and early 1980s.

The Lasker Awards, which carry an honorarium of $250,000, are being presented on Friday, September 19, in New York City. n

cebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol 30:362-371, 2012.

12. Fulghum R: All I Really Need to Know I Learned In Kindergarten, pp 6-7.

New York, Villard Books, 1990.

Randomize 1:1

blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 30:2039-2045, 2010.

9. Ferriss JS, Java J, Burger RA, et al:

Primary Endpoint:

Alectinib1

Crizotinib

Secondary Endpoints:

• Progression-free survival (PFS), investigator-assessed,

• Objective response rate, investigator-assessed,

by RECIST 1.1

using RECIST 1.1 • Time to CNS progression, IRC-assessed, using

RECIST 1.1 • PFS, IRC-assessed, using RECIST 1.1 • Duration of response • Overall survival • Safety: incidence of adverse events • AUC of alectinib • Patient-reported outcomes

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Advanced, recurrent, or metastatic ALK-positive NSCLC

• Prior malignancy in past 3 years

• Life expectancy ≥12 weeks

• Any ≥ grade 3 toxicity (NCI CTCAE 4.0) from

• ECOG performance status of 0-2 • No prior systemic therapy for advanced, recurrent, or

metastatic disease • Measurable disease by RECIST 1.1

a prior therapy

• Baseline QTc >470 ms or symptomatic

bradycardia <45 beats per minute • Concomitant strong cytochrome P4503A

inhibitors/inducers or QT-prolonging medications

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com.

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for the use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002445101 Printed in USA.

The ASCO Post | SEPTEMBER 15, 2014

PAGE 34

Updates on Radiation Oncology Webinar Thoracic Oncology

Optimal Chemoradiotherapy Dosing and Recurrence After Stereotactic Body Radiotherapy Explored in Lung Cancer Webinar

By Caroline McNeil

C

etuximab (Erbitux) added no survival benefit to chemoradiation in stage III non–small cell lung cancer (NSCLC), according to results reported in a Plenary Session of the 2013 World Conference on Lung Cancer in Sydney, Australia.1 It was the second surprise result from the Radiation Therapy Oncology Group (RTOG) 0617 trial. Two years ago, investigators reported that contrary to expectation, a higher dose of radiation therapy (74 Gy) reduced, rather than increased, overall survival and local control compared to the standard 60 Gy. The findings reported in Sydney showed that the addition of cetuximab had no effect on survival in either arm and increased the number of grade 3 and higher adverse events.

Several possible reasons for the surprising results are under review, including cardiac toxicity, said Maria Werner-Wasik, MD, Director of Clinical Research in the Department of Radiation Oncology at Thomas Jefferson University, Philadelphia. Dr. WernerWasik discussed highlights of the Sydney meeting in a live webinar organized by the International Association for the Study of Lung Cancer (IASLC). The webinar also covered radiation oncology highlights from the 2014 ASCO Annual Meeting (see page 35). The recorded webinar is available on the IASLC website.2

Smart Dose Escalation Despite the RTOG 0617 results, the study of dose escalation in stage III NSCLC is not over, said Dr. WernerWasik. Studies are now looking at other strategies to increase the total dose of radiation to the lung tumor without harming surrounding tissues.

“Smart dose escalation is in,” she said.

One kind of smart dosing is isotoxic dose escalation, in which dose is personalized for each patient. In the UK’s Isotoxic Dose Escalation and Acceleration in Lung Cancer (IDEAL) trial, for example,

doses are adjusted based on computed tomography (CT) scan monitoring of the heart, spinal cord, and brachial plexus.

Other ways to increase dose, such as hypofractionation (higher doses in fewer radiation sessions) or use of protons/ charged particles, are also under study.

Recurrence After SBRT Dr. Werner-Wasik also focused on several studies with stereotactic body radiation therapy (SBRT), a technique that precisely locates tumors in the body to avoid

damage to surrounding tissue and delivers few (1–5) large radiation doses or fractions. RTOG 0915, for example, a randomized phase II trial, compared SBRT delivered with a single 34-Gy fraction to 48 Gy given with four fractions of 12 Gy each, in patients with inoperable stage I peripheral NSCLC.3 The results favored the more con-

Radiotherapy for Non–Small Cell Lung Cancer ■■ Optimal radiotherapy dosing remains unclear for locally advanced non– small cell lung cancer.

■■ “Smart dose” escalation trials are ongoing.

■■ Normal tissue tolerance doses and criteria for identifying local failure after stereotactic body radiotherapy are being refined.

An important study used CT scans to assess potential high-risk features associated with biopsy-confirmed recurrences, finding that the presence of three or more factors was highly sensitive and specific for recurrence.5 The most predictive single feature was enlarging opacity after 12 months.

Another concern with stereotactic body radiotherapy is that toxicity may limit its use for central tumors. But in a large multinational data set, patients

Evaluation of recurrence after SBRT remains an unresolved and vexing issue for all of us in clinical practice.

—Maria Werner-Wasik, MD

venient one-dose regimen, showing no difference between the two arms in grade 3 and higher adverse events, the primary endpoint of the trial. There was also no difference in overall survival or local control at 1 year. Plans are underway for a phase III trial, once longer follow-up confirms the same local control in both groups.

One of the issues with stereotactic body radiotherapy is that it produces fibrosis, which can make it difficult to monitor for local recurrence. “Evaluation of recurrence after SBRT,” Dr. ­Werner-Wasik said, “remains an unresolved and vexing issue for all of us in clinical practice.”

treated with SBRT had the same overall survival and the same rate of grade 3 and higher adverse events, regardless of whether they had central or peripheral tumors.6 The conclusion, Dr. WernerWasik said, was that SBRT is safe for both central and peripheral tumors, although optimal SBRT dose for central tumors remains to be established. n Disclosure: Dr. Werner-Wasik reported no potential conflicts of interest.

References 1. Bradley J, Masters G, Hu C, et al: An intergroup randomized phase III comparison of standard-dose (60 gy) versus highdose (74 gy) chemoradiotherapy (CRT)

+/- cetuximab (cetux) for stage III nonsmall cell lung cancer (NSCLC): Results on cetux from RTOG 0617. World Conference on Lung Cancer. Abstract PL03.05.

Presented October 29, 2013.

2. Updates on Radiation Oncology: WCLC 2013 AND ASCO 2014. July 18, 2014. Available at www.iaslc.org/webinars/ updates-radiation-oncology-wclc-2013-andasco-2014. Accessed August 25, 2014.

3. Videtic G, Hu C, Anurag Singh A, et al: Radiation Therapy Oncology Group (RTOG) protocol 0915: A randomized phase II study comparing 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable patients (pts) with stage I peripheral non-small cell lung cancer. World Conference on Lung Cancer. Abstract O10.02. Presented October 28, 2013.

4. Dosimetric predictors of esophageal toxicity after stereotactic body radiotherapy for central lung tumors. World Conference on Lung Cancer. Abstract MO17.09.

Presented October 29, 2013.

5. Senthi S, Huang K, Palma D, et al: Blinded assessment of radiological changes after stereotactic ablative radiotherapy for early-stage lung cancer: Local recurrences versus fibrosis. World Conference on Lung Cancer. Abstract O10.05. Presented October 28, 2013.

6. Grills IS, Mangona VS, Hope A, et al: Recurrence, survival, and toxicity after stereotactic lung radiotherapy (SBRT) for central versus peripheral stage I nonsmall cell lung cancer (NSCLC): Results from an international collaborative research group. World Conference on Lung Cancer. Abstract MO17.05. Presented October 29, 2013.

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 35

Updates on Radiation Oncology Webinar Thoracic Oncology

Lung Cancer Webinar Highlights Brain Metastases and Thoracic Radiotherapy

By Caroline McNeil

P

ostoperative radiation therapy, given after adjuvant chemotherapy, significantly increased overall survival in non–small cell lung cancer (NSCLC) compared to chemotherapy alone, according to a study reported at ASCO’s 2014 Annual Meeting.1 That study, an analysis of records in the

Academic Center Outcomes Two other studies he selected explain why institutional experience might affect choice.

In one, researchers used the National Cancer Data Base (jointly sponsored by the American College of Surgeons and the American Cancer Society) to com-

We think [thoracic radiotherapy] should be offered now in addition to [prophylactic cranial irradiation] to all patients responding to initial chemotherapy.

—Berend J. Slotman, MD, PhD

National Cancer Database, was one of nine lung cancer abstracts from ASCO singled out for their relevance to practicing radiation oncologists in a recent webinar.

“Modern [postoperative radiotherapy],” said Berend J. Slotman, MD, PhD, who discussed this and eight other studies at the webinar, “may increase overall survival by 5% compared to adjuvant chemotherapy alone.”

The webinar, organized by the International Association for the Study of Lung Cancer (IASLC), also included radiation oncology highlights from the most recent World Conference on Lung Cancer (see page 34). The recorded webinar is available on the IASLC ­website.2 Two other phase III trials selected by Dr. Slotman, who is Chair of Radiation Oncology at VU University and Medical Center in Amsterdam, suggest that current chemoradiation therapies for stage III NSCLC are not improved by the addition of either surgery or consolidation chemotherapy. In one trial, surgery was compared to definitive concurrent chemoradiation in stage III NSCLC.3 In the other, patients with inoperable stage III NSCLC were randomly assigned to either concurrent chemoradiation or chemoradiation followed by consolidation chemotherapy with docetaxel and paclitaxel.4 In both trials, outcomes in the two arms were similar.

“So the choice between definitive chemoradiation and surgery should also be based on patient preference,” Dr. Slotman concluded. “And personally I would add experience of the center.”

pare outcomes in stage IIIA NSCLC in academic vs community cancer centers.5 They found that 30-day mortality was significantly lower at academic centers.

The other study looked at the association between an institution’s clinical trial enrollment numbers and outcome in one large trial (Radiation Therapy Oncology Group [RTOG] 0617), finding that median overall survival and progression-free survival were both significantly better in high-volume centers.6 Asked why outcomes would be better in academic centers, webinar speakers mentioned several potential reasons, including possibly better treatment care and facilities and the higher number

tactic radiosurgery in this study’s selected patient group.

In another randomized trial, prophylactic cranial irradiation was compared to observation in resected stage IIIA N2 NSCLC patients at high risk of brain metastases following adjuvant chemotherapy.8 This trial was closed early due to slow accrual, but key results showed that prophylactic cranial irradiation increased disease-free, though not overall, survival and reduced the incidence of brain metastases.

Two small cell lung cancer (SCLC) trials also involved prophylactic cranial irradiation. Both were follow-ups of an earlier trial, which showed that prophylactic cranial irradiation reduced brain metastases and increased overall survival in patients with extensive SCLC, compared to observation alone. That trial was led by Dr. Slotman and published in The New England Journal of Medicine in 2007.9 In one of the follow-up trials, prophylactic cranial irradiation was again compared to observation in patients with extensive SCLC, but magnetic resonance imaging (MRI) was used to confirm the absence of brain metastases before trial entry.10 This trial was terminated because of futility; however, with a median follow-up of 9.4 months and 111 observed deaths, the median overall survival was higher in the observation arm—15.1 months compared to 10.1 months in the prophylactic cranial irradiation arm.

Radiotherapy for Lung Cancer ■■ Modern postoperative radiation therapy after chemotherapy may increase survival in NSCLC. ■■ Prophylactic cranial irradiation continues to be studied in NSCLC and SCLC in combination with other strategies.

■■ Patients in academic cancer centers, as a group, may have better outcomes than those in community cancer centers.

■■ Thoracic radiotherapy improves long-term survival in extensive-stage SCLC.

of board-certified thoracic surgeons in academic centers.

Cerebral Radiation Four other studies highlighted by Dr. Slotman related to brain metastases.

A phase III trial in NSCLC examined whether early stereotactic radiosurgery prior to systemic chemotherapy increased overall survival in patients with asymptomatic oligometastases to the brain compared to chemotherapy alone.7 No benefit was seen for stereo-

Patients in the radiotherapy arm, despite their lower overall survival, had significantly fewer brain metastases.

“This is a very interesting study that requires further analysis to see whether use of MRI should change our policy in patients who will receive [prophylactic cranial irradiation],” Dr. Slotman ­observed.

Adding Thoracic Radiotherapy The final highlighted trial of the ­ ebinar compared thoracic radiotherw apy plus prophylactic cranial irradia-

tion to prophylactic cranial irradiation alone, also in extensive SCLC.11 Led by Dr. Slotman, this study found that adding thoracic radiotherapy to prophylactic cranial irradiation increased overall and progression-free survival as well as ­intrathoracic control.

“We think [thoracic radiotherapy] should be offered now in addition to [prophylactic cranial irradiation] to all patients responding to initial chemotherapy,” Dr. Slotman concluded. n

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

References 1. Robinson CG, Patel A, Bradley JD, et al: Postoperative radiotherapy (PORT) for pathologic N2 non-small cell lung cancer (NSCLC) treated with adjuvant chemotherapy: A review of the National Cancer Database. ASCO Annual Meeting. Abstract 7509. Presented June 1, 2014.

2. Updates on Radiation Oncology: WCLC 2013 AND ASCO 2014. July 18, 2014. Available at www.iaslc.org/webinars/updates-radiation-oncology-wclc2013-and-asco-2014. Accessed August 25, 2014.

3. Eberhardt WE, Gauler TC, Pöttgen C, et al: Phase III study of surgery (S) versus definitive concurrent chemoradiotherapy boost (def ccCRTx-BOx) in patients (pts) with operable (OP+) stage IIIA(N2)/selected IIIb (sel IIIB) non-small cell lung cancer (NSCLC) following induction (IND) chemotherapy (CTx) and concurrent CRTx (ESPATUE). ASCO Annual Meeting. Abstract 7510. Presented June 1, 2014.

4. Park K, Ahn Y, Ahn J, et al: A multinational phase III randomized trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III nonsmall cell lung cancer (CCheIN). ASCO Annual Meeting. Abstract 7500. Presented June 2, 2014.

5. Samson P, Patel A, Crabtree T, et al: Multidisciplinary treatment for stage IIIA non-small cell lung cancer (NSCLC): Does institution matter? ASCO Annual Meeting.

Abstract 7512. Presented June 1, 2014.

6. Eaton BR, Pugh SL, Bradley JD, et al: The effect of institutional clinical trial enrollment volume on survival of patients with stage III non-small cell lung cancer treated with chemoradiation: A report of the Radiation Therapy Oncology Group (RTOG) 0617. ASCO Annual Meeting.

Abstract 7551. Presented May 31, 2014. continued on page 40

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

REVLIMID is not indicated and not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

For patients with

RELAPSED OR REFRACTORY MANTLE CELL LYMPHOMA WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning.

EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death.

• Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception.

REVLIMID is available only through a restricted distribution program called the REVLIMID REMS™ program (formerly known as the “RevAssist® program”).

HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia.

• For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter.

VENOUS THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma receiving REVLIMID with dexamethasone.

For more information, please visit www.REVLIMID.com or call 1-888-423-5436.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS™.

Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on the following pages.

Efficacy and safety of REVLIMID were evaluated in pretreated patients with advanced disease1 • In a multicenter, single-arm, single-agent, open-label study (N=134)* • 92% (124/134) of patients had stage III-IV disease; 78% (105/134) of patients had received ≥3 prior systemic therapies; 60% (81/134) of patients were refractory to prior bortezomib; 55% (74/134) of patients were refractory to last prior therapy • Refractory disease was defined as without any response of PR or better during treatment with bortezomib or a bortezomib-containing regimen; relapsed disease was defined as progression within one year after treatment with bortezomib or a bortezomib-containing regimen† • Patients received REVLIMID 25 mg orally, once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent *134 patients evaluated for safety; 133 patients evaluated for efficacy.1 † Had received prior treatment with anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination.1

REVLIMID may help continue the fight against relapsed or refractory MCL1‡

26 ORR %

§

(34/133)

Overall response rate (CR + CRu + PR) (95% CI: 18.4, 33.9)

7 CR %

(9/133)

Complete response rate (CR + CRu) (95% CI: 3.1, 12.5)

median

16.6 months DOR (n=34)

Median duration of response (95% CI: 7.7, 26.7) • Median time to response was 2.2

months (range: 1.8 to 13 months)

CI=confidence interval; CR=complete response; CRu=complete response unconfirmed; DOR=duration of response; ORR=overall response rate; PR=partial response. ‡ §

Based on all evaluable patients who received ≥1 dose of REVLIMID.1 Response was determined based on review of radiographic scans by an independent review committee, according to a modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999); ORR was defined as: CR + CRu + PR.1,2

CONTRAINDICATIONS

Pregnancy: • REVLIMID can cause fetal harm when administered to a pregnant female. Lenalidomide is contraindicated in females who are pregnant.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: • REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

ADVERSE REACTIONS

Mantle Cell Lymphoma • Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%) • Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia • Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%) • Adverse events occurring in patients treated with REVLIMID in the MCL trial resulted in at least one dose interruption in 76 (57%) patients, at least one dose reduction in 51 (38%) patients, and discontinuation of treatment in 26 (19%) patients References: 1. Revlimid [package insert]. Summit, NJ: Celgene Corp; 2013. 2. Cheson BD, Horning SJ, Coiffier B, et al.

Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17(4):1244-1253.

REVLIMID® is a registered trademark of Celgene Corporation.

REVLIMID REMSTM is a trademark of Celgene Corporation. © 2013 Celgene Corporation 12/13 US-REV130050h

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program).

Information about the REVLIMID REMS™ Program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndrome (MDS) had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma (MM) who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

CONTRAINDICATIONS

Pregnancy: • REVLIMID can cause fetal harm when administered to a pregnant female. Lenalidomide is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: • REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death.

An embryo-fetal development study in monkeys indicated that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID

REVLIMID REMS Program

Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the “RevAssist®” Program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Patients may require dose interruption and/or dose reduction. MCL: Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients.

Grade 3 or 4 thrombocytopenia was reported in 28% of the patients.

Venous Thromboembolism: Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MCL treated with lenalidomide monotherapy. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism.

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41], consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Second Primary Malignancies: Patients with MM treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide.

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone.

The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.

Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Tumor Flare Reaction: Tumor flare reaction (TFR) occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. In the MCL trial, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion.

Patients with Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

ADVERSE REACTIONS

Mantle Cell Lymphoma • Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%) • Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia • Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%) • Adverse events occurring in patients treated with REVLIMID in the MCL trial resulted in at least one dose interruption in 76 (57%) patients, at least one dose reduction in 51 (38%) patients, and discontinuation of treatment in 26 (19%) patients

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID.

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

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

Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established.

Geriatric Use: Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.

Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr <30 mL/min) and in patients on dialysis.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS™.

Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on the following pages.

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Updates on Radiation Oncology Webinar Lung Cancer Webinar continued from page 35

7. Lim S, Lee J, Lee M, et al: Randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small cell lung cancer (NSCLC). ASCO Annual Meeting.

Abstract 8037. Presented June 2, 2014.

8. Wang S, Li N, Ou W, et al: A randomized trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA N2 non-small cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy. ASCO Annual Meeting. Abstract 7508. Presented June 1, 2014.

9. Slotman B, Faivre-Finn C, Kramer G,

et al: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664-672, 2014.

10. Seto T, Takahashi T, Yamanaka T, et al: Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese

REVLIMID [lenalidomide] capsules, for oral use The following is a brief summary for mantle cell lymphoma; refer to full prescribing information for complete product information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study.

Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2).

Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s tollfree number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia.

Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study.

Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)].

Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy.

Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors [see Warnings and Precautions (5.4)].

1 INDICATIONS AND USAGE 1.3 Mantle Cell Lymphoma REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

1.4 Limitations of Use: REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)].

2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed.

2.3 Mantle Cell Lymphoma The recommended starting dose of REVLIMID is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity.

Treatment is continued, modified or discontinued based upon clinical and laboratory findings.

Dose Adjustments for Hematologic Toxicities During MCL Treatment Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to REVLIMID.

randomized phase III trial. ASCO Annual Meeting. Abstract 7503. Presented June 2, 2014.

11. Slotman BJ, Faivre-Finn C, van Tinteren H, et al: Randomized trial on thoracic radiotherapy (TRT) in extensive-stage small cell lung cancer. ASCO Annual Meeting. Abstract 7502. Presented June 2, 2014.

Platelet counts Thrombocytopenia during treatment in MCL When Platelets Recommended Course Fall to <50,000/mcL Interrupt REVLIMID treatment and follow CBC weekly Return to ≥50,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Absolute Neutrophil counts (ANC) Neutropenia during treatment in MCL When Neutrophils Recommended Course Fall to <1000/mcL for at least 7 days Interrupt REVLIMID treatment and follow OR CBC weekly Falls to < 1,000/mcL with an associated temperature ≥ 38.5°C OR Falls to < 500 /mcL Return to ≥1,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Other Grade 3 / 4 Toxicities in MCL For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2.

Starting Dose Adjustment for Renal Impairment in MCL: 2.4 Starting Dose for Renal Impairment in MCL Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with MCL are as follows: Table 1: Starting Dose Adjustments for Patients with Renal Impairment in MCL Category Renal Function Dose in MCL (Cockcroft-Gault) Moderate Renal CLcr 30-60 mL/min 10 mg Impairment Every 24 hours Severe Renal CLcr < 30 mL/min 15 mg Impairment (not requiring dialysis) Every 48 hours End Stage CLcr < 30 mL/min 5 mg Renal Disease (requiring dialysis) Once daily. On dialysis days, administer the dose following dialysis.

After initiation of REVLIMID therapy, subsequent REVLIMID dose modification is based on individual patient treatment tolerance, as described elsewhere (see section 2).

4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female.

Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)].

4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.8)].

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of Cosmos Communications K

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Announcements

Fox Chase Cancer Center Announces New Staff

F

ox Chase Cancer Center has announced the appointment of two staff to the Center’s Department of Radiation Oncology and Surgical Oncology, respectively. Mark A. Hallman, MD, PhD, joins the Department of Radiation Oncology

having served there recently as the Department’s Chief Resident. Sanjay S. Reddy, MD, has joined the Department of Surgery having recently completing his 2-year fellowship there.

female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy.

REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)].

Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.

Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy.

Two negative pregnancy tests must be obtained prior to initiating therapy.

The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].

Males Lenalidomide is present in the semen of patients receiving the drug.

Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)].

Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID. 5.2 REVLIMID REMS™ program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program).

Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements.

• Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)].

• Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements.

Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.

5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia.

Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction [see Dosage and Administration (2.1, 2.2, 2.3)].

Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days [see Boxed Warning and Dosage and Administration (2.2)].

In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone [see Adverse Reactions (6.1)].

Dr. Hallman’s primary area of focus is the treatment of patients with thoracic, hematologic, and genitourinary malignancies. He has extensive training in several specialized radiation techniques, including Mark A. Hallman, MD, PhD

Sanjay S. Reddy, MD

In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients.

5.4 Venous Thromboembolism Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with multiple myeloma treated with lenalidomide combination therapy [see Boxed Warning] and patients with MDS or MCL treated with lenalidomide monotherapy. A significantly increased risk of DVT and PE was observed in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy in a clinical trial [see Boxed Warning]. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil.

In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death.

The trial was halted for safety in July 2013.

Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

5.6 Second Primary Malignancies Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide.

5.7 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

5.8 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions.

REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.

5.9 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

5.10 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to Cosmos Communications K

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continued on page 42

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Announcements Fox Chase Staff continued from page 41

intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and prostate brachytherapy.

Dr. Hallman received his medical degree as well as a doctorate in cell and molecular pharmacology and ex-

perimental therapeutics from the Medical University of South Carolina in Charleston.

Dr. Reddy, who completed his residency in general surgery at Beth Israel Medical Center in New York, specializes in the care of patients with colorectal, liver, pancreatic, stomach cancers, melanoma and sarcomas. n

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withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1.

Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Deep vein thrombosis and pulmonary embolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] • Second Primary Malignancies [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Allergic Reactions [see Warnings and Precautions (5.8)] • Tumor lysis syndrome [see Warnings and Precautions (5.9)] • Tumor flare reactions [see Warnings and Precautions (5.10)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.3 Clinical Trials Experience in Mantle Cell Lymphoma In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years.

Table 7 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events.

Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 Grade 3/4 AEs2 System Organ Class/Preferred Term (N=134) (N=134) n (%) n (%) General disorders and administration site conditions Fatigue 45 (34) 9 (7) Pyrexia$ 31 (23) 3 (2) Edema peripheral 21 (16) 0 Asthenia$ 19 (14) 4 (3) General physical health deterioration 3 (2) 2 (1) Gastrointestinal disorders Diarrhea$ 42 (31) 8 (6) Nausea$ 40 (30) 1 (<1) Constipation 21 (16) 1 (<1) Vomiting$ 16 (12) 1 (<1) Abdominal pain$ 13 (10) 5 (4) Musculoskeletal and connective tissue disorders Back pain 18 (13) 2 (1) Muscle spasms 17 (13) 1 (<1) Arthralgia 11 (8) 2 (1) Muscular weakness$ 8 (6) 2 (1) Respiratory, thoracic and mediastinal disorders Cough 38 (28) 1 (<1) Dyspnea$ 24 (18) 8 (6) Pleural Effusion 10 (7) 2 (1) Hypoxia 3 (2) 2 (1) Pulmonary embolism 3 (2) 2 (1) Respiratory distress$ 2 (1) 2 (1) Oropharyngeal pain 13 (10) 0 Infections and infestations Pneumonia@ $ 19 (14) 12 (9) Upper respiratory tract infection 17 (13) 0 Cellulitis$ 3 (2) 2 (1) Bacteremia$ 2 (1) 2 (1) Staphylococcal sepsis$ 2 (1) 2 (1) Urinary tract infection$ 5 (4) 2 (1) (continued)

Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 Grade 3/4 AEs2 System Organ Class/Preferred Term (N=134) (N=134) n (%) n (%) Skin and subcutaneous tissue disorders Rash + 30 (22) 2 (1) Pruritus 23 (17) 1 (<1) Blood and lymphatic system disorders Neutropenia 65 (49) 58 (43) Thrombocytopenia% $ 48 (36) 37 (28) Anemia$ 41 (31) 15 (11) Leukopenia$ 20 (15) 9 (7) Lymphopenia 10 (7) 5 (4) Febrile neutropenia$ 8 (6) 8 (6) Metabolism and nutrition disorders Decreased appetite 19 (14) 1 (<1) Hypokalemia 17 (13) 3 (2) Dehydration$ 10 (7) 4 (3) Hypocalcemia 4 (3) 2 (1) Hyponatremia 3 (2) 3 (2) Renal and urinary disorders Renal failure$ 5 (4) 2 (1) Vascular disorders Hypotension@ $ 9 (7) 4 (3) Deep vein thrombosis$ 5 (4) 5 (4) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor flare 13 (10) 0 Squamous cell carcinoma of skin$ 4 (3) 4 (3) Investigations Weight decreased 17 (13) 0 1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects 2-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects $-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects @ - AEs where at least one resulted in a fatal outcome % - AEs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed + - All PTs under HLT of Rash will be considered listed The following adverse events which have occurred in other indications and not described above have been reported (5-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma.

General disorders and administration site conditions: Chills Musculoskeletal and connective tissue disorders: Pain in extremity Nervous system disorders: Dysguesia, headache, neuropathy peripheral Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis Skin and subcutaneous tissue disorders: Dry skin, night sweats The following serious adverse events not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma.

Respiratory, Thoracic and Mediastinal Disorders: Chronic obstructive pulmonary disease Infections and Infestations: Clostridium difficile colitis, sepsis Neoplasms benign, malignant and unspecified (incl cysts and polyps): Basal cell carcinoma Cardiac Disorder: Supraventricular tachycardia 6.4 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis and transient abnormal liver laboratory tests.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.5 to 5.8)].

Cases of hypothyroidism and hyperthyroidism have also been reported.

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News

Researchers at University of Michigan Receive $2.3 Million Grant to Promote Safety, Reduce Exposure Risk, at Chemotherapy Infusion Sites

R

esearchers at the University of Michigan School of Nursing and Comprehensive Cancer Center have received a $2.3 million grant to study oncology nurses’ exposure to hazardous drugs, includ-

ing identifying ways to reduce exposure.

“There are significant acute and longterm side effects from hazardous drug exposures in oncology settings, but not enough evidence-based, risk-reduction

treatment. Baseline and ongoing monitoring of thyroid function is recommended.

7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions.

In vitro studies demonstrated that REVLIMID is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2.

In vitro, lenalidomide is a substrate, but is not an inhibitor of P-glycoprotein (P-gp).

7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin.

7.3 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone [see Warnings and Precautions (5.4)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1)] Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue.

Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.

Lenalidomide caused thalidomide-type limb defects in monkey offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats.

In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the

efforts to protect health-care workers,” said Christopher ­ Friese, PhD, RN, AOCN®, FAAN, University of Michigan School of Nursing Assistant Professor and Member of University of Michigan’s

rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide.

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

8.4 Pediatric use Safety and effectiveness in pediatric patients below the age of 18 have not been established.

8.5 Geriatric use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age.

Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients.

REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age.

Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs.

33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.

8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy.

Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.

Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation.

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Comprehensive Cancer Center and Institute for Healthcare Policy and Innovation. Dr. Friese aims to lower the risk through a new study called DEFENS: continued on page 44

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News Chemotherapy Infusion Sites continued from page 43

Drug Exposure Feedback and Education for Nurses’ Safety. The 4-year study, with funding from the National Institute for Occupational Safety and Health (NIOSH), will examine oncology nurses’ use of personal protective equipment and biological exposure to hazardous

drugs at approximately a dozen healthcare institutions nationwide.

“Nurses are the single largest group of oncology care providers,” Dr. Friese said.

“Patients and families work with nurses the most when chemotherapy is part of treatment. It’s important to recognize the need for well-prepared oncology nurses to deliver care safely and avoid poor outcomes.”

Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)].

8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment.

The elimination of unchanged lenalidomide is predominantly by the renal route.

10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients; although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose studies, some patients were exposed to up to 400 mg.

In studies, the dose-limiting toxicity was essentially hematological. In the event of overdose, supportive care is advised.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies with lenalidomide have not been conducted.

Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindicatons (4.1)]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

• Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy.

• Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test.

• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy.

Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.

• Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.

• Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy.

• Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

• All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Worker exposure to hazardous drugs like chemotherapy is a “persistent problem” and may result in adverse health effects (NIOSH Alert 2004-165). In a preliminary study, Dr. Friese found that among 242 surveyed oncology nurses, 16.9% reported skin or eye exposure to hazardous drugs in the past year.

Organizational factors such as nursing

REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)].

• Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)].

• REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product.

Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)].

Venous Thromboembolism Inform patients that REVLIMID/dexamethasone has demonstrated significant increased risk of DVT and PE in patients with multiple myeloma [see Boxed Warnings and Warning and Precautions (5.4)].

Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)].

Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID. Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.

Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation.

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.

Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.

Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water.

Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.

Manufactured for: Celgene Corporation Summit, NJ 07901 REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation.

REVLIMID REMS™ is a trademark of Celgene Corporation.

U.S. Pat. Nos. 5,635,517; 6,045,501; 6,281,230; 6,315,720; 6,555,554; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 7,119,106; 7,189,740; 7,468,363; 7,465,800; 7,855,217; 7,968,569 ©2005-2013 Celgene Corporation, All Rights Reserved.

REV_MCL_HCP_BSv18 11_2013

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workloads, practice environments, and performance of safety behavior are associated with an increased risk of spills.

Key Components The 4-year study has two key components. First, nurses will provide information concerning chemotherapy spills in the clinic and provide blood samples to determine whether the agents are detectable. Second, nurses will receive an educational module on safe drug handling, with and without specific feedback about how to im-

Over 20 million doses of [chemotherapy] are given annually in infusion centers.

The data gathered from this study can be used to inform practice and make policy changes that will improve the safety of a large number of health-care workers.

—Christopher Friese, PhD, RN, AOCN®, FAAN

prove their practice. The goal is to increase the number of nurses who use protective equipment likes gowns and gloves on a consistent basis. Eleven of the nation’s leading cancer centers and more than 300 nurses will participate.

Coinvestigators for this multidisciplinary study will include Duxin Sun, PhD, Professor at the University of Michigan College of Pharmacy and Director of University of Michigan Pharmacokinetics Core, and ­Marjorie ­McCullagh, PhD, RN, APHN-BC, COHN-S, Associate Professor of Nursing, Director of the Occupational Health Training Program, and Contributing Faculty to University of Michigan’s NIOSH-Funded Education and Research Center.

“Over 20 million doses of [chemotherapy] are given annually in infusion centers. We believe the data gathered from this study can be used to inform practice and make policy changes that will improve the safety of a large number of health-care workers,” Dr. Friese said. n

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Inside the Black Box Patient-Reported Outcomes in Hematology and Oncology Product Development A Conversation With Virginia Kwitkowski, MS, RN, ACNP-BC, and Elektra Papadopoulos, MD, MPH INSIDE THE BLACK BOX is an occasional column providing insight into the U.S. Food and Drug Administration (FDA) and its policies and procedures. In this installment, Virginia Kwitkowski, MS, RN, ACNP-BC, and Elektra Papadopoulos, MD, MPH, discuss FDA’s current approach to the review of study endpoints reported by patients (patient-reported outcomes) to support hematology and oncology drug approvals. Ms. Kwitkowski is a Clinical Team Leader in the Division of Hematology Products, and Dr. Papadopoulos is Acting Associate Director of the Study Endpoints Team in the Office of New Drugs’ Study Endpoints and Labeling Development Staff.

I

n December 2009, the FDA published a Guidance for Industry titled “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.” Here, Ms. Kwitkowski and Dr. Papadopoulos respond to questions about the use of patient-reported outcomes in drug development for hematology and oncology products.

Strict Definition What is a patient-reported outcome?

Dr. Papadopoulos: A patient-reported outcome (PRO) is a measurement based on a report that comes directly from the patient about the status of his or her health condition without amendment or interpretation of the patient’s report by a clinician or anyone else. A patient-reported outcome can be measured by self-report or by interview, provided that the interviewer records only the patient’s response without interpretation. One example of a PRO endpoint is self-reporting of pain intensity.

Important Perspective Why is it important to capture the patient’s perspective in trials of investigational hematology and oncology products?

Ms. Kwitkowski: New cancer treatments are approved by the FDA based upon the demonstration of “clinical benefit.” Clinical benefit can be demonstrated by prolonging overall survival or by improving how the patient feels or functions. Obtaining data on how long

patients survive can take a long time. In some diseases, waiting for overall survival data to mature can delay getting safe and effective drugs to patients. An improvement in cancer-related symptoms can also provide evidence of clinical benefit. No one other than the patient knows how he or she truly feels.

Patients have also told us that when choosing a treatment for their cancer in conjunction with their health-care pro-

treatment product labels. In order to use a patient-reported outcome in a clinical trial to measure treatment efficacy, the disease being treated must cause symptoms that are measurable by an instrument that has been shown to accurately measure the symptom. Some cancers do not cause clear symptoms until they progress to later stages.

Some examples of cancers that can be asymptomatic in early stages include breast cancer, ovarian cancer, renal cell cancer, colon cancer, and melanoma.

Patient-reported outcomes measuring cancer symptoms would not be appropriate efficacy endpoints for trials in early stages of these cancers. Also, some cancers may have a variety of potential symptoms, which makes assessing them more difficult. It is easier if there is a cardinal symptom such as pain in patients with metastatic prostate cancer or difficulty swallowing in patients with an obstructing esophageal cancer.

Another reason for the omission of this information is that the FDA can only label information that is supported by substantial evidence. Moreover, there are few instruments that have

We need more drug companies to prioritize the use of patient-reported outcomes as primary or key secondary endpoints in their trials. This requires early planning and communication between drug companies and the FDA during drug development to ensure agreement on the goal of the measurement.

—Elektra Papadopoulos, MD, MPH

vider, they would like to know whether they can still work or take care of their families while receiving the treatment.

Measuring how patients feel and function during treatment may help future patients understand how the treatment may impact them.

Product Labeling Why do so few hematology and oncology product labels contain the patient’s perspective?

Ms. Kwitkowski: There are many different reasons why the patient’s perspective is absent from many cancer

been found to accurately measure the symptoms of interest. If the instrument used to measure the patient’s symptoms is not known to do this accurately, the data may not be appropriate for a labeling claim.

Finally, the PRO endpoint is often at the bottom of a long list of other secondary endpoints in the protocol, without statistical control of the type I error rate (the risk of the results occurring at random, or the risk of a false-positive result).

What can be done outside the FDA to increase the number of product labels that

FDA Clinical Reviewers

Virginia Kwitkowski, MS, RN, ACNP-BC

Elektra Papadopoulos, MD, MPH

contain the patient’s perspective?

Dr. Papadopoulos: We need more drug companies to prioritize the use of patient-reported outcomes as primary or key secondary endpoints in their trials. This requires early planning and communication between drug companies and the FDA during drug development to ensure agreement on the goal of the measurement (ie, what the tool is intended to measure), such as symptoms of a disease or condition, and the patient population in which the measure will be used. Once there is clarity on these issues, an appropriate PRO instrument can be selected or a new one developed.

FDA Guidance What is the FDA doing to facilitate the use of patient-reported outcomes in cancer and hematology clinical trials?

Dr. Papadopoulos: As stated previously, the FDA issued a written guidance titled “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.” The guidance describes how we review and evaluate existing, modicontinued on page 46

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Inside the Black Box Patient Reported Outcomes continued from page 45

fied, or newly created PRO instruments intended to support claims in approved product labeling.

There are two pathways for obtaining FDA input on a PRO instrument (or other types of clinical outcome assessment tools). One pathway is for an individual drug company to seek advice related to the use of a measure within their own drug development program.

Another option is through a relatively new pathway called the “clinical outcome assessment drug development tool qualification process” for groups who want to qualify a clinical outcome assessment for use in clinical trials that could support a labeling claim.

Qualification means that the FDA has reviewed the PRO (or other clinical outcome assessment) and agrees that it is an accurate and reliable measurement of an outcome in the right patient population. Once an instrument is qualified,

it is made publicly available, and drug companies may feel more secure about using it in a clinical trial to support a labeling claim as long as it is used in a manner consistent with its qualification.

Formal qualification is a voluntary process. A clinical outcome assessment does not need to be qualified to be acceptable for use in a clinical trial.

Ms. Kwitkowski: FDA’s Patient-Focused Drug Development initiative is a commitment under the fifth authorization of the Prescription Drug User Fee Act (PDUFA V) that aims to more systematically gather patients’ perspectives on their condition and available therapies to treat their condition. As part of this commitment, FDA is holding at least 20 public meetings over the course of PDUFA V, each focused on a specific disease area. Voice of the Patient reports will summarize the input provided by patients and patient representatives at each of these public meetings.

Meetings have already been held

on lung cancer and sickle cell disease.

There are plans for future meetings on breast cancer and heritable bleeding disorders.

The National Cancer Institute is also developing a Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). This electronic-based system will provide for patient self-reporting of symptomatic adverse events listed in the CTCAE in an effort to improve the accuracy and precision of grading of this class of adverse events.

Some FDA staff have worked collaboratively with the group developing the PRO-CTCAE. The FDA will continue to strongly encourage pharmaceutical companies to include PRO endpoints in their clinical trial designs when possible so that information on the patient’s perspective can be included in prescription drug labeling. The patient’s perspective can be captured through the in-

GUEST EDITOR

Richard Pazdur, MD

Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. clusion of disease symptom endpoints and/or patient reports of adverse drug reactions.

Disclosure: Ms. Kwitkowski and Dr. Papadopoulos reported no potential conflicts of interest.

Peer-to-Peer Viewpoints on Issues in Oncology Visit ASCOPost.com to view the series Recorded Live at ASCO’s 50th Annual Meeting, Chicago The ASCO Post is pleased to present a special video series of interviews by and with leaders in oncology as recorded live at ASCO’s 50th Annual Meeting in Chicago. Visit ASCOPost.com/video or use the QR code to access the program and view these one-on-one interviews: James O. Armitage, MD, speaks with:

■■

Brian I. Rini, MD: Advances in Renal Cell Carcinoma

■■

Franco Cavalli, MD: Important Data in Lymphoma Presented at ASCO 2014

■■

■■

Richard I. Fisher, MD: Standard of Care in Mantle Cell Lymphoma

Siu-Long Yao, MD: Prostate Cancer: A Statistician’s Perspective

■■

Clifford A. Hudis, MD, FACP: ASCO Today: Science and Society

James L. Mulshine, MD, speaks with:

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Michael Pfreundschuh, MD: Diffuse Large B-Cell Lymphoma

■■

Carolyn Aldige: Issues in Lung Cancer Screening: An Advocate’s Perspective

■■

Fred R. Hirsch, MD, PhD: Issues in the Early Detection of Lung Cancer

■■

Natasha Leighl, MD: Issues in Lung Cancer Screening

Nancy E. Davidson, MD, speaks with: ■■

Lisa Carey, MD: Anti-HER2 Therapy for Breast Cancer

Derek Raghavan, MD, PhD, speaks with: ■■

Karim Fazizi, MD: French Genitourinary Tumor Group Studies

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Maha Hussein, MD: Prostate Cancer, Bladder Cancer

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Daniel Petrylak, MD: Bladder Cancer: Neoadjuvant and Adjuvant Therapy

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David I. Quinn, MD: Prostate Cancer, Bladder Cancer, Adrenocortical Carcinoma

Plus, the following presentations: ■■

Halle C.F. Moore, MD, on Fertility Preservation in Young Women With Breast Cancer

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John F. Smyth, MD, on Improving the Efficacy of Developing New Medicines—and Finding Solutions to Making Them More Affordable

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Alok A. Khorana, MD, on Colorectal Cancer: Results From CALGB/SWOG 80405

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 47

Journal Spotlight Breast Cancer

Study Quantifies Risk of Hereditary Breast Cancer in Carriers of PALB2 Mutations

By Matthew Stenger

I

n a study reported in The New England Journal of Medicine, Antonis C. Antoniou, PhD, Reader in Cancer Risk Prediction and Cancer Research UK Senior Cancer Research Fellow at the University of Cambridge, and colleagues identified lifetime risk of breast cancer in families with germline loss-offunction mutations in PALB2.1 Estimated cumulative risk among female mutation carriers was 14% by 50 years of age and 35% by 70 years of age. Compared with risk in the general UK population, risk was increased eight- to ninefold in mutation carriers aged < 40 years, six-

cific risk was estimated using a modified segregation analysis that accounted for effects of PALB2 genotype and residual familial aggregation.

Cumulative and Age-Related Risk The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI] = 9%–20%) by 50 years of age and 35% (95% CI = 26%–46%) by 70 years of age.

Mean annual breast cancer incidence in mutation carriers and relative risk of breast cancer compared with the general

Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them.

—Antonis C. Antoniou, PhD, and colleagues

to eightfold in those aged 40 to 60 years, and fivefold in those aged > 60 years.

PALB2 (partner and localizer of BRCA2) was first identified as a protein integral to BRCA2 genome caretaker functions and was also found to interact with BRCA1. Monoallelic loss-offunction mutations have been associated with increased risks of breast and pancreatic cancers. These loss-of-function mutations have been identified in persons from many countries and have been found in 0.6% to 3.9% of families with a history of breast cancer.

Study Details The study involved analysis of risk of breast cancer among 362 members of 154 families with truncating, splice, or deletion mutations in PALB2. Age-spe-

population by age group were 0.01% and 9.01 for 20 to 24 years of age, 0.07% and 8.97 for 25 to 29 years, 0.23% and 8.85 for 30 to 34 years, 0.50% and 8.54 for 35 to 39 years , 0.85% and 8.02 for 40 to 44 years, 1.27% and 7.31 for 45 to 49 years, 1.60% and 6.55 for 50 to 54 years, 1.45% and 5.92 for 55 to 59 years, 1.47% and 5.45 for 60 to 64 years, 1.19% and 5.10 for 65 to 69 years, 1.34% and 4.82 for 70 to 74 years, and 1.34% and 4.56 for 75 to 79 years.

Effects of Birth Cohort and Family History As has been observed among carriers of loss-of-function mutations in BRCA1 and BRCA2, there is an increase in risk PALB2 mutation carriers in later birth cohorts. Compared with risk in those born before 1940, relative

Role of PALB2 in Breast Cancer ■■ Cumulative risk of breast cancer among female carriers of PALB2 mutation was 14% by 50 years of age and 35% by 70 years of age.

■■ Risk was significantly increased in later birth cohorts and by positive family history.

risk was 2.84 (95% CI = 1.64–4.93) in those born between 1940 and 1959 and 6.29 (95% CI = 2.81–14.10) in those born in 1960 or later (P < .001).

Risk was also increased by family history of breast cancer, with absolute risk by age 70 years among mutation carriers ranging from 33% (95% CI = 25%–44%) in those with no family history of breast cancer to 58% (95% CI = 50%–66%) in those with two or more first-degree relatives with breast cancer by age 50 years.

Receptor Status Among 129 affected PALB2 mutation carriers with known estrogen receptor status, 95 (74%) had estrogen receptor–positive tumors, a rate similar to that in patients with BRCA2 mutations and those with sporadic breast cancer. Among 63 affected patients with known progesterone receptor and HER2 status, 19 (30%) had triple-negative disease, a rate higher than the 12% to 17% prevalence found in unselected populations of breast cancer patients.

Other Associations?

The investigators noted that they also found a nonsignificant 2.3-fold increased risk of ovarian cancer in PALB2 mutation carriers and that larger studies would be required to adequately address the potential association. Risk of male breast cancer was increased by approximately eightfold in mutation carriers, although the confidence interval for the estimate was very large. PALB2 mutations have also been associated with

increased risk of pancreatic cancer, but lifetime risks have yet to be assessed.

The investigators concluded, “Lossof-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.”

They noted: Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers.

Because of the widespread availability of multigene panels and whole-exome sequencing, screening for inherited loss-offunction mutations in PALB2 has begun to enter clinical practice. As families with PALB2 mutations are identified, it will be valuable to collect family history and other data for future analysis, in order to refine estimates of the cancer risks for PALB2 mutation carriers. n Disclosure: The study was funded by the European Research Council and many others.

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

Reference 1. Antoniou AC, Casadei S, Heikkinen T, et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506, 2014.

See commentary by Judy E. Garber, MD, MPH on page 52.

More on Mutations in PALB2 Gene See page 141 in this issue of The ASCO Post for an interview with Theodora Ross, MD, PhD, on mutations in the PALB2 gene.

XOFIGO® IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

Bone metastases?

1

First sign of symptoms?

1

Start

to extend survival

1,2

Important Safety Information • Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

Myelosuppression—notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

• Bone Marrow Suppression: In the randomized trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death.

Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigotreated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure

© 2014 Bayer HealthCare Pharmaceuticals Inc. BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer.

• Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care • Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have

600-10-0007-14d

07/14

Printed in USA

• In the ALSYMPCAa exploratory updated analysis,b median overall survival was 14.9 months for Xofigo (95% confidence interval [CI]: 13.9-16.1) vs 11.3 months for placebo (95% CI: 10.4-12.8) [hazard ratio (HR)=0.695; 95% CI: 0.581-0.832]1 • In the ALSYMPCA prespecified interim analysis, median overall survival was 14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2) [P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)]1

a

30% reduction in the risk of death vs placebo1

ALSYMPCA was a phase 3, randomized, double-blind, controlled trial that evaluated Xofigo plus best standard of care (n=614) vs placebo plus best standard of care (n=307).1

b

An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1

To learn more, visit www.xofigo-us.com

not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)

• Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit.

Therefore, radiation protection precautions must be taken in accordance with national and local regulations

References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013.

2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see brief summary of full Prescribing Information on following pages.

• Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were

radium Ra 223 dichloride INJECTION

Xofigo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE Because clinical trials are conducted under widely varying conditions, adverse reaction rates Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of symptomatic bone metastases and no known visceral metastatic disease. another drug and may not reflect the rates observed in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with 2 DOSAGE AND ADMINISTRATION bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) 2.3 Instructions for Use/Handling of Xofigo and best standard of care and 301 patients received placebo and best standard of care General warning once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, organization. vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% Xofigo should be handled by the user in a manner which satisfies both radiation safety and of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).

Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, Treatment discontinuations due to adverse events occurred in 17% of patients who received caregivers and patient’s household members) from radiation or contamination from spills of bodily Xofigo and 21% of patients who received placebo. The most common hematologic laboratory fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). accordance with national and local regulations.

Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal Xofigo exceeds the incidence for placebo. precautions for handling and administration such as gloves and barrier gowns when handling Table 3: Adverse Reactions in the Randomized Trial blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected System/Organ Class Xofigo (n=600) Placebo (n=301) area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 safety officer should be contacted immediately to initiate the necessary measurements and required % % % % procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamineBlood and lymphatic system disorders tetraacetic acid (EDTA) solution is recommended to remove contamination.

Pancytopenia 2 1 0 0 For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times Gastrointestinal disorders after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect Nausea 36 2 35 2 caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly Diarrhea 25 2 15 2 and separately from other clothing.

19 2 14 2 Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. Vomiting The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. General disorders and administration site conditions The external radiation exposure associated with handling of patient doses is expected to be low, Peripheral edema 13 2 10 1 because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is Renal and urinary disorders recommended to minimize the time spent in radiation areas, to maximize the distance to radiation Renal failure and impairment 3 1 1 1 sources, and to use adequate shielding. Any unused product or materials used in connection with Laboratory Abnormalities the preparation or administration are to be treated as radioactive waste and should be disposed of Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which in accordance with local regulations. the incidence for Xofigo exceeds the incidence for placebo.

The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Table 4: Hematologic Laboratory Abnormalities 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy.

Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression.

In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo.

The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized.

In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)].

Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure.

The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

Hematologic Laboratory Abnormalities

Xofigo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle.

As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.

Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia.

Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo.

Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)].

However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial.

Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed.

3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹ CHANNELÂŹ blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XoďŹ go.

8.3 Nursing Mothers XoďŹ go is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from XoďŹ go, 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 efďŹ cacy of XoďŹ go in pediatric patients have not been established.

In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight.

8.5 Geriatric Use Of the 600 patients treated with XoďŹ go in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ RADIUM ÂŹ ISÂŹ neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.

8.7 Patients with Renal Impairment No dedicated renal impairment trial for XoďŹ go has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].

8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with XoďŹ go.

Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation

by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies.

There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 1 clinical trial and no dose-limiting toxicities were observed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats.

Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation.

Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action.

17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGO ÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGO ÂŹ &OLLOWÂŹ good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers.

Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily ďŹ&#x201A;uids to avoid contamination.

When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹPOTENTIALÂŹ to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. Š 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

Revised: 05/2013 "3

The ASCO Post | SEPTEMBER 15, 2014

PAGE 52

Perspective

PALB2 Study: Researchers and Patients Must ‘Pal’ for Progress

By Judy E. Garber, MD, MPH

T

he recent publication by Antoniou et al on risk of breast cancer in PALB2 carriers,1 reviewed in this issue of The ASCO Post (page 47), is a contribution to the interesting history of the PALB2 gene, and an important milestone in the expansion of hereditary cancer susceptibility testing in the post-BRCA1/2 era.

PALB2 (partner and localizer of BRCA2, aka “pal of B2”) was identified by functional studies in the Livingston lab in 2006.2 It encodes a BRCA2 binding protein that serves as a critical DNA repair gene in the homologous recombination repair pathway. Soon after, PALB2 was shown to be a Fanconi anemia gene (FANCN)3 and was reported as a susceptibility gene in BRCA1/2negative hereditary breast cancer families4 with a founder mutation in the Finnish population,5 setting the standard for criteria for the identification of new breast cancer susceptibility genes.

In another pioneering study, the Vogelstein group identified PALB2 by complete exomic sequencing of the germ lines of probands from hereditary pancreatic cancer families.6 It has been disappointing that the prevalence of PALB2 mutations among both breast/pancreatic and pancreatic cancer families is low.

ate penetrance” genes for which epidemiology studies have not yet provided clear penetrance estimates.7,8 The lack of stable cancer risk estimates often leaves patients and their health-care providers in the unsettling position of trying to extrapolate risk management options from data gathered over 20 years from the thousands of BRCA1- and ­BRCA2-mutation carriers in epidemiologic and clinical studies for these very high-penetrance genes. This should be unsettling in the era of data-driven care.

Research Paradigm The Antoniou et al paper allows PALB2 to emerge from the pack, and again provides a paradigm for the genes to come after. The investigators used modern modified segregation analysis in 311 women and 51 men with mutations

Essential Data Contribution In addition to important data for counseling individuals with PALB2 mutations, what should we take away from the Antoniou publication? First, valuable data came from the pooled study of only 311 probands. It is going to be absolutely essential for individuals found to carry mutations in the even less prevalent genes included in current and future panels to contribute their data to such efforts, so that we can provide reliable estimates of cancer risk as quickly as possible.

The cancer genetics research communities have long collaborated on studies of cancer risk, screening, prevention, and, most recently, treatment of these relatively rare populations would otherwise be impossible. Given that many of the genes in the panels are only rarely mutated, and since panel testing in the

Only rigorous and careful study will provide reliable data on which we can base recommendations for management of our patients found to carry [PALB2] mutations.

—Judy E. Garber, MD, MPH

International Collaboration In the study by Antoniou and colleagues, PALB2 is again leading the way.

The study represents an international collaboration of breast cancer geneticists who contributed their PALB2 families.

The analysis provides important data on which to base genetic counseling for individuals and families found to carry germline PALB2 mutations.

Despite the identification of PALB2 families in 2007, commercial testing for PALB2 mutations only recently became widely available with the introduction of breast cancer susceptibility gene panels. These include genes beyond the initial higher penetrance group, BRCA1, BRCA2, TP53, PTEN, CDH1, and STK11, for which lifetime breast cancer risks were approximately 40% or greater.

Concerns have been raised about the use of these panels, which include increasing numbers of so-called “moderDr. Garber is Director, Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, and Professor of Medicine, Harvard Medical School, Boston.

to account for family aggregation, and included only definitive mutations. They estimated that cumulative breast cancer risks among female mutation carriers were 14% by age 50 and 35% by age 70, considerably higher than U.S. risks (2% by age 50 and 12% by age 90 years).

Most relevant for clinical counseling, they estimated a 33% (95% confidence interval [CI] = 25%–44%) absolute risk of breast cancer by age 70 in those without family breast cancer history, but 58% (95% CI = 50%–66%) in those with two or more first-degree relatives with breast cancer diagnosed by age 50 years. Examination of breast cancer subtypes was limited to 129 cases, showing a small excess of triple-negative breast cancers (30%), with the remainder being hormone receptor–positive.

An excess of ovarian cancer could not be documented, and no pancreatic cancer data were provided. The authors are careful to say that ovarian cancer risk may still be increased, but the excess may not be high enough to have been observed in this relatively small cohort.

United States is increasingly used by physicians and genetic counselors outside of academic centers, many of the individuals who can contribute important data to these studies will not be coming through the usual paths to research.

Challenges may be different outside of the United States, where genetic testing is generally performed within specialized health-care settings linked to research, but the decisions about which genes to include may be more complex.

In the US, at least, it will be more important than ever for physicians and genetic counselors to encourage their patients to contribute to research on their genes, and for the academic community to find creative ways to expand its reach and provide easier ways for individuals and families tested in the broader community to contribute their data to these efforts.

The City of Hope network, the ENIGMA consortium, and the PROMPT project will provide essential early routes. The testing laboratories must also contribute to these efforts, sharing their data on mutations

and variants and providing other support as appropriate.

Penetrance Estimates It is also interesting that the penetrance estimates for PALB2 are high enough to place it above the “moderate penetrance” group. It is difficult to predict what the cancer risks will be for the other genes yet to be more fully evaluated, and we cannot and should not guess the numbers, the range of tumors, or the implications for management of the cancer risks.

Only rigorous and careful study will provide reliable data on which we can base recommendations for management of our patients found to carry these mutations. Those studies will require the same kind of meticulous data collection and follow-up that have been devoted to BRCA1/2 mutations, even though these mutations will be less prevalent. Our patients and their families deserve no less. n

Disclosure: Dr. Garber has received research funding from Myriad Genetics Laboratories, Ambry Genetics, Novartis Pharmaceuticals, and Astra Zeneca and is a consultant for Pfizer.

References 1. Antoniou AC, Casadei S, Heikkinen T, et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506, 2014.

2. Xia B, Sheng Q, Nakanishi K, et al: Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.

Mol Cell 22:719-729, 2006.

3. Xia B, Dorsman JC, Ameziane N, et al: Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 29:159-161, 2007.

4. Tischkowitz M, Xia B, Sabbaghian N, et al: Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci USA 104:6788-6793, 2007.

5. Erkko H, Xia B, Nikkilä J, et al: A recurrent mutation in PALB2 in Finnish cancer families. Nature 446:316-319, 2007.

6. Jones S, Hruban RH, Kamiyama M, et al: Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324:217, 2009.

7. Domchek SM, Bradbury A, Garber JE, et al: Multiplex genetic testing for cancer susceptibility. J Clin Oncol 31:1267-1270, 2013.

8. Robson M: Multigene panel testing: Planning the next generation of research studies in clinical cancer genetics. J Clin Oncol 32:1987-1989, 2014.

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 53

News Thoracic Oncology

NCCN Marks 20 Years of Evidence-Based Decision-Making in Small Cell Lung Cancer

T

he National Comprehensive Cancer Network (NCCN) recently announced publication of the 20th annual edition of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC).

One of the eight original NCCN Guidelines, the NCCN Guidelines for SCLC was initially published in November 1996.

“There have indeed been major improvements in the NCCN process since 1996,” said Greg Kalemkerian, MD, Professor, Medical Oncology, University of Michigan Comprehensive Cancer Center, and NCCN Guidelines Panel Chair

Greg Kalemkerian, MD

for SCLC. “Such improvements include the integration of a broader discipline representation on the NCCN Guidelines Panels, the availability of more evidencebased studies to support recommendations and choices, and the inclusion of the ‘Principles of’ sections that provide more detailed information of rationale and details of therapeutic regimens.”

Notable Improvements Dr. Kalemkerian noted improvements in the treatment of SCLC since 1996, highlighting NCCN Guidelines recommendations such as the demonstration of survival benefit for prophylactic cranial radiation (PCI), raising PCI—a highly controversial procedure—from category 3 in 1996 to its current status as a category 1 recommendation, based on highquality evidence and uniform consensus.

Similarly, the demonstration of a survival benefit for second-line chemotherapy in relapsed SCLC raised subsequent chemotherapy from a category 3 in 1996 to a category 1 recommendation today. Another improvement was the demonstration of a survival benefit for hyperfractioned thoracic radiotherapy in limited-stage SCLC. Today, NCCN develops and publishes a library of 59 NCCN Guidelines, covering 97% of cancers affecting people in the United States.

On March 12 – 14, 2015, the NCCN 20th Annual Conference: Advancing the Standard of Cancer Care™ will be held at

The Diplomat in Hollywood, Florida. In recognition of NCCN’s 20th Anniversary, NCCN is planning to hold a special live roundtable during the NCCN Annual Conference comprised of NCCN leader-

ship—past and present—as well as other stakeholders who have had a significant impact on the development, progression, and success of NCCN over the years; noteworthy historical NCCN accom-

Trim: 7.625 X 10.5

plishments and events will be discussed, as well as the impact NCCN has had and continues to have on the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. n

After progression following initial antiestrogen therapy in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer...

Go with FASLODEX.

Primary Endpoint: Progression-Free Survival (PFS)1,*

Secondary Endpoint: Overall Survival (OS)1

Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg in CONFIRM2,†

Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg in CONFIRM2

At minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2

• Not statistically signifcant as no adjustments were made for multiplicity2

At minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2

Important Safety Information About FASLODEX • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema have been reported in association with FASLODEX • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants • FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) Please see additional Important Safety Information on reverse and brief summary of full Prescribing Information for FASLODEX on adjacent pages. * PFS is defned as the time between randomization and the

earliest evidence of progression or death from any cause. 2 † COmparisoN of FASLODEX In Recurrent or Metastatic Breast Cancer.1

Go with Confdence Learn more at www.faslodex.com/hcp

The ASCO Post | SEPTEMBER 15, 2014

PAGE 54

In Memorium Oncology Worldwide Cancer Prevention

Rwanda Offers Women Free Cervical Cancer Screening, HPV Vaccination

C

ervical cancer is one of the major killers among women in Rwanda, and with the support of Rwanda’s First Lady, Jeannette Kagame, the country is rolling out a free human papillomavirus (HPV) vaccination and cervical cancer screening program in collaboration with

Marck, Qiagen (a Dutch pharmaceutical company), the World Health Organization (WHO), and Unicef.

Half a million women, of whom 97% are school-going girls, have been administered the HPV vaccine (types 16 and 18) (Cervarix). More than 150,000 girls will

receive the vaccine before end of 2014, and the government says that at least 2.72 million more school-going girls between the age of 11 and 15 are expected to be vaccinated by 2015.

Cervical cancer is a growing cause of high morbidity and mortality rates

Trim: 7.625 X 10.5

among women in Africa. In Rwanda, 678 of 986 women diagnosed with cervical cancer since 2011 have died. Health Minister, Agnes Binagwaho, MD, says that Rwanda is investing in facilities and training more medical staff to fight cervical cancer and other illnesses. n

FASLODEX is indicated for the treatment of hormone receptor-positive (HR+) metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Prolonged PFS With FASLODEX 500 mg vs 250 mg in CONFIRM2,*,†

FASLODEX 500 mg Showed a Comparable Safety Profle to FASLODEX 250 mg in CONFIRM1

• Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg at minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2

Additional Important Safety Information About FASLODEX (continued)

• Objective response rates (ORRs)‡ were not signifcantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2

• Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX

— Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261)2 — ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

FASLODEX 500 mg vs 250 mg in the updated OS analysis in CONFIRM2,§ • Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg at minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2 Not statistically signifcant as no adjustments were made for multiplicity.2 • In the initial OS analysis after a minimum duration of 18 months, there was no statistically signifcant difference in OS between the 2 treatment groups2

• The most common, clinically signifcant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot fash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent

Indication For FASLODEX • FASLODEX is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

* The CONFIRM trial was a randomized, double-blind, controlled phase III

study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1 † PFS was the primary endpoint.1 ‡ ORR is defned as the number of patients with complete response or partial response.2 § OS was a secondary endpoint.1

Please read brief summary of full Prescribing Information for FASLODEX on adjacent pages.

References: 1. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594-4600. 2. Full Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

Go with Confdence FASLODEX is a registered trademark of the AstraZeneca group of companies.

©2013 MedImmune, Specialty Care Division of AstraZeneca.

All rights reserved.

2873001

10/13

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 55

Announcements

City of Hope Investigator Receives Grant for Immunotherapy Research

T

he Damon Runyon Cancer Research Foundation has awarded a $450,000 grant to an investigator studying T cells at City of Hope in Duarte. Elizabeth Budde, MD, PhD, Assistant Professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of

Hope, Duarte, received The Jake Wetchler Foundation for Innovative Pediatric Cancer Research-Damon Runyon Cancer Research Foundation Clinical Investigator award, which will support a 3-year study of immunotherapy treatment for AML. “Support as this generous award Trim:such 7.625 X 10.5

FASLODEX® (fulvestrant) Injection

is critical to our clinical research efforts,” said Steven T. Rosen, MD, Provost and Chief Scientific Officer at City of Hope.

“The project that Dr. Budde has developed will expand the field of T-cell immunotherapy in a very significant way and extend the benefit of treatment to

Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population Body System Number (%) of Patients Fulvestrant 500 mg N=361

Fulvestrant 250 mg N=374

Injection Site Pain

42 (11.6)

34 (9.1)

Headache

28 (7.8)

25 (6.7)

DOSAGE AND ADMINISTRATION

Back Pain

27 (7.5)

40 (10.7)

Recommended Dose

Fatigue

27 (7.5)

24 (6.4)

Pain in Extremity

25 (6.9)

26 (7.0)

Asthenia

21 (5.8)

23 (6.1)

24 (6.6)

22 (5.9)

Nausea

35 (9.7)

51 (13.6)

Vomiting

22 (6.1)

21 (5.6)

Anorexia

22 (6.1)

14 (3.7)

Constipation

18 (5.0)

13 (3.5)

Bone Pain

34 (9.4)

28 (7.5)

Arthralgia

29 (8.0)

29 (7.8)

Musculoskeletal Pain

20 (5.5)

12 (3.2)

Cough

19 (5.3)

20 (5.3)

Dyspnea

16 (4.4)

19 (5.1)

BRIEF SUMMARY For full Prescribing Information, see package insert.

INDICATIONS AND USAGE FASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter [see Clinical Studies (14) in full Prescribing Information].

Dose Modification Hepatic Impairment: A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter.

FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions and Use in Specific Populations].

Administration Technique

The proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged.

2. Remove perforated patient record label from syringe.

3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions refer below to the “Directions for Use of SafetyGlide™.”

4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap.

5. Twist to lock the needle to the luer connector.

6. Remove needle sheath.

7. Remove excess gas from the syringe (a small gas bubble may remain).

8. Administer intramuscularly slowly in the buttock.

9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered.

10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector.

11. Repeat steps 1 through 10 for second syringe.

For additional directions for use, see Administration Technique (2.3) in full Prescribing Information.

CONTRAINDICATIONS FASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX.

WARNINGS AND PRECAUTIONS Blood Disorders Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.

Hepatic Impairment The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.

Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended [see Dosage and Administration].

FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations].

Use in Pregnancy Based on its mechanism of action and findings in animals, FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area. There are no adequate and wellcontrolled studies in pregnant women using FASLODEX. Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients).

Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month.

and Adverse Reaction Body as a Whole

Vascular System Hot Flash Digestive System

Musculoskeletal System

Respiratory System

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms.

Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3) The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups, regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis.

Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2).

Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day.

Table 2: Combined Data from Studies 2 and 3, Adverse Reactions ≥ 5% Body System FASLODEX 250 mg Anastrozole 1 mg N=423 N=423 and Adverse Reactiona (%) (%) Body as a Whole Asthenia Pain Headache Back Pain Abdominal Pain Injection Site Painb Pelvic Pain Chest Pain Flu Syndrome Fever Accidental Injury Cardiovascular System Vasodilatation Digestive System Nausea Vomiting Constipation Diarrhea Anorexia Hemic and Lymphatic Systems Anemia

68.3 22.7 18.9 15.4 14.4 11.8 10.9 9.9 7.1 7.1 6.4 4.5 30.3 17.7 51.5 26.0 13.0 12.5 12.3 9.0 13.7 4.5

67.6 27.0 20.3 16.8 13.2 11.6 6.6 9.0 5.0 6.4 6.4 5.7 27.9 17.3 48.0 25.3 11.8 10.6 12.8 10.9 13.5 5.0 —continued

patients with few options.”

Dr. Budde leads the research under the mentorship of Stephen J. Forman, MD, the Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplatation at City of Hope. n

The ASCO Post | SEPTEMBER 15, 2014

PAGE 56

Perspective Robert Peter Gale, MD, PhD, DSc(hc), FACP continued from page 1

vocabulary … often vague in meaning— that can get us into deep trouble.

Stem Cell Dilemma Consider our hematology and oncology colleagues who do blood cell

or bone marrow transplants for diverse cancers such as leukemia, lymphoma, myeloma, and neuroblastoma. Lately they have taken to calling what they do “stem cell transplants.” Why they use this term is unclear: few scientific data convincingly show we are transplanting stem cells, especially when we do autotransplants afterXhigh-dose chemoTrim: 7.625 10.5

therapy. Perhaps it is cachet, or a way to increase the likelihood of funding, or merely a comfortable jargon.

And here is where the problem starts. There is substantial disagreement over what a stem cell is. For example, developmental biologists have a completely different definition of a stem cell than hematologists and oncologists.

FASLODEX® (fulvestrant) Injection Body System and Adverse Reactiona

FASLODEX 250 mg N=423 (%) Metabolic and Nutritional Disorders 18.2 Peripheral Edema 9.0 Musculoskeletal System 25.5 Bone Pain 15.8 Arthritis 2.8 Nervous System 34.3 Dizziness 6.9 Insomnia 6.9 Paresthesia 6.4 Depression 5.7 Anxiety 5.0 Respiratory System 38.5 Pharyngitis 16.1 Dyspnea 14.9 Cough Increased 10.4 Skin and Appendages 22.2 Rash 7.3 Sweating 5.0 Urogenital System 18.2 Urinary Tract Infection 6.1

Anastrozole 1 mg N=423 (%) 17.7 10.2 27.9 13.7 6.1 33.8 6.6 8.5 7.6 6.9 3.8 33.6 11.6 12.3 10.4 23.4 8.0 5.2 14.9 3.5

a A patient may have more than one adverse reaction. b All patients on FASLODEX received injections, but only those anastrozole patients who were in the North American Study 2 received placebo injections.

Post-Marketing Experience For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions including angioedema and urticaria.

Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered.

Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

DRUG INTERACTIONS There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro, drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics.

Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area (BSA). Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed.

Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.

Geriatric Use For FASLODEX 250 mg, when tumor response was considered by age, objective responses were seen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years of age and older, who were treated with FASLODEX in Study 2 and Study 3, respectively.

Hepatic Impairment FASLODEX is metabolized primarily in the liver.

The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (ChildPugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (ChildPugh class B) [see Dosage and Administration and Warnings and Precautions].

Renal Impairment Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine.

OVERDOSAGE Animal studies have shown no effects other than those related directly or indirectly to antiestrogen activity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

Nursing Mothers It is not known if fulvestrant is excreted in human milk. Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FASLODEX, 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 A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCuneAlbright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8).

The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.

2

Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.

Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known.

Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died.

Pharmacokinetics The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis.

In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively.

SafetyGlide™ is a trademark of Becton Dickinson and Company.

FASLODEX is a trademark of the AstraZeneca group of companies. © AstraZeneca 2013 Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, England By: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany Rev. 11/12 2873001 10/13

Many biologists consider the term “hematopoietic stem cell” an oxymoron: if a cell is committed to hematopoiesis, it’s not a stem cell.

The public, many of our colleagues, and we all hope stem cells will cure many if not most diseases and even the most dreaded process, aging. Upon hearing that hematologists and oncologists are transplanting stem cells, it was only logical for them to consider whether such a transplant might cure end-stage heart and liver diseases and other ills. The rest is a reasonably predictable story.

Hope Over Reason Ten to 15 years ago, data from experiments in mice reported that bone marrow–derived cells—let’s call them “hematopoietic stem cells”—could differentiate or transdifferentiate into diverse end cells including heart, liver, and nerve cells, under appropriate conditions. The concept was fascinating, and some of the data were convincing.

However, there were already warnings of uncertainty at this early stage. For example, numbers of new end cells in these studies were few, and some techniques used to determine their origin from bone marrow progenitors questionable. Although some of these data came from excellent labs, other scientists could not reproduce the results.

Oncologists know a plausible rationale combined with a strong belief, especially if underpinned by even the most modest supporting preclinical data (mice and cell lines are great for this) are enough to get a clinical trial off and running. This is especially so when the target disease is serious and there are few or no effective other therapies.

Some call this “the triumph of hope over reason.”

Which brings us to the question of whether oncologists will be the first to cure heart disease. Beginning about 10 years ago, our cardiology colleagues, often in cahoots with hematologists and oncologists, began clinical trials of blood cell and bone marrow transplants in persons with acute myocardial infarction and/or congestive heart failure.

The underlying hypotheses were a bit foggy. Some investigators believed the transplanted hematopoietic stem cells would differentiate or transdifferentiate into new cardiac myocytes. Others thought cells in the graft might reduce ischemia-induced damage via some illdefined anti-inflammatory effect. Some just hoped for the best: run it up the flagpole, and let’s see what happens.

Clinical trials followed the usual

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PAGE 57

Perspective

sequence and claims: phase I studies proved feasibility and safety with some encouraging results (“round up the usual suspects”). Results of phase II studies were supportive, but there were questions regarding subject selection because appropriate controls were missing. (Sound familiar?)

So off we go into phase III studies, sometimes controlled, sometimes blinded, often neither. And here is

ally the recipient (autotransplant) but are sometimes another person (allotransplant) who may or may not be genetically related to the recipient.

And to get closer to home, some recipients received cyclophosphamide to mobilize (another bit of jargon) the desired hematopoietic stem cells into the blood.

Endpoints of these studies are equally heterogeneous, including changes

No one would die of acute myelogenous leukemia if what we can accomplish in mice were readily transferable to humans. It isn’t.

—Robert Peter Gale, MD, PhD, DSc(hc), FACP

where the real trouble begins. More than 10,000 people have or are participating in these trials, and more are clamoring to join every day. However, results of these studies are inconclusive at best, and most large, properly conducted studies have been either negative or report a modest transient clinical benefit.

Heterogeneity Aplenty Attempts to critically analyze these clinical trials data nearly gave me a heart attack! (No stem cell transplant, please.)

The technician at Kinkos laughed when I tried to put these data into a chart. He suggested I try printing it on the side of the Goodyear blimp.

Studies include different types of subjects, often in the same study, including some with acute myocardial infarction, others with chronic congestive heart failure, and yet others with diverse cardiomyopathies. Transplants (another jargon term, these are really infusions, but that sounds too prosaic) use blood cells, bone marrow cells, or a combination. Cell composition of the graft (jargon again) is rarely defined or quantified. What are we trying to transplant: hematopoietic stem cells, mesenchymal cells, mesecnchymal stem cells (whatever these are), monocytes/macrophages, regulatory T cells, a combination of these, or something else?

Transplant routes are equally complex: intravenous, intra-arterial, into a coronary artery, direct injections into the myocardium at the site of injury, or all of the above. Donors are usu-

in cardiac enzymes such as troponins and brain natriuretic peptide, echocardiography (including left-ventricular ejection fraction), quality-of-life measures, freedom from hospitalization, survival, and many more. Cardiologists are fortunate in having lots of things to measure, and some of these, such as leftventricular ejection fraction and quality of life, are validated endpoints, but only if the subjects and reader are blinded.

This is rarely the case. And if a trial has many coprimary endpoints, it’s easy to pick a winner.

Bottom Line What is the bottom line of these clinical data? The bottom line is that there is no bottom line. A recent review in BMJ

two camps seem not so discordant.

Similarly, an opinion piece in Science declared it a draw.4 Complicating the controversy are recent retractions of several key reports in The Lancet and Circulation and investigations of academic conduct of several key scientists and clinical trialists.

To no one’s surprise, however, recruitment to clinical trials continues.

Some prestigious medical centers promote the therapy, others see an important revenue source, whereas most U.S. and European centers think the jury is still out. Nevertheless, this therapy is gaining currency worldwide. If you have heart disease and can’t get a stem cell transplant in the United States or Europe, find a medical tourism agency that can send you to a lovely venue, transplant and all meals included. Recently, I saw a video advertising stem cell therapy for heart disease on the Shanghai metro.

Back to the Drawing Board As I see it, it’s back to the drawing board. We need to return to animal models and determine the impact, if any, of purified populations of bone marrow–derived cells. And we need to study old mice with heart disease and comorbidities, not 10-week-old healthy mice from Charles River Laboratories (which seems the mouse equivalent to the Golden Door Spa). To put this in context, no one would die of acute myelogenous leukemia if what we can accomplish in mice were readily transferable to humans. It isn’t.

Our experience to date has several important lessons that apply to all fields

Jargon can be dangerous, not just in this context but in every context. Science requires precision. We should be careful of what we say and how we say it.

—Robert Peter Gale, MD, PhD, DSc(hc), FACP

by Francis and coworkers1 strongly criticized many of the conclusions of these studies, pointing out numerous biases and errors of commission and omission.

Authors of some of these studies seem heavily influenced by their a priori beliefs. (Who isn’t, but this is not science.)

In contrast, two Cochrane reviews concluded this approach was of shortterm benefit and the best thing since sliced bread.2,3 However, the Cochrane reviews lumped all studies together and failed to consider discrepancy counts.

After appropriate adjustments, the

of medical research and especially oncology. One is that jargon can be dangerous, not just in this context but in every context. Science requires precision.

We should be careful of what we say and how we say it. For example, when we talk about “MRD” do we mean minimal residual disease or measureable residual disease? These are different concepts.5 When we discuss outcomes, do we mean freedom from progression, event-free survival, or progression-free survival? Again, these are different.

And can someone explain why we

use “overall survival” rather than simply “survival”? Is there some special survival state that is not overall? (Existentialists, attention!) I am reminded of a joke amongst statisticians: One statistician asks another, “What’s your wife like?”

After a 10-minute silence, he replies, “Compared to what?”

The confused story about trying to cure heart disease with hematopoietic stem cell transplants has played out in the same unfortunate way in the arena of end-stage liver disease, where hundreds of these transplants are being done globally.6 Not far behind are Alzheimer and Parkinson diseases and aging. Hemorrhoids next? Fortunately, we can successfully transplant kidneys, hearts, and livers, without having to rely on hematopoietic stem cells. If only we had an adequate supply.

So, back to the question: will oncologists be the first to cure heart disease?

Who knows? But I think we can play an important and perhaps critical role by integrating our expertise with that of our cardiology colleagues. And if cardiologists are curing Ebola with statins,7 why shouldn’t oncologists cure heart disease? Stay tuned. n Disclosure: Dr. Gale reported no potential conflicts of interest.

Acknowledgement: The NIHR Biomedical Research Centre funding scheme. Armand Keating, Darrell Francis and Iman Saramipoor kindly reviewed the typescript.

References 1. Nowbar AN, Mielewczik M, Karavassilis M, et al: Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): Weighted regression and meta-analysis.

BMJ 348:g2688, 2014.

2. Clifford DM, Fisher SA, Brunskill SJ, et al: Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev 2:CD006536, 2012.

3. Fisher SA, Brunskill SJ, Doree C, et al: Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev 4:CD007888, 2014.

4. Couzin-Frankel J: The elusive heart fix. Science 345:252-254, 2014.

5. Goldman J, Gale RP: What does MRD in leukemia really mean? Leukemia 28:1131, 2014.

6. Behbahan IS, Keating A, Gale RP: Bone marrow autotransplant for liver disease? Stem Cells 31:2313-2329, 2013.

7. Fedson DS, Poal SM: Can statins help cure Ebola. New York Times. August 15, 2014.

NEW PHASE 3 DATA

IMBRUVICA® demonstrated single-agent survival in previously treated CLL INDICATIONS: IMBRUVICA® is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with: • Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy • CLL with 17p deletion

Significantly improved overall survival (OS)—secondary endpoint • 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA® arm (HR=0.43; 95% CI: 0.24, 0.79) • Median OS not yet reached in either treatment arm • 29% of ofatumumab patients crossed over to receive IMBRUVICA® upon progression

Significantly extended progression-free survival (PFS)—primary endpoint 78% statistically significant reduction in the risk of death or progression (independent review) 100

PFS (%)

80 60 40 Hazard ratio (HR) for progression or death: 0.22 (95% CI: 0.15, 0.32) P<0.0001 by log-rank test

20 0

0

3

6

183 161

116 83

Number at risk IMBRUVICA® 195 Ofatumumab 196

Months

Ofatumumab 9

12

15

38 15

7 1

0 0

Results from the randomized, multicenter, open-label, Phase 3 RESONATE™ trial of IMBRUVICA® vs ofatumumab in patients with previously treated CLL. Patients (N=391) were randomized 1:1 to receive either IMBRUVICA® 420 mg orally daily until disease progression or unacceptable toxicity or IV ofatumumab at an initial dose of 300 mg, followed 1 week later by a dose of 2000 mg weekly for 7 doses, and then every 4 weeks for 4 additional doses. Fifty-seven patients randomized to ofatumumab crossed over following Independent Review Committee-confirmed progression to receive IMBRUVICA®. Primary endpoint: PFS as assessed by an Independent Review Committee (IRC) according to modified International Workshop on CLL Criteria.

Significantly improved PFS in patients with previously treated del 17p CLL • 75% reduced risk of progression or death (HR=0.25; 95% CI: 0.14, 0.45) — Median PFS not reached with IMBRUVICA® vs 5.8 months with ofatumumab

In CLL studies, approximately 5% of patients discontinued due to adverse events Please review the Important Safety Information on adjacent page.

ORAL, ONCE-DAILY DOSING

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - 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 anti-platelet or anti-coagulant 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®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 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 10%) including carcinomas (range, 1 to 3%) have occurred in

© Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 07/14 PRC-00483

patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

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.

ADVERSE REACTIONS The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® 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.

DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. 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 baseline hepatic impairment.

Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit us at

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. Improvements in survival or disease-related symptoms have not been established. 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].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: 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. Twenty-five percent of patients with MCL and 26% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 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 10%) including 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 8%).

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, 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] 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.

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

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis

All Grades (%) 51 31 25 24 23 17 11

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

34 14 14 14 13

0 3 7 5 1

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

Preferred Term

General disorders and administrative site conditions

Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

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

All Grades (%)

Grade 3 or 4 (%)

41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

5 3 1 3 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 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 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

Preferred Term 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

Metabolism and nutrition disorders Neoplasms benign, malignant, Second malignancies* unspecified Injury, poisoning and Laceration procedural complications Psychiatric disorders Anxiety Insomnia Vascular disorders Hypertension *One patient death due to histiocytic sarcoma.

All Grades (%) 63 23 21 21 19 15 13

Grade 3 or 4 (%) 4 2 2 0 2 0 0

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

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

10*

0

10

2

10 10 17

0 0 8

IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules 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].

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

11

0

3

0

10

0

3

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 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.

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 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].

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 and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see 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].

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) 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].

• 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, Inc. 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, Inc. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 PRC-00526 07/14

The ASCO Post | SEPTEMBER 15, 2014

PAGE 62

Journal Spotlight Genitourinary Oncology

No Difference in Complication Rates or Hospital Stay With Robot-Assisted vs Open-Surgery Cystectomy in Bladder Cancer

By Matthew Stenger

R

etrospective analyses indicate that robot-assisted laparoscopic surgery for radical cystectomy in patients with bladder cancer is associated with reduced risk of complications and shorter hospital stay compared with open surgery.

In a small single-institution randomized trial reported in a letter to The New England Journal of Medicine, Bernard H. Bochner, MD, and colleagues at Memorial Sloan Kettering Cancer Center, New York, found no difference in complication rates or length of hospital stay with robot-assisted laparoscopic surgery vs open surgery in this setting.1 Intraoperative blood loss was greater and procedure time shorter with open surgery.

the 90-day rate of Clavien grade 2 to 5 complications on intention-to-treat analysis. Four patients assigned to robot-assisted surgery declined the assignment and underwent open surgery.

The robot-assisted surgery and opensurgery groups were generally well balanced for age (median, 66 and 65 years), sex (85% and 72% male), body mass index (median, 27.9 and 29.0 kg/m2), American Society of anesthesiologists

■■ Robot-assisted and open surgery groups had similar rates of perioperative complications and length of hospital stay.

■■ Open surgery was associated with greater blood loss and shorter procedure duration.

to 5 complications occurred in 62% of patients in the robot-assisted surgery group vs 66% of patients in the open-

[T]hese results highlight the need for randomized trials to inform the benefits and risks of new surgical technologies before widespread implementation.

Study Details In the trial, 118 patients with clinical stage Ta-3,N0-3,M0 bladder cancer scheduled for definitive treatment with radical cystectomy at Memorial Sloan Kettering between March 2010 and March 2013 were randomly assigned to receive robot-assisted surgery (n = 60) or open surgery (n = 58). Four surgeons with experience in open surgery performed all open procedures, and three surgeons with experience in robotassisted pelvic surgery performed the robotic procedures.

The primary outcome measure was

Radical Cystectomy in Bladder Cancer

—Bernard H. Bochner, MD, and colleagues

score (2 in 28% and 21%, 3 in 70% and 74%, 4 in 2% and 5%), and clinical stage (Tis in 14% and 4%, Ta in 2% and 5%, T1 in 36% and 33%, T2 in 41% and 49%, T3 in 7% and 9%, T4 in 2% and 0%).

Outcomes Enrollment was closed early after an interim analysis showed that results met predefined criteria for futility. Grade 2

surgery group (difference = −4%, 95% confidence interval = −21% to 13%, P = .66). Grade 3 to 5 complications occurred in 22% vs 21% (P = .90).

Intraoperative blood loss was lower in the robot-assisted surgery group (mean difference = 159 cm3). Length of surgery was significantly shorter in the open-surgery group (mean = 456 vs 329 minutes, mean difference = 127

minutes, P < .001). Mean length of hospital stay was 8 ± 3 days in the robotassisted surgery group and 8 ± 5 days in the open-surgery group (difference = 0, 95% CI = −2 to 1, P = .53).

The investigators noted: “Because the trial was performed by experienced surgeons at a single, high-volume referral center, the results may not be generalizable to all clinical settings. Nonetheless, these results highlight the need for randomized trials to inform the benefits and risks of new surgical technologies before widespread implementation.” n Disclosure: The study was supported by Memorial Sloan Kettering Cancer Center, Pin Down Bladder Cancer, and the Michael A. and Zena Wiener Research and Therapeutics Program in Bladder Cancer. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Bochner BH, Sjoberg DD, Laudone VP: A randomized trial of robot-assisted laparoscopic radical cystectomy (letter). N Engl J Med 371:389-390, 2014.

Complications No Different Between Open and Robot-Assisted Radical Cystectomy When Open Urinary Diversion Performed

By Piyush K. Agarwal, MD, Mani Menon, MD, and Adam R. Metwalli, MD

W

e read the letter to the editor in the July 24, 2014, issue of The New England Journal of Medicine entitled, “A Randomized Trial of Robot-Assisted Laparoscopic Radical Cystectomy,” with great interest.1 Dr. Agarwal is Head of the Bladder Cancer Section, Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Dr. Menon is The Raj and Padma Vattikuti Distinguished Chair, Director, Vattikutin Uroloigy Institute, Henry Ford Health System Detroit. Dr. Metwalli is Senior Clinical Staff and Faculty Member, Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute.

Provocative Results In the letter, reviewed in this issue of The ASCO Post, Bochner and colleagues report on their randomized trial, NCT01076387, at Memorial Sloan Kettering Cancer Center comparing robot-assisted laparoscopic radical cystectomy to open radical cystectomy.

The study enrolled patients with bladder cancer (clinical stages Ta–3, N0–3, M0) with a primary outcome of grade 2 to 5 complications within 90 days of surgery. The trial was halted early after accruing 118 patients due to a predetermined interim futility analysis that stipulated ending the trial if no differences in the primary outcome were seen.

On the basis of an intention-to-treat

analysis, 37 patients (62%) who underwent robot-assisted laparoscopic radical cystectomy and 38 patients (66%) who underwent open radical cystectomy had a complication of grades 2 to 5 (P = .66). The authors concluded: “These results highlight the need for randomized trials to inform benefits and risks of new surgical technologies before widespread implementation.”

These results are provocative and force the medical community and the lay public to assess current practice patterns and call into question the purported benefits of minimally invasive surgery for bladder cancer. However, the authors do not address potential study design issues that may have significantly

undermined the final conclusions.

First, the primary endpoint evaluating overall complications instead of perioperative outcomes, complications specific to surgical approach, or oncologic outcomes is problematic. Also, a significant expertise differential exists between the open and robotic surgeons in the study.

In addition, limited data are presented, preventing an adequate analysis of complications, blood loss, and length-of-stay differences. Therefore, we would caution readers to acknowledge these caveats when interpreting the results of this trial.

Teasing Out Complications The aim of this study was to detect a difference in complications be-

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 63

Perspective

tween open radical cystectomy and robot-assisted laparoscopic radical cystectomy. However, radical cystectomy entails two distinct surgical portions: an extirpative portion, in which the bladder and lymph nodes are removed, and a reconstructive portion, in which a urinary diversion made out of bowel is created and connected to the ureter(s). Teasing out complications resulting from the extirpative portion or the reconstructive portion may be difficult, but we would argue that bowel-related complications are likely a result of the latter while surgical complications (eg, vascular injury) would be a reflection of the former.

Unfortunately, the published letter and its supplementary materials do not list the complications seen, but Memorial Sloan Kettering investigators and others have described gastrointestinal problems (eg, ileus, small bowel obstruction) as the most common early postoperative complications, occurring in up to 29% of patients.2 In the study of open radical cystectomies by Shabsigh and colleagues, American Society of Anesthesiologists score, gender, and type of urinary diversion were significant predictors of any grade complication. Others have also confirmed bowel-related complications as the leading causes of early (within 30 days) readmission to the hospital after radical cystectomy.3 In the Bochner et al trial, while the cystectomy portion was randomized, the urinary diversion was not. Because the majority of complications seen are related to the urinary diversion, we would argue that no difference should be expected to be seen in this trial. This significantly diminishes the benefit of randomization.

Question of Experience Another point of concern is whether the surgeons in each arm had comparable experience. Indeed, previously published literature suggests that not only does surgical experience and volume impact morbidity, but specific subspecialization in bladder cancer also appears to influence outcomes.4-6 Thus, it is conceivable that the robotic surgeons in this protocol were at somewhat earlier points along their learning curve with this specific procedure compared to their open surgery colleagues.

In this study, the authors used the years after fellowship as a surrogate for surgeon experience. Also, the open surgeons had to have completed a

minimum of 100 open cystectomies whereas the robotic surgeons had to have completed at least 100 minimally invasive pelvic procedures, not necessarily 100 robot-assisted cystectomies. A more direct comparison would have been more instructive: How many open cystectomies had the open surgeons performed and how many robot-assisted cystectomies had the robotic surgeons performed at the time the study was conceived?

This clinical care pathway specifies preoperative, perioperative, and postoperative management, allowing for minimization of hospital stay and optimization of postoperative outcomes.

Implementation of such patient care protocols can result in an earlier time to hospital discharge, among other benefits.9,10 Assuming that these pathways are applied equally to both cohorts of patients, we would not expect a difference in length of hospital stay.

Perioperative Outcomes

Multicenter Data Awaited

Perioperative outcomes were not primary endpoints of this trial, but blood loss and length of hospital stay were compared between the groups.

A lower blood loss rate was noted in the robotic arm of the trial, with

Finally, it is important to note that this is a single-center trial at one of the premier institutions for urologic surgery in the world. Outcomes at such a high-volume, specialized cancer center may not accurately identify

The authors do not address potential study design issues that may have significantly undermined the final conclusions…. [W]e would caution readers to acknowledge these caveats when interpreting the results of this trial.

—Piyush K. Agarwal, MD (left), Mani Menon, MD (center), and Adam R. Metwalli, MD (right)

a mean difference of 159 mL. However, no P value is reported.

Since no data on transfusion rates between the arms was specifically presented, it is hard to determine if any clinical significance is associated with this finding. These data would certainly be informative to put the relatively small difference in estimated blood loss into clinical context. Nevertheless, the difference seen in estimated blood loss has been seen in previous robotic vs open cystectomy series,7 and some data suggest that transfusions alone are associated with poorer survival.8 As for the length of hospital stay, there was no difference between the two groups (mean length of stay of 8 days in each group, P = .53). Although not specified, we would presume that Memorial Sloan Kettering has an enhanced recovery after surgery (ERAS) protocol.

real-world differences due to the exceptional, and difficult to reproduce, clinical outcomes they produce.

This trial confirms the results of a previous randomized single-institution study that also demonstrated no significant difference in complications or hospital stay between the open and robotic groups.7 Furthermore, it provides us with thought-provoking data to consider while we eagerly await the results of a multicenter SWOG trial (NCT01157676) that may better address differences between open radical cystectomy and robot-assisted laparoscopic radical cystectomy.

The primary endpoint of the SWOG trial is 2-year progression-free survival difference between randomized arms (open cystectomy and robot-assisted cystectomy). Presumably, differences in this endpoint will reflect true differ-

ences in the oncologic or extirpative portion of the procedure. Secondary endpoints will address differences in outcomes such as complications related to technique (eg, injury to surrounding structures) or surgical quality measures such as extent of lymphadenectomy and surgical margin status that may better reflect any true differences between open cystectomy and robot-assisted cystectomy, as well. n

Disclosure: Drs. Agarwal, Menon, and Metwalli reported no potential conflicts of interest.

References 1. Bochner BH, Sjoberg DD, Laudone VP: A randomized trial of robot-assisted laparoscopic radical cystectomy. N Engl J Med 371:389-390, 2014.

2. Shabsigh A, Korets R, Vora KC, et al: Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol 55:164-174, 2009.

3. Stimson CJ, Chang SS, Barocas DA, et al: Early and late perioperative outcomes following radical cystectomy: 90-day readmissions, morbidity and mortality in a contemporary series. J Urol 184:1296-1300, 2010.

4. Bhindi B, Yu J, Kuk C, et al: The importance of surgeon characteristics on impacting oncologic outcomes for patients undergoing radical cystectomy. J Urol 192:714-720, 2014.

5. Finks JF, Osborne NH, Birkmeyer JD: Trends in hospital volume and operative mortality for high-risk surgery. N Engl J Med 364:2128-2137, 2011.

6. Leow JJ, Reese S, Trinh QD, et al: The impact of surgeon volume on the morbidity and costs of radical cystectomy in the United States: a contemporary population-based analysis. BJU Int 2014; doi: 10.1111/bju.12749.

7. Nix J, Smith A, Kurpad R, Nielsen ME, Wallen EM, Pruthi RS: Prospective randomized controlled trial of robotic versus open radical cystectomy for bladder cancer: perioperative and pathologic results.

Eur Urol 57:196-201, 2010.

8. Linder BJ, Frank I, Cheville JC, et al: The impact of perioperative blood transfusion on cancer recurrence and survival following radical cystectomy. Eur Urol 63:839845, 2013.

9. Arumainayagam N, McGrath J, Jefferson KP, Gillatt DA: Introduction of an enhanced recovery protocol for radical cystectomy. BJU Int 101:698-701, 2008.

10. Pruthi RS, Nielsen M, Smith A, Nix J, Schultz H, Wallen EM: Fast track program in patients undergoing radical cystectomy: results in 362 consecutive patients. J Am Coll Surg 210:93-99, 2010.

The ASCO Post | SEPTEMBER 15, 2014

PAGE 64

Issues in Oncology 9/11 and Cancer continued from page 1

tients is understandable. People want to explain their cancers. They want to attribute a cause, and not one involving some esoteric random mutation occurring in one of the body’s cells.”

Dr. Berry continued, “The recent media attention seems to be a reaction to the continuing reports of cancer among 9/11 workers. The question is whether the incidence of cancer among the workers is greater than it would be had 9/11 not occurred. I sympathize with the unfortunate people exposed to [the toxins created by] 9/11 who got cancer, just as I do with all cancer patients. But their cancers are about as likely to have been caused by 9/11 as were the cancers of Nebraskans who watched the aftermath of 9/11 on television.”

Federal and State Response In response to potential health issues associated with 9/11 exposure, President Obama signed into law the James Zadroga 9/11 Health and Compensation Act of 2011, which established the World Trade Center (WTC) Health Program. The Director of the National Institute for Occupational Safety and Health (NIOSH) administers the WTC Health Program, which is paid for by the federal government and New York City.

A representative from the WTC Health Program explained the complicated process to The ASCO Post: “The WTC Health Program providers— Mount Sinai Hospital is one of our clinical centers—make a determination based on a clinical evaluation of a member’s specific exposure situation and the type of health condition they have developed (the diagnosis) as to whether or not the condition was likely a result of their exposures from the WTC disaster and response. Then the WTC Health Program must approve (certify) the evaluation and diagnosis to permit a member to receive treatment for the specific health condition through a Clinical Center of Excellence or the Nationwide Provider Network at no cost to the member.”

In 2012, the Associated Press reported that, “After months of study, the National Institute for Occupational Safety and Health [NIOSH] said in an administrative filing that it favored a major expansion of an existing $4.3 billion 9/11 health program to include people with 50 types of cancer, covering 14 broad categories of the disease.”

Dr. Berry, concerned that NIOSH caved to political pressure and public

emotion commented, “The notion that 9/11 exposures played a role in causing 50 types of cancers is beyond the pale.

With the exception of a heavy dose of radiation, it is difficult for any single event to cause cancer. Moreover, causes of cancer and factors that promote cancer growth are limited in their effects to a small number of cancers. This is true even for smoking, which is implicated in at most a dozen types of cancer.

Amassing the Data Roberto Lucchini, MD, Professor of Preventive Medicine, Director of Occupational Medicine, and Director of the WTC Health Program Data Center at Mount Sinai Hospital, told The ASCO Post that he doubted the reported doubling of 9/11-related cases in a year. “It’s a complicated issue, but in modern society we cannot hide behind complexity; we must answer all questions that are vital to public health. That said, given our data, it is too early in latency time to determine a causal relation between 9/11 toxic exposure and cancers,” said Dr. Lucchini.

Dr. Lucchini said that analysis of available data that they published in 2010 showed a 20% increase in the rate between observed and expected cancer among those exposed to 9/11 toxins.

He pointed out, however, that numbers in themselves are interesting, but they have to be put in the proper context. For example, epidemiologists expect the number of observed cancers to increase simply because cancer is an age-related disease, increasing everyone’s risk as time passes.

Dr. Lucchini and his colleagues are in the process of updating their data.

“This is a long process. We used selfreported surveys filled out by exposed

Given our data, it is too early in latency time to determine a causal relation between 9/11 toxic exposure and cancers.

—Roberto Lucchini, MD

In the rescue-recovery group, we found a significantly higher increased rate of three cancers—prostate, thyroid, and multiple myeloma. Although certain solid tumors have a long latency period, it’s important to track these cancers as we move forward.

—Steven D. Stellman, PhD

people who developed cancer. Unfortunately, it is challenging to conduct yearly follow-ups among such a large, heterogeneous population. We access cancer registries from states across the country and match that data against the self-reported numbers. It is a labor-intensive process,” said Dr. Lucchini, adding that he believes as years pass, “we will see a further increase in 9/11-­related cancers.”

Dr. Lucchini continued, “Although we still do not have the data to definitively link exposure to 9/11 toxins and cancers…. We think about Chernobyl or Fukushima, but this is a totally different situation. We are doing as much as we can with our resources, but it will take years before conclusions are made.”

Important Resources

P

ersons whose illnesses are related to exposure to the World Trade Center disaster may be eligible for medical services or monetary compensation under two Federal programs.

The World Trade Center (WTC) Health Program provides medical monitoring and treatment for responders at the World Trade Center and related sites in New York City, the Pentagon, and Shanksville, Pennsylvania. It also provides services for survivors who were in the New York disaster area. It is administered by the National Institute for Occupational Safety and Health (NIOSH).

For information about the WTC Health Program, including how to apply, information on WTC health effects and research, and program resources, visit www.cdc.gov/wtc, call 888-982-4748, or email wtc@cdc.gov.

The September 11th Victim Compensation Fund provides monetary compensation for certain persons who suffered injuries, illnesses, or economic losses related to the September 11 attacks, or their survivors. For information please contact http://www.vcf.gov/. n

Early Findings Require Long-Term Follow-up In 2012, JAMA published a study titled, “Association Between World Trade Center Exposure and Excess Cancer Risk.”3 To date, it remains the most cited work on this topic. The study followed 55,778 residents of New York State who were enrolled in the WTC Health Registry from 2003 to 2004. Of these, 21,850 were rescue-recovery workers and 33,928 were not involved in 9/11 rescue-recovery. All of the participants were followed from enrollment until December 2008. The researchers identified cancer cases through linkages with 11 state cancer registries.

“We focused on cancers diagnosed in 2007 to 2008 because these were most likely to be related to exposure during September 11 and its aftermath,” said study coauthor Steven D. Stellman, PhD, Research Director, World Trade Center Health Registry, New York City Department of Health and Mental Hygiene and Professor of Clinical Epidemiology, Mailman School of Public Health, Columbia University. By December 31, 2008, 1,187 new cancers had been reported in the study population. Of these, 439 cancers (37%) were diagnosed in rescue-recovery workers and 748 (63%) were diagnosed in those not involved in rescue-recovery. The median age at cancer diagnosis was 57 years.

“The goal of the study was to determine whether cancer incidence in the two groups is greater than what would be expected based on background continued on page 66

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PAGE 66

Issues in Oncology 9/11 and Cancer continued from page 64

New York State cancer rates. In both the rescue-recovery workers and the non–rescue-recovery group, we did not find any different overall cancer rate from what we determined as the background rate of the state cancer registries,” said Dr. Stellman.

“However,” he added, “in the rescue-recovery group, we found a significantly higher increased rate of three cancers—prostate, thyroid, and multiple myeloma. Although most solid tumors have a long latency period, it’s important to track these cancers as we move forward.”

Asked to comment on the JAMA study, Dr. Berry noted, “The authors

highlighted three cancer types as having statistically significantly elevated rates of the 23 cancer types considered. In the context of multiple comparisons, 3 out of 23 is not unusual.”

He continued, “To reinforce the notion that the results are random, the three types—prostate, thyroid, and multiple myeloma—were unrelated, and it’s difficult to imagine a cause that would affect these three and not others. Besides, nine cancer types had a numerically lower incidence than expected. One of those was lung, a cancer that one would expect to be most susceptible to breathing all the bad substances in the air at Ground Zero.”

Conclusions All health-care experts might agree that spending months on end working at the uniquely toxic site of Ground Zero would be deleterious to physical and mental human health. But determining a causal relationship between 9/11 exposure and specific cancers is very difficult. To that end, the oncology community is most comfortable with the randomized controlled trial, which is obviously not possible in this setting.

Therefore, we are left with epidemiologic studies comparing cancer rates in other populations, attempting to define the comparison populations to be as nearly like the population of those exposed to 9/11 toxins as possible. We

know this method is imperfect, but it is all we have in this important mission.

The painstaking process needs to move forward unimpeded by politics, emotion, and haste. n

Disclosure: Drs. Berry, Lucchini, and Stellman reported no potential conflicts of interest.

Reference 1. Edelman S: 2,500 Ground Zero workers have cancer. New York Post. July 27, 2014.

2. Lillemoe KD, Yeo CJ, Cameron JL: Pancreatic cancer: State-of-the-art care. CA Cancer J Clin 50:241-268, 2000.

3. Li J, Cone JE, Kahn AR, et al: Association between World Trade Center exposure and excess cancer risk. JAMA 308:24792488, 2012.

CDC’s Breast and Cervical Screening Program Benefits Millions of Underserved Women in the United States

M

ore than 4.3 million women with limited access to health care received breast and cervical cancer screening and diagnostic services in the first 20 years of the Centers for Disease Control and Prevention (CDC) National Breast and Cervical Cancer Early Detection Program.

From 1991 to 2011, 56,662 breast cancers, 3,206 cervical cancers, and 152,470 precancerous cervical lesions were detected. More than 90% of these women received appropriate and timely follow-up care, according to the CDC report published recently in a supplement to Cancer.1 “Today, millions of women have benefited from the timely screening and diagnostic services offered by CDC’s National Breast and Cervical Cancer Early Detection Program,” said Ursula E. Bauer, PhD, MPH, Director, CDC’s National Center for Chronic Disease Prevention and Health Promotion.

“This program has made tremendous contributions in public health through strengthening partnerships, health-care

collaborations, and quality of care, but also at a personal level by serving women directly.”

The Cancer supplement, titled “National Breast and Cervical Cancer Early Detection Program: Two Decades of Service to Underserved Women,” contains 13 new papers evaluating multiple aspects of the [early detection programs] and shows consistent value in the program, including beyond its original purpose of detecting cancers in underserved women.

Strategies and Successful Interventions The papers describe the number of actual cancers detected, outreach, education, and health-care collaboration activities. Data quality, evaluation, cost estimates, and suggestions for future programming are also noted. This is the first time detailed information has been published describing the program’s screening activities—and strategies beyond

screening—used to reach underserved population. Also included are state examples of successful interventions.

Among the findings: • Public education and outreach help raise awareness and address barriers to care.

• One of the uses for data reported to CDC is quality assurance, which monitors the quality of services provided by the programs funded by the National Breast and Cervical Cancer Early Detection Program. This monitoring can help identify issues with the services, determine the causes of the issues, and check whether these issues were corrected.

• The estimated cost of providing cancer screening and diagnostic services was $145 per woman. Cost estimates can be useful in future program ­planning.

• Performance management and program effectiveness strategized improved service delivery through use of data, strong quality indicators, and investment in the pro-

gram to ensure women are receiving timely screening, diagnostic follow-up, and referral to treatment when needed.

• Partnerships at national and local levels with national organizations and their members, community-based organizations, government agencies, tribes, health-care systems, and professional organizations have played a critical role in achieving Program’s goals.

• The National Breast and Cervical Cancer Early Detection Program has made tremendous contributions to breast and cervical cancer screening for Alaska Native/American Indian women and strengthened local tribal screening capacity.

For more information, visit http:// www.cdc.gov/cancer/nbccedp/. n Reference 1. National Breast and Cervical Cancer Early Detection Program: Two decades of service to underserved women.

Cancer 120(suppl 16):2537–2624, 2014.

Visit The ASCO Post website at ASCOPost.com

indications

ignited we stand with

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

Important Safety Information CONTRAINDICATIONS WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a doselimiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non– small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

Important Safety Information (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis • Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with singleagent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/ asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported • Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229) • In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%) • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Non–Small Cell Lung Cancer (NSCLC) Study • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin– treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group • Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively • Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively • Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 04/14 US-ABR140005

Pancreatic Adenocarcinoma Study • See next page for most common adverse reactions • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%) Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel 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, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended for patients with moderate and severe hepatic impairment.

Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN • For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely

For more information, please visit www.abraxane.com.

ABRAXANE® is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

in first-line MPAC

ignite survival ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone 1.0

Median OS

0.9

ABRAXANE + gemcitabine (n=431)

Proportion of survival

0.8 0.7

Gemcitabine (n=430)

0.6 0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months (95% CI: 6.0-7.2)

0.4 0.3

HR: 0.72 (95% CI: 0.62-0.83)a

0.2

P<0.0001b

0.1 0.0 Patients at risk A+G: G:

0

3

6

9

12

15

18

21

24

27

30

33

36

39

431 430

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

1 0

0 0

Time (months)

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival.

Stratified Cox proportional hazard model. b Stratified log-rank test stratified by geographic region (North America vs Others), KPS (70-80 vs 90-100), and presence of liver metastasis (yes vs no). a

STUDY DESIGN The multinational, randomized, phase 3 MPACT trial compared ABRAXANE (125 mg/m2) + gemcitabine (1000 mg/m2) on Days 1, 8, and 15 of each 28-day cycle vs gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks, followed by a 1-week rest period in Cycle 1, then on Days 1, 8, and 15 of each subsequent 28-day cycle) in 861 patients with MPAC. The primary end point was OS.

Most common adverse reactions in the pancreatic adenocarcinoma study • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

ABRAXANE is also indicated in MBC and NSCLC ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Prior therapy should have included an anthracycline unless clinically contraindicated.

• The primary end point in the metastatic breast cancer (MBC) phase 3 trial was reconciled target lesion response rate (recTLRR) vs paclitaxel injection ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

• The primary end point in the NSCLC phase 3 trial was overall response rate (ORR) vs paclitaxel injection + carboplatin

Overall survival (secondary end point) was not statistically significant in the MBC and NSCLC trials vs comparator arms.

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary; refer to full Prescribing Information for complete product information.

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies (14.2)].

2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].

2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.

For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.

For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated.

Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc MBC NSCLCc Adenocarcinoma Mild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2 ≤ 1.25 x ULN Moderate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not 2 x ULN recommended 50 mg/m2 not Severe < 10 x ULN AND 2.01 to 130 mg/m2 b 5 x ULN recommended > 10 x ULN OR > 5 x ULN not not not recommended recommended recommended MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer.

2.5 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].

Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.

• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL) Neutropenic Fever (ANC less than First 75 4.5 500/mm3 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm3 OR ANC less than 500/mm3 for more than 7 days Platelet count less than 50,000/mm3 Severe sensory Neuropathy – Grade 3 or 4

Second

Third First Second First Second Third

50

3

Discontinue Treatment 75 4.5 Discontinue Treatment 75 4.5 50 3 Discontinue Treatment

Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2) Full dose 125 1000 1st dose reduction 100 800 2nd dose reduction 75 600 If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine Day 1 < 1500 OR < 100,000 Delay doses until recovery Day 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count.

Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at Febrile Neutropenia: Grade 3 or 4 next lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at next No dose reduction lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at Grade 3 mucositis or diarrhea next lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.

• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer.

Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.

In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.5)].

In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)].

5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].

5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine.

5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug.

5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution.

The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.

There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)].

5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS 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 most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)].

The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).

In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%).

The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).

6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 175 mg/m2 over 3 hb 260 mg/m2 over 30 min (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity.

Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials.

Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.

Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention.

ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.

Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.

No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial.

Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible.

Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days.

Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.

Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported.

6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion.

The differences in paclitaxel dose and schedule between the two arms limit direct comparison of doseand schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment.

The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group).

Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (200 mg/m2 every 3 weeks) (100 mg/m2 weekly) plus carboplatin plus carboplatin Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 MedDRA v 12.1 Toxicity Toxicity Toxicity Toxicity System Organ Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General disorders Edema peripheral 10 0 4 <1 and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0 and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective Myalgia 10 <1 19 2 tissue disorders a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).

For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.

Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/ Gemcitabine Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE Gemcitabine (N=402) (125 mg/m2) and gemcitabine (N=421) Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%) General disorders and administration site Peripheral conditions edema 194 (46%) 13 (3%) 122 (30%) 12 (3%) Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%) Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%) Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%) 228 (54%) 27 (6%) 192 (48%) 14 (3%) Gastrointestinal disorders Nausea Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%) Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%) Alopecia 212 (50%) 6 (1%) 21 (5%) 0 Skin and subcutaneous tissue disorders Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%) Nervous system disorders Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%) Dysgeusia 68 (16%) 0 33 (8%) 0 Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%) Metabolism and nutrition Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%) disorders Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%) Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%) Respiratory, thoracic and Cough 72 (17%) 0 30 (7%) 0 mediastinal disorders Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%) Infections and infestations Urinary tract infectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%) Musculoskeletal and Pain in connective tissue extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%) disorders Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%) Myalgia 44 (10%) 4 (1%) 15 (4%) 0 Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0 a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.

Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.

Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died.

6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. 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. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.

Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.

Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline.

Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.

Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration.

Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.

Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.

6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)].

There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.

8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older.

Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old.

Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.

No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.

8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.

8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment.

10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.

16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light.

16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].

• Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved.

Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABR_ALL_HCP_BSv007 10_2013

The ASCO Post | SEPTEMBER 15, 2014

PAGE 74

Direct From ASCO

ASCO Launches New Publication for Oncology Trainees and Early-Career Professionals

I

n February 2014, ASCO launched a new member publication, ASCO Connection: Trainee & Early-Career Oncologists. This quarterly magazinestyle publication is dedicated to topics

print version—I take it to lunch and enjoy being unplugged—but the online version is great too. It’s important for the younger audience to be engaged and connected, and ASCO Con-

It’s important for the younger audience to be engaged and connected, and ASCO Connection: Trainee & Early-Career Oncologists is an ideal opportunity, with the ability to write, blog, and network.

—Marcia S. Brose, MD, PhD

of interest to medical students, interns, residents, fellows, and junior faculty.

All ASCO Student/Non-Oncology Resident Members, Members in Training, and Full Members eligible for discounted dues have direct access to the interactive digital edition as a member benefit, delivered each quarter in a dedicated email with links to new articles and related expert commentary on ASCOconnection.org. U.S.-based members in these categories also receive the print edition by mail.

“I hear nothing but positive feedback” about the publication, said Marcia S. Brose, MD, PhD, of Abramson Cancer Center of the University of Pennsylvania School of Medicine and 2013-2014 Chair of the ASCO Career Development Subcommittee. “Personally, I like to read the

nection: Trainee & Early-Career Oncologists is an ideal opportunity, with the ability to write, blog, and network.”

Focused Topics for the Next Generation of Oncology Leaders Topics covered in the first three issues include professional development, grants and awards, career paths in oncology, board preparation, and work/ life balance, as well as news on ASCO programs and member achievements.

Contributors represent established members of the field as well as members currently engaged in their training and first professional experiences.

Articles, such as those highlighted in the sidebar, provide practical advice for professional success in oncology that can be implemented immediately.

Issue Highlights Career and Training • Transitioning From Fellowship to Career: Expectations vs Reality • Start Expanding Your Oncology Network Today: Five Tips to Get You Networking • Mentoring for New Community Physicians: The Toledo Clinic Experience • Don’t Call Your Program Director “Dude”… and Other Tips for Maintaining Professionalism During Fellowship • Maximize Your Opportunities: Professional Development Tips for EarlyCareer Flexibility • ASCO In-Training Exam Score Report: What You Do With It Matters Most

Grants and Awards • Grant Writing: 10 Tips From a Successful Researcher • Five Mistakes to Avoid on Your Young Investigator Award Application • Submitting a Great Mentor Letter for Your Grant and Award Applications

Work/Life Balance • Make Your Resolutions Stick: Five Tips for Success • Life as an Oncologist and New Parent: Maintaining the Balance • Be a Better Physician: Take a Vacation Every issue features interviews with Conquer Cancer Foundation of ASCO grant and award recipients, as well as ASCO members in diverse career paths discussing their professional journeys.

Career paths highlighted include community practice, industry, and physicianeducator/training program director.

Each issue also includes board preparation multiple-choice questions from the latest edition of ASCO-SEP®, the Society’s self-evaluation program, to help readers assess their oncology

Third Quarter 2014

An official publication from the American Society of Clinical Oncology

ASCOconnection.org/TEC

TRAI NE E & E A R LY- CA R EER O N CO LO G I STS

From Fellowship to Career

Making a Successful Transition 14

Interpreting Your Medical Oncology In-Training Exam Score 12 Mistakes to Avoid on Your YIA Application 6

First Quarter 2014

An official publication from the American Society of Clinical Oncology

ASCOconnection.org/TEC

TRAI N EE & EAR LY- CAR EER O N CO LOG I STS

New Year, New Skills Expert grant-writing tips you can implement today 4 Networking, demystified: How to make productive professional connections 8 Strategies for making (and keeping) your personal and professional resolutions 12

knowledge. Full rationales and additional reading are available online at ascoconnection.org/TEC for further study. Covered subject areas currently include breast cancer, molecular biology, lung cancer, symptom management, genitourinary cancers, and leukemias, with new subjects covered in each issue.

Promote Professional Accomplishments Readers are invited to share and celebrate their professional successes in ASCO Connection: Trainee & EarlyCareer Oncologists’ regular “Member Achievements” column. Highlight a new job, promotion, award, grant, publication, or other success story by emailing ascoconnection@asco.org (please include a high-resolution digital headshot).

Read the latest issues of ASCO Connection: Trainee & Early-Career Oncologists online at ascoconnection .org/TEC, where you can comment on articles, read commentary by ASCO leaders, and network with colleagues and other ASCO members. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 75

Direct From ASCO

A Vision That Endured: Celebrating ASCO’s Founders

Arnoldus Goudsmit, MD, PhD, FASCO

Fred J. Ansfield, MD, FASCO

A

Herman A. Freckman, MD, FASCO

Robert W. Talley, MD, FASCO

s 2014 marks the 50th Anniversary of the founding of the American Society of Clinical Oncology (ASCO), it seems only appropriate to highlight the founders of the Society and the vision they shared for its future.

The 1960s were the early days of the use of chemotherapy for the treatment of cancer, and oncology was a fledgling field of medicine. At that time Arnoldus Goudsmit, MD, PhD, FASCO, and Fred J. Ansfield, MD, FASCO, were both early pioneers of the use of chemotherapy and sought to learn as much as possible about the use of these anticancer drugs; however, they found that information and educational opportunities were lacking.

and Robert W. Talley, MD, FASCO, and, at the first organizational meeting in early 1964, they were joined by Harry F. Bisel, MD, FASCO, William Wilson, MD, FASCO, and Jane C. Wright, MD, FASCO. As members of the American Association for Cancer Research (AACR),

A New Society

the seven founders recognized the need to create a new society that would focus solely on issues unique to clinical oncology. Dr. Goudsmit emphasized the importance of such a society at the

Drs. Goudsmit and Ansfield began to discuss the idea for a new organization with fellow “chemotherapists” Herman A. Freckman, MD, FASCO,

Harry F. Bisel, MD, FASCO

William Wilson, MD, FASCO

first meeting of 51 charter members held in November 1964: “A society of clinical oncology… has the potential of becoming the means for advancing and disseminating medical knowledge and contributing greatly to the improved diagnosis, treatment, wellbeing, and longevity of hundreds and

A society of clinical oncology… has the potential of becoming the means for advancing and disseminating medical knowledge and contributing greatly to the improved diagnosis, treatment, well-being, and longevity of hundreds and thousands of fellow citizens.

—Arnoldus Goudsmit, MD, PhD, FASCO

thousands of fellow citizens.”

The first scientific ASCO Annual Meeting, during which Dr. Bisel presided as the Society’s first President, was held in 1965 in Philadelphia with

Jane Cook Wright, MD, FASCO

more than 70 members and invited guests, and it featured three presentations on leukemia and multiple myeloma.

In the 50 years since its founding, ASCO and its members have made tremendous strides in the development of breakthrough treatments for cancer.

With membership having grown to more than 35,000, the Society continues to stay true to the vision first set out by its founders, all of whom continued to dedicate their careers to the treatment of patients with cancer.

To read more about ASCO’s history and the Society’s remarkable progress against cancer, visit ASCO’s CancerProgress.Net. n Selected portions reprinted from CancerProgress.Net. © American Society of Clinical Oncology. “Oncology Luminaries: ASCO Founders” www.cancerprogress. net December 9, 2013. All rights reserved.

CMS Approval, New Platform Making QOPI® Participation Easier

A

SCO’s Quality Oncology Practice Initiative (QOPI®) is transforming to meet the reporting needs of its members. The approval of new reporting pathways by the Centers for Medicare and Medicaid Services (CMS), along with a new QOPI platform, will offer new opportunities for practices participating or wishing to participate in the fall QOPI round beginning on September 18.

Reporting for Federal Programs A provision in the American Taxpayer Relief Act of 2012 established that clinical data registries approved by the U.S. Department of Health and Human Services (HHS) can provide pathways for physicians to meet their federal quality reporting requirement. CMS has approved QOPI as such a registry for

oncologists to satisfy Physician Quality Reporting System (PQRS) measures.

Starting in the fall of 2014, oncology practices registered with QOPI will have the opportunity to fulfill CMS PQRS requirements by manually or electronically submitting data through QOPI for the oncology measures group or by submitting data through QOPI via a Qualified Clinical Data Registry (QCDR) reporting pathway, which offers 20 measures chosen by ASCO. Practices will be able to submit data for PQRS for 2014 through QOPI from September 18, 2014, to February 13, 2015.

Once in the QOPI platform, practices can submit their required data for PQRS measures and QOPI can send the measures to CMS on behalf of the practice. Participation in PQRS

is required by all eligible providers in 2014 to avoid a 2.0% financial penalty in 2016.

To see a more detailed summary of changes to full reporting round, please

go to: qopi.asco.org/documents/Fall_ Reporting_Changes_070214.pdf. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCO to Participate in 2014 Rally for Medical Research Hill Day

A

SCO volunteers will be participating in the Rally for Medical Research Hill Day in Washington, DC, on September 18 to help bring attention to the need for a sustained federal investment in the National Institutes of Health.

This will be the second year that ASCO, a gold sponsor of the event and member of the messaging committee, will join a broad coalition of groups

from the medical research community to meet with legislators on Capitol Hill.

ASCO members are encouraged to participate in the event either in person or online through social media. For more information, visit the Rally’s website at www.rallyformedicalresearch.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | SEPTEMBER 15, 2014

PAGE 76

Direct From ASCO

September Is Conquer Cancer Foundation Challenge Month All Donations Will Be Matched 2-to-1 by Raj Mantena, RPh

A

t the 50th Annual Meeting of the American Society of Clinical Oncology, Conquer Cancer Foundation Board Member Raj Mantena, RPh, announced that for the coming year he would match individual donations to the Conquer Cancer Foundation up to $1 million, allowing meeting attendees the opportunity to double their gifts in support of the Foundation’s Mission Endowment.

This September, for a limited time Mr. Mantena is stepping up his challenge even further, offering a matching gift opportunity unique to the Foundation’s history. From September 1 to September 30, 2014, he will match all donations 2-to-1, effectively tripling their impact.

To take advantage of this inspiring challenge, the Conquer Cancer Foundation

has set the ambitious goal of raising $50,000 before September 30.

Donors can direct the additional support wherever they feel they can make the biggest difference—whether that’s by supporting the Conquer Cancer Foundation Grants and

#WeConquerCancer The Matching Gift Challenge will also apply to donations made via the #WeConquerCancer peer-to-peer platform, making September the perfect time to set up a personalized online fundraising campaign in honor of a loved one, special event or athletic endeavor.

Visit support.conquercancerfoundation.org to get started!

Conquer Cancer Foundation Board Member Raj Mantena, RPh, with Gayatri Nimmagadda, MD, at the 2014 Conquer Cancer Foundation Celebration Dinner. Mr. Mantena will match all individual donations to the Foundation 2-to-1 during the month of September.

Kirsten Goldberg (left) and Kristin Ludwig (right) biked a combined 150 miles and raised more than $5,000 for the Conquer Cancer Foundation.

Awards Program; the patient information site Cancer.Net; or helping to develop CancerLinQ, ASCO’s Rapid

Learning System. As always, donors can also choose to support the Foundation’s “Area of Greatest Need.”

Donors can make gifts in support of the matching gift challenge at www.conquercancerfoundation.org/ match, or by mailing a check to the Conquer Cancer Foundation at PO Box 896076, Charlotte, NC 282896076. Mail donations must be postmarked by September 30, 2014, to qualify for the 2-to-1 match. n © 2014. American Society of Clinical Oncology. All rights reserved.

Save the Date

Conquering

Cancer.

Gastrointestinal Cancers Symposium January 15-17, 2015

Together, anything is possible.

The Conquer Cancer Foundation. Our name says a lot.

Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supportingthe world’s preeminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

Moscone West Building San Francisco, California

Genitourinary Cancers Symposium February 26-28, 2015

DonATe ToDAY! ConquerCancerFoundation.org

Rosen Shingle Creek Orlando, Florida

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 77

Direct From ASCO

ASCO University’s New Cancer Genetics Program

O

ver the past decade, ASCO has launched multiple initiatives on cancer genetics that complement the rapid progress in the field. These initiatives have resulted in educational offerings and policy recommendations that have improved both preventive and therapeutic options for patients with cancer and their families at hereditary risk. While these initiatives have brought about large improvements in the documentation of first- and second-

cancer genetics. The course also contains site-specific sections that focus on general risk assessment, genetic epidemiology, and available means of medical and surgical detection and prevention within different disease sites.

“The introduction of next-generation sequencing is redefining the role of genetic testing in clinical practice,” said Noralane M. Lindor, MD, who led the program’s planning group with Kenneth Offit, MD, MPH. Dr. Lindor

The ASCO University program arose from identification of the need to provide in-depth yet concise education in genetic risk assessment and counseling to ensure that oncologists can competently integrate the power of the new genetics into their practices.

—Noralane M. Lindor, MD

can easily access one comprehensive collection on this topic. The Cancer Genetics Program was launched on ASCO University at this year’s ASCO Annual Meeting and may be taken for continuing medical education (CME)/ continuing education (CE) credit. n Kenneth Offit, MD, MPH

This timely, sizable program will be delivered as a new eLearning course on ASCO University, where professionals

Volume 7, Issue 3

May 2011

Journal of oncology Practice

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

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting

By Michael N. Neuss, MD, et al

degree family history, research shows that rates of documentation of complete family history as well as interpretation of the data remain suboptimal.

eLearning Course To address this need, ASCO University® is introducing a new resource: ASCO University’s Cancer Genetics Program, which will focus on multiple facets of cancer genetics. This slidebased, expert-led course consists of several core sections that include a general overview of the science, as well as topics such as recognition of hereditary cancer syndromes, quantitative risk assessment, establishing a cancer risk assessment service and special counseling, as well as ethical, legal, and social issues in

described how before next-generation sequencing, genetic testing was constrained by high costs that limited its availability to highly trained genetic experts. Next-generation sequencing has dramatically reduced the cost of testing, opening the door to more mainstream use by a more diverse range of physicians, many of whom are relatively new to working with this type of technology.

“The ASCO University program arose from identification of the need to provide in-depth yet concise education in genetic risk assessment and counseling to ensure that oncologists can competently integrate the power of the new genetics into their practices,” said Dr. Lindor.

New Cancer.Net Fact Sheets Now Available for Your Practice

B

e sure to check out Cancer.Net’s latest ASCO Answers fact sheet titles on hereditary breast and ovarian cancer and metastatic breast cancer.

These one-page (front and back) introductions to a variety of topics include

an overview, illustrations, terms to know, and questions to ask the doctor.

Find these and a library of other titles at www.cancer.net/factsheets. Or, order copies for your practice at www.cancer .net/estore. Shipping is free, and ASCO members save 20%. n © 2014. American Society of Clinical Oncology. All rights reserved.

For more information, visit university.asco .org/geneticsprogram. Originally printed in ASCO Connection. © American Society of Clinical Oncology. “ASCO University’s New Cancer Genetics Program.” ASCO Connection, May 2014: p 50. All rights reserved.

Subspecialization in Community Oncology: Option or Necessity?

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

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

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

By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

What’s Hot in

JOP

JOP.ascopubs.org Comorbidity, Chemotherapy Toxicity, and Outcomes Among Older Women Receiving Adjuvant Chemotherapy for Breast Cancer on a Clinical Trial: CALGB 49907 and CALGB 361004 (Alliance)

by Heidi D. Klepin, et al

Creation of a Diagnostic Wait Times Measurement Framework Based on Evidence and Consensus

by Julie E. Gilbert, et al

Oncologists' Response to New Data Regarding the Use of Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer

by Efrat Dotan, et al

Diversity by Race, Hispanic Ethnicity, and Sex of the United States Medical Oncology Physician Workforce Over the Past Quarter Century

by Curtiland Deville, et al

Impact of Financial Burden of Cancer on Survivors' Quality of Life

by Kathleen M. Fenn, et al

The ASCO Post | SEPTEMBER 15, 2014

PAGE 80

Palliative Care in Oncology Timing and Meaning of Do-Not-Resuscitate Orders in the Palliative Care Setting A Conversation With Mary F. Mulcahy, MD

By Jo Cavallo

Mary F. Mulcahy, MD

A

lthough a do-not-resuscitate (DNR) order does not mean “do not treat,” that is how it is often interpreted, according to a study examining the level of care oncology inpatients at a tertiary care hospital received.1 The study found that the interpretation of DNR orders among oncology nurses and especially among physicians is variable and results in less aggressive care in general, and that DNR-status patients are more likely to die compared to full code–status patients, regardless of their disease severity. Other studies also show DNR orders influence care more broadly than perhaps patients intended.2,3 Having ongoing conversations with patients from the time of their initial diagnosis and throughout their illness about their likely cancer trajectory, treatment options including benefits and alternatives, and their goals of care are crucial to ensuring that patients’ treatment wishes are followed during a medical emergency.

“If patients have a very clear feeling about what they would or would not want at the end of their life and understand they have a terminal illness and they do not wish to be resuscitated at the time of their death, then a DNR order is appropriate,” said Mary F. Mulcahy, MD, Associate Professor in Medicine, Hematology/Oncology at Northwestern University Feinberg School of Medicine in Chicago, and cofounder of Life Matters Media. “But a lot of patients are afraid of signing a DNR order because they think their treatment is going to be compromised or withheld.”

A more comprehensive directive than a DNR order is the Physician Orders for Life-Sustaining Treatment (POLST) paradigm (www.polst.org), which aug-

ments traditional methods for advance care planning and treatment preferences, including those for cardiopulmonary resuscitation (CPR), artificial nutrition by feeding tube, and antibiotic use, according to Dr. Mulcahy.

The ASCO Post talked with Dr. Mulcahy about the timing of DNR and POLST orders, the difficult end-of-life medical decisions for physicians even when a DNR order is in place, and how devices like pacemakers and implantable cardioverter-defibrillators are impacting end-of-life care.

Clarifying DNR At what point in a patient’s care should DNR orders be applied?

Once a patient is diagnosed with an incurable cancer, regardless of how long that person may live, having an advance directive stating the patient’s wishes about the extent of medical care at the end of life is critical. The most important thing is that the directive be a living document and that there is ongoing conversation between the patient and the oncologist as the status of the cancer and the patient’s health changes.

Having a do-not-resuscitate order only applies at the time of the patient’s death. It is a directive for when the pa-

physicians cannot assume that they do not want medical intervention. We are asking patients if they want to be resuscitated at the point of death, but we are not asking terminally ill patients with no further treatment options, “What would you like us to do in the event you develop pneumonia; would you want to go to the hospital for treatment?” This is the gap in conversation that POLST addresses.

I prefer the POLST paradigm approach to end-of-life medical planning because it includes two possible orders for resuscitation: do not attempt CPR (DNR) or attempt CPR, so it gives the patient more options. I had a patient— a physician—with metastatic colon cancer, and when she handed me her advance care directive, she said to do everything regardless of cost and chances of recovery, because she had seen firsthand that medical staff back off if a patient has a DNR order, and she was afraid that she wouldn’t be treated for a problem that was potentially treatable.

That experience really hit home with me and made me appreciate what patients feel when they sign DNR orders.

Some patients are very clear about the care they want at the end of life, but they are in the minority. Most patients

Having ongoing conversations with patients over the course of their cancer progression will help ensure that there is no misunderstanding about patients’ expectations for their end-of-life care.

—Mary F. Mulcahy, MD

tient has stopped breathing and the patient’s heart has stopped beating. If a patient has lung cancer and develops pneumonia, what should the oncologist do if the patient has a DNR order in place—not treat the pneumonia?

Well, maybe, or maybe not. A study investigating the preferences for other treatments among patients with DNR orders and those with attempt CPR orders found that half of the patients with DNR orders wanted comfort measures only and half wanted a higher level of treatment at a hospital.4 The POLST paradigm tries to address this middle ground, which is the hardest part to interpret. Just because patients have a DNR order in place,

do not like to commit to a DNR order in the event a medical issue arises that is potentially fixable.

Ongoing Conversations How can oncologists help patients in their end-of-life care decision-making?

More important than just checking off a DNR or resuscitate box on a form is understanding what someone’s goals are for care. That comes from having conversations with patients that outline those goals and may include possible medical scenarios as their cancer progresses and their health declines.

Some patients absolutely know that they never want to be in a hospital again, never want to be transferred to

GUEST EDITOR

Jamie H. Von Roenn, MD

A

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.

an intensive care unit, and don’t want treatment for extenuating circumstances beyond their cancer. Other patients may want treatment for anything that is potentially treatable. Having ongoing conversations with patients over the course of their cancer progression will help ensure that there is no misunderstanding about patients’ expectations for their end-of-life care.

Complicating Factors Please describe how DNR orders can inadvertently complicate medical care.

The POLST form clearly states the two possible orders for resuscitation, which we have discussed. There is also a section that addresses the aggressiveness of care at the end of life, which is the harder part in the decision-making process.

When a patient has stopped breathing and his heart has stopped beating, not resuscitating that patient is a clear-cut decision. What is more difficult is the case in which a patient has impending health decline and there is a question, for example, of whether to intubate because of a health complication like pneumonia. We tend to put all the attention on the DNR order, but we need more attention focused on impending health catastrophes.

One morning I was on service and had a conversation with a patient with advanced breast cancer that was pro-

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 81

Palliative Care in Oncology gressing rapidly. She was not my patient, but she wanted to fill out a DNR order, and she did. That evening, the patient went to the radiology department for a brain scan and had a seizure. The rapid-response team called to ask me if she should be intubated.

I was really unsure about what to do.

I was the one who had had the conversation with the patient about her DNR order. I had even helped her fill out the form and I signed the form, and I didn’t know what to do. I finally decided to intubate her because I wasn’t sure if she had had a chance to talk to her family about her decision. The patient never recovered, but at least her family had time to process what was happening to her and to learn about the conversation I had had with her that morning, and I think it helped them come to terms with her death.

Legal Issues Were you concerned about potential legal jeopardy?

I wasn’t worried at the time, but when I think about this case and all the legal avenues it could have taken, I am troubled. I have questioned myself over and over again about whether I made the right decision, and I’ve concluded

that I did. But the end result certainly could have gone another way.

The family could have faulted me for going against the patient’s wishes not to be resuscitated, and I could have gotten into trouble. But these types of cases are always going to present themselves, and it is always going to be a struggle knowing patients’ true values and goals, and what is important to them.

That is why advance care planning is an ongoing process and not simply a DNR box to be checked off on a form.

It is a process in which the patient accepts his or her illness and whereby the patient, family members, and medical team work together to do the right thing for the patient.

Sometimes patients want us to tell them what to do, and doctors can’t be afraid to do that, because these are hard decisions to make. When I meet patients for the first time, I try to get a sense of their character and what they want because I want to guide them in the right direction.

Some patients are never going to accept that they are going to die from their cancer and will always hold onto hope that there is something more that can be done. As oncologists, we have to

change that unrealistic hope [for futile care] to hope for comfort and peace at the end of life.

Implantable Devices How are implantable devices like pacemakers and defibrillators impacting oncology care in the palliative setting?

They are definitely complicating care.

When a patient has a terminal illness, he or she will eventually go into an arrhythmia, and that implantable device is going to fire and keep the heart beating.

We have to tell these patients that there is going to come a time when it will be appropriate to shut off the pacemaker and let the heart beat naturally, but that is a hard discussion to have. When is that appropriate time to turn off these devices?

Is it as the person is dying, because the heart is beating and maybe the patient is still reaping a benefit? I don’t always have the answer to that one, and this is where we need input and guidance from the patient’s cardiologist.

Part of what we are doing at Life Matters Media (www.lifemattersmedia.org) is providing a platform where people can share information and resources to help others participate in the decision-making for their advance care

directive and presenting end-of-life issues in a narrative form to start this difficult dialogue. Our goal is to ensure that patients have the knowledge they need to make the end-of-life choices that are important to them, so they can die in dignity and peace. n

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

References 1. Lund CR, Samant R: Interpretation of do-not-resuscitate (DNR) orders among oncology health care professionals and the potential for these orders to influence care for medical issues unrelated to resuscitation. J Clin Oncol 28(15 suppl):Abstract 9078, 2010.

2. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research: Deciding to forgo life-sustaining treatment, p 251.

Washington, DC; U.S. Government Printing Office; 1983.

3. Beach MC, Morrison RS: The effect of do-not-resuscitate orders on physician decision-making. J Am Geriatr Soc 50:2057-2061, 2002.

4. Fromme EK, Zive D, Schidt TA, et al: POLST registry do-not-resuscitate orders and other patient treatment preferences.

JAMA 307:34-35, 2012.

Announcements

Kenneth S. Ramos, MD, PhD, PharmB, Named New MD-PhD Head at University of Arizona College of Medicine, Tucson

K

enneth S. Ramos, MD, PhD, PharmB, has been named the new MD-PhD Program Director at the University of Arizona College of Medicine, Tucson. The Program was established in 1990 to provide dual training in medicine and research to students interested in careers as research-intensive physicians working in the public and private sectors.

Dr. Ramos, Associate Vice President of Precision Health Sciences and Professor of Medicine, will work closely with members of the MD-PhD Committee, the UA Graduate College, UA Admissions Committee, the Office of Diversity and the College of Medicine, Phoenix to increase recruitment and retention of

outstanding scholars into the program.

“The [University of Arizona] is committed to building the pipeline of future physician-scientists,” says Dr. Ramos, who with support from the Arizona Health Sciences Center Office of the Senior Vice President for Health Sciences, will invest additional resources to ensure the growth and sustainability of the program with unparalleled education along with tools to establish a rewarding career in medicine by combining the discovery of new knowledge with the practice of clinical medicine.

Dr. Ramos is an expert in genomics and predictive biology and environmental and molecular medicine and

Kenneth S. Ramos, MD, PhD, PharmB

toxicology. He has received more than $50 million in research funding, including R01, P01 and P30 grants, and has made seminal contributions in the areas of molecular toxicology, environmental health sciences, toxicogenom-

ics, and molecular medicine.

An expert in the study of gene-gene and gene-environment interactions and genomic medicine, his research program integrates diverse approaches, ranging from molecular genetics to populationbased public health studies to understand the genetic and genomic basis of human disease and to advance the goals of precision medicine. Ongoing basic science studies in his laboratory focus on repetitive genetic elements in the mammalian genome and their role in genome plasticity and disease, while his clinical work focuses on the characterization of diagnostic and prognostic biomarkers for chronic disease and cancer. n

Kyprolis速 (carfilzomib) for Injection Now Has a Permanent J Code: J9047 For the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate.

Clinical benefit, such as improvement in survival or symptoms, has not been verified.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma.

Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients.

Monitor for cardiac complications and manage promptly.

Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients.

Evaluate with cardiac imaging and/or other tests as indicated.

Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.

Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported.

Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline.

Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.

KYPROLIS is engineered for selective inhibition1 • Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each) ADVERSE REACTIONS The safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma.

• Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%) *Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391.

2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle.

In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%).

KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver enzyme abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently.

Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).

The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of the full Prescribing Information on adjacent pages.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2013 Onyx Pharmaceuticals, Inc., South San Francisco, CA 0512-CARF-243R1 December 2013

The ASCO Post | SEPTEMBER 15, 2014

PAGE 84

Announcements

NIH Launches Human Safety Study of Ebola Vaccine Candidate

T

he National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has launched initial human testing of an investigational vaccine to prevent Ebola virus disease, according to a news release issued

by NIH. The early-stage trial has begun

initial human testing of a vaccine codeveloped by NIAID and GlaxoSmithKline (GSK) to evaluate the experimental vaccine’s safety and ability to generate an immune system response in healthy adults.

Testing is taking place at the NIH Clinical Center in Bethesda, Maryland.

First in Series of Accelerated Safety Studies The study is the first of several phase I clinical trials that will examine the investigational NIAID/GSK Ebola vaccine and an experimental Ebola vaccine developed by the Public Health

KYPROLIS™ (carfilzomib) for Injection KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. for full prescribing information.

INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If2 tolerated in Cycle 1, the cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m . If tolerated Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in2 in subsequent 2 dose should be escalated to 27 mg/m beginning in Cycle 2 or and continued at 27 mg/m subsequent cycles.

Treatment may be continued until disease progression until unacceptable toxicity in occurs [see cycles.and Treatment may be continued disease progression until unacceptable Dosage Administration].

The doseuntil is calculated using the or patient’s actual bodytoxicity surfaceoccurs area [see at Dosage and Administration].

The dose is calculated using the patient’s actual body surface areaa at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon 2 baseline.

Patients with a 2body surface area greater than 2.2 m should receive a dose based upon a body surface area of 2.2 m . Dose adjustments do not need to be made for weight changes of less than area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than orbody equalsurface to 20%. or equal to 20%.

Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Cycle 1 Week 1 Week 2 Week 3 Week 4 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days Days 8Day 9Day 10–14 Days 15Day 16Day 17–21 Days 22–28 Days 1Day 2Day 3–7 3–7 208 209 10–14 2015 2016 17–21 22–28 KYPROLIS No No No No 201 202 KYPROLIS 2 No 20 20 20 No 20 20 No No 20 (20 mg/m ):2 Dosing Dosing Dosing Dosing (20 mg/m ): Dosing Dosing Dosing Dosing Cycles 2 and Beyonda a Cycles 2 and Beyond Week 1 Week 2 Week 3 Week 4 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days Day Day Days Day Day Days Day Days Days Day 2 3–7 8 9 10–14 15 16 17–21 22–28 1 3–7 278 279 10–14 2715 2716 17–21 22–28 KYPROLIS No No No No 271 272 KYPROLIS 27 Dosing No 27 27 Dosing No 27 27 Dosing No Dosing No 27 (27 mg/m2): Dosing Dosing Dosing Dosing (27 mg/m2): a Ifaprevious cycle dosage is tolerated.

If previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor Hydration and Fluid Hydrate patients to reduce risk of renal Maintain toxicity and of tumor lysis syndrome (TLS) withMonitoring.

KYPROLIS treatment [see Warnings andthePrecautions]. adequate lysisvolume syndrome with KYPROLIS [seeblood Warnings and Precautions]. adequate fluid status(TLS) throughout treatmenttreatment and monitor chemistries closely. PriorMaintain to each dose in fluid volume status throughout and monitor closely. Prior to each dose in Cycle 1, give 250 mL to 500 mLtreatment of intravenous normal blood saline chemistries or other appropriate intravenous fluid.

Cycle 1, give 250 mL 500 mL of intravenous normal saline other appropriate intravenous fluid.

Give an additional 250 to mL to 500 mL of intravenous fluidsor as needed following KYPROLIS Give an additional 250 intravenous mL to 500 mL of intravenous as needed following administration.

Continue hydration, as needed, fluids in subsequent cycles.

Also KYPROLIS monitor administration.

Continue hydration, needed,and in Precautions]. subsequent cycles.

Also monitor patients during this period intravenous for fluid overload [see as Warnings Dexamethasone patients during this period for fluid overload [see Warnings and Precautions].

Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of Premedication.

Pre‑medicate dexamethasone 4 mg orallythe or first intravenously priorescalation to all doses KYPROLIS during Cycle 1 and priorwith to all KYPROLIS doses during cycle of dose to of during and prior all KYPROLIS doses during the cycle ofand dose escalation to 27KYPROLIS mg/m2 to reduceCycle 1 the incidence andtoseverity of infusion reactions [seefirst Warnings Precautions].

2 27 mg/mdexamethasone to reduce the incidence and severity of infusion reactions [see Warnings and Precautions].

Reinstate premedication (4 mg orally or intravenously) if these symptoms develop or Reinstateduring dexamethasone orally or intravenously) if these symptoms develop or reappear subsequentpremedication cycles. Dose(4 mg Modifications based on Toxicities.

Recommended reappear during subsequent cycles.

Dose Modifications based on Toxicities.

Recommended actions and dose modifications are presented in Table 2. actions Dose and dose modificationsforareToxicity presented in Table 2. a Table 2: Modifications during KYPROLIS Treatment Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity Recommended Action Hematologic Toxicity a • Withhold dose. Recommended Action • Grade 3 or 4 Neutropenia a Withhold dose.

Grade 3 or 4 Neutropenia • • If fully recovered before next scheduled dose, continue • • Grade 4 Thrombocytopenia • at If fully recovered before next scheduled dose, continue • Warnings Grade 4 Thrombocytopenia same dose level. [see and Precautions] at same dose level. [see Warnings and Precautions] • If recovered to Grade 2 neutropenia or Grade 3 • thrombocytopenia, If recovered to Grade 2 neutropenia or Grade 3 reduce dose by one dose level 2 thrombocytopenia, reduce 2dose one20 mg/m dose level (from 27 mg/m2 to2 20 mg/m , OR by from to 2 (from 27 mg/m to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m ).2 15 mg/m ).

• If tolerated, the reduced dose may be escalated to the • previous If tolerated, the reduced dose may be escalated to the dose at the discretion of the physician. previous dose at the discretionAction of the physician.

Non-Hematologic Toxicity Recommended Non-Hematologic Toxicity Recommended Action • Withhold until resolved or returned to baseline.

Cardiac Toxicity Withhold until resolved or returned to baseline.

Cardiac Toxicity • • After resolution, consider if restarting KYPROLIS at Grade 3 or 4, new onset or worsening of: • a reduced After resolution, consider if restarting KYPROLIS at dose is appropriate (from 27 mg/m2 to • Grade 3 or 4, new onset or worsening of: congestive heart failure; 2 2 2 (from 27 mg/m a reduced dose is 20 mg/m appropriate to , OR from to 15 mg/m2).

20 mg/m congestive heart failure; • • decreased left ventricular 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the • function; decreased left ventricular • previous If tolerated, the reduced dose may be escalated to the dose at the discretion of the physician. function; • or myocardial ischemia previous dose at the discretion of the physician.

• Warnings or myocardial ischemia [see and Precautions] [see Warnings and Precautions] Pulmonary Hypertension • Withhold until resolved or returned to baseline.

Pulmonary Withhold until resolved or returned to baseline.

• • Restart at the dose used prior to the event or reduced [see Warnings Hypertension and Precautions] • dose Restart at the dose used prior to the event or reduced [see Warnings and Precautions] (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 2 to 20 mg/m OR from 20 mg/m2 (from2),27 mg/m to dose 15 mg/m at the discretion of the2,physician.

2 to 15 mg/m ), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the • previous If tolerated, the reduced dose may be escalated to the dose at the discretion of the physician. previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Pulmonary Complications • Withhold until resolved or returned to baseline.

Pulmonary Complications • Consider restarting at the next scheduled treatment • Grade 3 or 4 • with Consider restarting at the next scheduled treatment • Warnings Grade 3 or 4 one dose level reduction (from 27 mg/m2 to [see and Precautions] 2 (from 27 mg/m with one2, dose level20 mg/m reduction OR from to 15 mg/m2). 2 to 20 mg/m [see Warnings and Precautions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the • previous If tolerated, the reduced dose may be escalated to the dose at the discretion of the physician. previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Hepatic Toxicity Withhold until resolved or returned to baseline.

Toxicity • • After resolution, consider if restarting KYPROLIS is • Hepatic Grade 3 or 4 elevation of • appropriate; may be reinitiated at a reduced dose (from After resolution, consider if restarting KYPROLIS is • transaminases, Grade 3 or 4 elevation of bilirubin or other 2 appropriate; may be reinitiated at a reduced dose (from 27 mg/m to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) transaminases, liver abnormalitiesbilirubin or other 2 27 mg/m tomonitoring 20 mg/m2,ofORliver from 20 mg/m2 to 15 mg/m2) with frequent function. liver abnormalities [see Warnings and Precautions)] with frequent monitoring of liver function.

• If tolerated, the reduced dose may be escalated to the [see Warnings and Precautions)] • previous If tolerated, the reduced dose may be escalated to the dose at the discretion of the physician. previous dose at the discretion of the physician. (continued) (continued)

Agency of Canada and licensed to NewLink Genetics Corp. The others are to launch later in the fall. These trials are conducted in healthy adults who are not infected with Ebola virus to determine if the vaccine is safe and induces an adequate immune response.

a Table 2: Dose Modifications forfor Toxicity KYPROLIS Treatment (continued) a Table 2: Dose Modifications Toxicityduring during KYPROLIS Treatment (continued) • Withhold until renal function has recovered to Grade 1 Renal Toxicity • Withhold until renal function has recovered to Grade 1 Renal Toxicity or to baseline and monitor renal function.

• • Serum creatinine equal to or or to baseline and monitor renal function.

Serum creatinine equal to or • • If attributable to KYPROLIS, restart at the next scheduled greater than 2 ×2 baseline If attributable to KYPROLIS, restart at the next scheduled greater than × baseline treatment at a reduced dose (from 27 mg/m2 to2 [see Adverse Reactions] to treatment at a reduced dose2 (from 27 mg/m [see Adverse Reactions] from 20 mg/m to 15 mg/m2).

20 mg/m2, OR 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If not attributable to KYPROLIS, restart at the dose used • If not attributable to KYPROLIS, restart at the dose used prior to the event. prior to the event.

• If tolerated, the reduced dose may be escalated to the • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Peripheral Neuropathy • Withhold until resolved or returned to baseline.

Peripheral Neuropathy • Restart at the dose used prior to the event or reduced • Grade 3 or 4 • Restart at the dose used prior to the event or reduced • Grade 3 or 4 2 dose (from 27 mg/m2 to2 20 mg/m2, OR [see Adverse Reactions] 2 from 20 mg/m (from2),27 mg/m to 20 mg/m OR from 20 mg/m2 [see Adverse Reactions] to dose 15 mg/m at the discretion of the ,physician. to 15 mg/m2), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Other • Withhold until resolved or returned to baseline.

Other • Grade 3 or 4 non-hematological • Consider restarting at the next scheduled treatment Consider restarting at the next scheduled treatment • toxicities Grade 3 or 4 non-hematological • with one dose level reduction (from 27 mg/m2 to2 with one 27 mg/m to toxicities 2 dose level reduction 2 , OR from 20 mg/m2 to(from 15 mg/m ).

20 mg/m 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. previous dose at the discretion of the physician. a

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg Administration Precautions.

The quantity of KYPROLIS single‑use (60 mg carfilzomib) may exceed the required dose. Caution shouldcontained be used in in one calculating the vial quantity carfilzomib) may exceed the Do required dose.

Cautionwith should be used as in an calculating the other quantity delivered to prevent overdosing. not mix KYPROLIS or administer infusion with deliveredproducts. to prevent not mix KYPROLIS with or an infusion other medicinal Theoverdosing. intravenousDoadministration line should be administer flushed withasnormal salinewith or 5% medicinal products. intravenous administration line should be flushed with normal should saline or Dextrose Injection, USPThe immediately before and after KYPROLIS administration.

KYPROLIS not5% Dextrose Injection, USP immediately before and after KYPROLIS administration.

KYPROLIS should be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitutionnot be administered KYPROLISAdministration. should be administered overvials 2 to 10 minutes. and Preparation asfora bolus.

Intravenous KYPROLIS contain no Reconstitution antimicrobial and Preparation Intravenous Administration.

KYPROLIS vials contain no antimicrobial preservatives and are for intended only for single use. Unopened vials of KYPROLIS are stable until the preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete reconstituted solutionprior contains carfilzomib Reconstitution/Preparation at a concentration of 2 mg/mL. Read the complete preparation instructions to reconstitution.

Steps: 1. Remove vial preparation instructions to reconstitution.

Steps: 1. Remove from refrigerator just priorprior to use.

2. AsepticallyReconstitution/Preparation reconstitute each vial by slowly injecting 29 mLvial from refrigerator just prior to use.

2.

Aseptically reconstitute each vial by slowly injecting 29 Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow of any tocake DOto NOT SHAKE to avoid foam generation. foaming occurs, allow solution restorinpowder vial foroccurs. about 2 5 minutes, until foaming subsides. 4.If After reconstitution, solution rest inforvialintravenous for about 2 to 5 minutes,The untilreconstituted foaming subsides.

After reconstitution, KYPROLIS to is ready administration. product 4.should be a clear, KYPROLIS is ready for intravenous administration.

The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.and from the dilute intothe50 unused mL 5%portion.

Dextrose USPof intravenous bag.

6. Administration] Immediately discard thevial vialand containing TheInjection, stabilities reconstituted 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3.

KYPROLIS under various temperature and container conditions are shown in Table 3.

Table 3: Stability of Reconstituted KYPROLIS Table 3: Stability of Reconstituted KYPROLIS Stabilitya per Container Stabilitya per Container Storage Conditions of Reconstituted Storage Conditions of Reconstituted IV Bag KYPROLIS b IV Bag KYPROLIS Vial Syringe (D5W ) Vial Syringe (D5Wb) Refrigerated (2°C to 8°C; 36°F to 46°F) 24 hours 24 hours 24 hours Refrigerated (2°C to 8°C; 36°F to 46°F) 24 hours 24 hours 24 hours Room Temperature (15°C to 30°C; 59°F to 86°F) 4 hours 4 hours 4 hours Room Temperature (15°C to 30°C; 59°F to 86°F) 4 hours 4 hours 4 hours a

Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP. a Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial WARNINGS Cardiac Arrest, Heart administration.

Failure, Myocardial Ischemia.

DeathAND due PRECAUTIONS: to cardiac arrest has occurred withinCongestive a day of KYPROLIS New Ischemia.

Deathofdue to cardiaccongestive arrest hasheart occurred within day of KYPROLIS administration.

New onset or worsening pre‑existing failure with adecreased left ventricular function or onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk 4 cardiac [see events until recovery and consider whether restart based onClass a benefit/risk assessment Dosage and Administration].

Patients withtoNew YorkKYPROLIS Heart Association III and assessment Dosage and Administration].

Patients with New York Association Class III and IV heart failure,[see myocardial infarction in the preceding 6 months, andHeart conduction abnormalities IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater medications were not eligible for the clinical trials. These patients may be at(PAH) greater riskuncontrolled for cardiacbycomplications.

Pulmonary Hypertension.

Pulmonary arterial hypertension risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients.

Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for patients. hypertension Evaluate with until cardiac imaging and/or other tests as and indicated. pulmonary resolved or returned to baseline considerWithhold whetherKYPROLIS to restart for pulmonary hypertension until resolved or returned baseline consider whether to restart KYPROLIS based on a benefit/risk assessment [see toDosage andand Administration].

Pulmonary KYPROLIS based on a benefit/risk assessment [see Dosage and Administration].

Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea Complications. occurred in 5%; no Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were Dosage andbyAdministration Adverse Reactions].

Infusion Infusionmyalgia, reactions were characterized a spectrum ofand systemic symptoms including fever,Reactions. chills, arthralgia, facial characterized by a spectrum of systemicshortness symptoms including fever, chills, arthralgia, facial flushing, facial edema, vomiting, weakness, of breath, hypotension, syncope, chestmyalgia, tightness, facial edema, vomiting, weakness, shortness of breath, chest tightness, or flushing, angina. These reactions can occur immediately following or up hypotension, to 24 hours syncope, after administration of or angina.Administer These reactions can occur prior immediately following or up tothe 24 incidence hours afterand administration KYPROLIS. dexamethasone to KYPROLIS to reduce severity of of KYPROLIS. to patients KYPROLIS to reduce incidenceand andto severity reactions [seeAdminister Dosage anddexamethasone Administration].prior Inform of the risk andthesymptoms contact of reactions [see Dosage andinfusion Administration].

Inform the risk and symptomsTumor and toLysis contact physician if symptoms of an reaction occur [seepatients PatientofCounseling Information]. physician if symptoms of an infusion reaction occur [see Patient Counseling Information].

Tumor Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% Lysis of Syndrome.

Tumor syndrome (TLS) following KYPROLIS patients.

Patients withlysis multiple myeloma andoccurred a high tumor burden should administration be consideredinto< be1% at of patients. with to multiple myeloma and ensure a high that tumor burdenareshould be considered to be at greater risk Patients for TLS. Prior receiving KYPROLIS, patients well hydrated [see Dosage risk for TLS.Monitor Prior toforreceiving ensure that patients well hydrated Dosage andgreater Administration]. evidenceKYPROLIS, of TLS during treatment, and are manage promptly.[see Interrupt and Administration]. evidence TLS Administration].Thrombocytopenia. during treatment, and manage promptly.

Interrupt KYPROLIS until TLS is Monitor resolvedfor[see Dosageofand KYPROLIS KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia.

KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following patients administration experienced thrombocytopenia, 4 in Thrombocytopenia following KYPROLIS resulted in a doseincluding reductionGrade in 1% of 10%. patients and discontinuation of KYPROLIS a doseMonitor reduction in 1% of patients andduring discontinuation treatment withadministration KYPROLIS in resulted < 1% of inpatients. platelet counts frequently treatment of treatment withReduce KYPROLIS in < 1%dose of patients.

Monitor platelet[see counts frequently during treatment with KYPROLIS. or interrupt as clinically indicated Dosage and Administration]. with KYPROLIS. Reduce or interrupt as of clinically [see Dosage and Administration].

Hepatic Toxicity and Hepatic Failure.dose Cases hepaticindicated failure, including fatal cases, have been Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

ASCOPost.com | SEPTEMBER 15, 2014

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Announcements

In parallel, NIH has partnered with a British-based international consortium that includes the Wellcome Trust and Britain’s Medical Research Council and Department for International Development to test the NIAID/GSK vaccine candidate among healthy volunteers in the United Kingdom and in the West African countries of Gambia

(after approval from the relevant authorities) and Mali.

Additionally, the U.S. Centers for Disease Control and Prevention has initiated discussions with Ministry of Health officials in Nigeria about the prospects for conducting a phase I safety study of the vaccine among healthy adults in that country.

Urgent Need for Protective Vaccine The pace of human safety testing for experimental Ebola vaccines has been expedited in response to the ongoing Ebola virus outbreak in West Africa. According to the World Health Organization (WHO), more than 1,400 suspected and confirmed deaths from Ebola infection

reported (< (< 1%).

KYPROLIS can can cause elevations of serum transaminases and and bilirubin. Withhold of Selected Adverse Drug Reactions.

Renal Events: The The mostmost common renalrenal reported 1%).

KYPROLIS cause elevations of serum transaminases bilirubin. Withhold Description Description of Selected Adverse Drug Reactions.

Renal Events: common KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other reactions werewere increase in blood creatinine (24%) and and renalrenal failure (9%),(9%), which werewere mostly KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other adverse adverse reactions increase in blood creatinine (24%) failure which mostly liverliver abnormalities until resolved or returned to baseline.

After resolution, consider if restarting Grade 1 or Grade 2 in severity.

Grade 3 renal adverse reactions occurred in 6% of patients and and abnormalities until resolved or returned to baseline. After resolution, consider if restarting Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients KYPROLIS is appropriate.

Monitor liver enzymes frequently [see Dosage and Administration and Grade 4 events occurred in 1%.

Discontinuations due to increased blood creatinine and acute renal KYPROLIS is appropriate. Monitor liver enzymes frequently [see Dosage and Administration and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered to a failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered to a failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal pregnant woman based on its mechanism of action and findings in animals. There are no adequate and function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including pregnant woman based on its mechanism of action and findings in animals. There are no adequate and function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.

ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection. of the labeling: DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase of the labeling: DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by • Pulmonary Hypertension [see Warnings and Precautions] concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected • Pulmonary Hypertension [see Warnings and Precautions] concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected • Pulmonary Complications [see Warnings and Precautions] to influence exposure of other drugs [see Clinical Pharmacology section of full PI].

• Pulmonary Complications [see Warnings and Precautions] to influence exposure of other drugs [see Clinical Pharmacology section of full PI].

• Infusion Reactions [see Warnings and Precautions] USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and • Infusion Reactions [see Warnings and Precautions] USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and • Tumor Lysis Syndrome [see Warnings and Precautions] Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while • Tumor Lysis Syndrome [see Warnings and Precautions] Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while • Thrombocytopenia [see Warnings and Precautions] being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS • Thrombocytopenia [see Warnings and Precautions] with KYPROLIS. Based ontoitsamechanism of actionCarfilzomib and findings in animals, KYPROLIS • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] canbeing causetreated fetal harm when administered pregnant woman. caused embryo‑fetal • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] can fetal rabbits harm when administered a pregnant caused embryo‑fetal The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical toxicity incause pregnant at doses that weretolower than in woman. patients Carfilzomib receiving the recommended The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical toxicity in pregnant rabbits at doses that were lower than becomes in patientspregnant receivingwhile the taking recommended trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, dose.

If KYPROLIS is used during pregnancy, or if the patient this trials ofand patients withClinical multipleTrials myeloma wereExperience. fatigue, anemia, nausea, thrombocytopenia, dyspnea,drug, dose.

If KYPROLIS duringof pregnancy, if the topatient becomes pregnant taking this diarrhea, pyrexia.

Safety Because clinical trials are conducted the patient shouldisbeused apprised the potentialorhazard the fetus.

Carfilzomib was while administered diarrhea, pyrexia.

Clinical Trialsreaction Safetyrates Experience. clinical are conducted drug, the patient should beand apprised the potential hazard to the fetus. Carfilzomib administered under widely and varying conditions, adverse observed inBecause the clinical trialstrials of a drug cannot intravenously to pregnant rats rabbitsofduring the period of organogenesis at doses ofwas 0.5, 1, and varyingwith conditions, reaction observed in and the clinical of a the drugrates cannot 2 mg/kg/day intravenously to pregnant during the in period of organogenesis at doses of 0.5, 1, and be under directlywidely compared rates in adverse the clinical trials rates of another drug, may nottrials reflect in rats and 0.2,rats 0.4,and andrabbits 0.8 mg/kg/day rabbits.

Carfilzomib was not teratogenic be directly compared with Arates anotherand/or drug,refractory and may multiple not reflect the rates at any 2 mg/kg/day in rats and 0.2, 0.4,was andan0.8 mg/kg/day in rabbits. Carfilzomib teratogenic observed in medical practice. total inof the 526clinical patientstrials with ofrelapsed myeloma dose tested.

In rabbits, there increase in pre‑implantation loss at ≥was 0.4 not mg/kg/day observed in medical practice. A total of 526 patients with relapsed and/or refractory myeloma any dose tested. rabbits, there an increase in loss pre‑implantation lossinatfetal ≥ 0.4 mg/kg/day received KYPROLIS as monotherapy or with pre‑dose dexamethasone.

Patients receivedmultiple a median of andatan increase in earlyInresorptions andwas post‑implantation and a decrease weight at received KYPROLIS monotherapy or with pre‑dose dexamethasone.

Patients receiveddue a median an increase early and post‑implantation decrease inin rabbits fetal weight four treatment cycles as with a median cumulative KYPROLIS dose of 993.4 mg. Deaths to all of the and maternally toxic in dose of resorptions 0.8 mg/kg/day.

The doses of 0.4 loss and and 0.8 amg/kg/day are at four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all approximately the maternally dose respectively, of 0.8 mg/kg/day.

The doses of dose 0.4 and 0.8 mg/kg/day in 2rabbits are causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not 20%toxic and 40%, of the recommended in humans of 27 mg/m based 2 causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not approximately 20% Nursing and 40%,Mothers. respectively, theknown recommended dose in humans of 27 in mg/m based attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, on body surface area.

It isofnot whether KYPROLIS is excreted human attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, on body surface area.

Nursing Mothers.

It is not known whether KYPROLIS is excreted in human cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure), milk. Since many drugs are excreted in human milk and because of the potential for serious adverse cardiacindisorder), end‑organ in 4 patients (multi‑organ failure, hepatic failure, renal failure), milk. Since manyinfants drugsfrom are excreted in ahuman milk and because the potential for serious adverse infection 4 patients (sepsis,failure pneumonia, respiratory tract bacterial infection), dyspnea and reactions in nursing KYPROLIS, decision should be made of whether to discontinue nursing infection hemorrhage in 4 patients tract bacterial infection), dyspnea in nursing infants frominto KYPROLIS, decision shouldofbethe made to discontinue nursing intracranial in 1(sepsis, patient pneumonia, each, and 1 respiratory patient found dead of unknown causes.

Seriousand or toreactions discontinue the drug, taking account athe importance drugwhether to the mother.

Pediatric intracranial hemorrhage in 1 inpatient each, andThe1 most patient found dead of adverse unknownreactions causes.were Serious Use.or The to discontinue drug, takingofinto account inthepediatric importance of thehave drugnot to the Pediatric adverse reactions were reported 45% patients. common serious safety andthe effectiveness KYPROLIS patients beenmother. established. adverse reactions were reported in 45% patients. The most common serious adverse reactions were Geriatric Use. The and ofeffectiveness of KYPROLIS in pediatric patients have not been in established. pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse Use.safety In studies KYPROLIS there were no clinically significant differences observed safety pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse Use. In patients studies ofless KYPROLIS there were noand clinically significant in safety reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive andGeriatric efficacy between than 65 years of age patients 65 yearsdifferences of age andobserved older. Renal reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive and efficacy between patients less than 65 years of age and patients 65 years of age and older. heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial Renal in heart failurereactions (2%), cardiac arrest, increased bloodare creatinine, acute4.renal failure (1% patients Impairment.

The renal pharmacokinetics KYPROLIS were in a Phase 2 trial in each).

Adverse occurring at dyspnea, a rate of 10% or greater presentedand in Table with normal function and and thosesafety with of mild, moderate, andevaluated severe renal impairment each). Adverse reactions occurring at a rate of 10% or greater are presented in Table 4. patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma andofpatients on2 chronic dialysis. average, patients were27treated usingbeyond.

KYPROLIS 2 Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma doses 15 mg/m on2 Cycle 1, 20 On mg/m on Cycle 2, and mg/m2for on 25.5 cycles Cycles 3 and Patients Treated with KYPROLIS of 15 mg/mand on safety Cycle of1, KYPROLIS 20 mg/m2were on Cycle 2, and 27bymg/m on Cycles 3 and renal beyond.

Patients Treated with KYPROLIS Thedoses pharmacokinetics not influenced the degree of baseline Patients (N = 526) The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrationsrenal Patients [n (%)](N = 526) impairment, including the patients on dialysis.

Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see Clinical [n (%)] has not been studied, shouldImpairment. be administered after the dialysis [see Clinical Grade 3 Grade 4 All Pharmacology section of fullthePI].drug Hepatic The safety, efficacy andprocedure pharmacokinetics Grade 3 Grade 4 Alla Pharmacology full PI]. Hepatic Impairment. safety, efficacy and pharmacokinetics Events Events Event Grades of KYPROLIS have section not beenofevaluated in patients with baselineThe hepatic impairment.

Patients with the Events Events Event Gradesa of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the Fatigue 292 (55.5) 38 (7.2) 2 (0.4) following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper Fatigue 292 (55.5) 38 (7.2) 2 (0.4) limitfollowing laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac Anemia 246 (46.8) 111 (21.1) 7 (1.3) limit of normal (ULN)with andNew bilirubin ≥ 2 ×Association ULN [see Clinical sectionwere of full Cardiac Anemia 246 (46.8) 111 (21.1) 7 (1.3) Impairment.

Patients York Heart Class IIIPharmacology and IV heart failure notPI]. eligible Nausea 236 (44.9) 7 (1.3) 0 Impairment.

Patients New York Heart Association Class III and IV heart failure were not eligible for the clinical trials.

Safetywith in this population has not been evaluated.

Nausea 236 (44.9) 7 (1.3) 0 Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3) for the clinicalThere trials.isSafety in thisspecific population has not evaluated.

OVERDOSAGE: no known antidote for been KYPROLIS overdosage. In the event of an Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3) OVERDOSAGE: is noand known specific antidotesupportive for KYPROLIS Dyspnea 182 (34.6) 25 (4.8) 1 (0.2)b b overdosage, monitor There the patient provide appropriate care.overdosage. In the event of an Dyspnea 182 (34.6) 25 (4.8) 1 (0.2) overdosage, monitor the patient and provide appropriate supportive Diarrhea 172 (32.7) 4 (0.8) 1 (0.2) NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, andcare.

Impairment of Fertility.

Diarrhea 172 (32.7) 4 (0.8) 1 (0.2) NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of inFertility.

Carcinogenicity studies have not been conducted with carfilzomib.

Carfilzomib was clastogenic the Pyrexia 160 (30.4) 7 (1.3) 2 (0.4) Carcinogenicity studies have not been conducted with carfilzomib.

Carfilzomib wasnot clastogenic in the Pyrexia 160 (30.4) 7 (1.3) 2 (0.4) in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was mutagenic Upper respiratory tract infection 149 (28.3) 17 (3.2) 0 in vitro chromosomal aberration test in peripheral blood lymphocytes.

Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse Upper respiratory tract infection 149 (28.3) 17 (3.2) 0 Headache 145 (27.6) 7 (1.3) 0 in marrow the in vitro bacterial reverse (Ames)with test carfilzomib and was nothave clastogenic in conducted. the in vivo No mouse bone micronucleus assay. mutation Fertility studies not been Headache 145 (27.6) 7 (1.3) bone onmarrow micronucleus Fertility during studies with carfilzomib conducted.

Cough 137 (26.0) 1 (0.2) 0 0 effects reproductive tissues assay. were noted 28‑day repeat‑dosehave rat not and been monkey toxicity No Cough 137 (26.0) 1 (0.2) 0 effects reproductive were noted chronic during toxicity 28‑day studies. repeat‑dose rat Toxicology and monkeyand/ toxicity Blood creatinine increased 127 (24.1) 13 (2.5) 1 (0.2) studies or inon6‑month rat andtissues 9‑month monkey Animal Blood creatinine increased (24.1) 13 (2.5) 1 (0.2) studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ or Pharmacology.

Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg Lymphopenia 126127 (24.0) 84 (16.0) 11 (2.1) 2 or Pharmacology.

Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg Lymphopenia 126 (24.0) 84 (16.0) 11 (2.1) (approximately 1.3 times recommended dose in humans of 27 mg/m based on body surface area) Edema peripheral 126 (24.0) 3 (0.6) 0 (approximately 1.3 times recommended humans serum of 27 levels mg/m2ofbased on body experienced hypotension, increased heart rate,dose andin increased troponin‑T. The surface repeatedarea) Edema peripheral (24.0) 3 (0.6) Vomiting 117126 (22.2) 5 (1.0) 0 0 experienced hypotension, increased heart rate,atand increased serum levels of troponin‑T. The repeated bolus intravenous administration of carfilzomib ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in Vomiting 117 (22.2) 5 (1.0) 0 Constipation 110 (20.9) 1 (0.2) 0 bolus using intravenous of carfilzomib at ≥ 2clinically mg/kg/dose in in ratsmortalities and 2 mg/kg/dose monkeys dosingadministration schedules similar to those used resulted that were in Constipation 110 (20.9) 1 (0.2) 0 monkeys using dosing schedules similar to those used clinically resulted in mortalities that Neutropenia 109 (20.7) 50 (9.5) 4 (0.8) due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluidwere Neutropenia (20.7) due to toxicities occurring in the cardiovascular gastrointestinal (cardiac failure, (necrosis/hemorrhage), cardiac fibrosis, pericardial accumulation, cardiac hemorrhage/degeneration), renalfluid Back pain 106109 (20.2) 15 50 (2.9)(9.5) 04 (0.8) accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal Back pain (20.2) 15 (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) Insomnia 94106 (17.9) 0 (2.9) 0 0 (glomerulonephropathy, tubular innecrosis, dysfunction), half andthe pulmonary (hemorrhage/inflammation) systems.

The dose of 2 mg/kg/dose rats is approximately recommended dose in humans Insomnia (17.9) Chills 84 94 (16.0) 1 (0.2)0 0 0 systems. doseonofbody 2 mg/kg/dose in rats approximately half theinrecommended dose in humans of 27 mg/m2The based surface area.

Theisdose of 2 mg/kg/dose monkeys is approximately Chills 84 (16.0) 1 (0.2) 2 Arthralgia 83 (15.8) 7 (1.3) 0 0 of 27 mg/m based on bodydose surface area. The doseonofbody 2 mg/kg/dose in monkeys is approximately equivalent to the recommended in humans based surface area.

Arthralgia 83 (15.8) 7 (1.3) 0 equivalent to the recommended dose in humans based on body surface area.

Muscle spasms 76 (14.4) 2 (0.4) 0 PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with Muscle spasms 76 (14.4) 2 (0.4) PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms:

Hypertension 75 (14.3) 15 (2.9) 2 (0.4)0 KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: Hypertension 75 (14.3) 15 (2.9) 2 (0.4) fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS Asthenia 73 (13.9) 12 (2.3) 1 (0.2) rigors, chest pain, cough, or swelling of the pressure. feet or legs.

Advise patients KYPROLIS mayfever, causechills, fatigue, dizziness, fainting, and/or drop in blood Advise patients not that to drive or Asthenia 73 (13.9) 12 (2.3) 1 (0.2) Hypokalemia 72 (13.7) 14 (2.7) 3 (0.6) may machinery cause fatigue, fainting, drop in blood pressure. patients not to drive or operate if theydizziness, experience any ofand/or these symptoms.

Advise patientsAdvise that they may experience Hypokalemia 72 (13.7) Hypomagnesemia 71 (13.5) 2 14 (0.4)(2.7) 03 (0.6) operateofmachinery if they experience any of these patients that theyoccurs may experience shortness breath (dyspnea) during treatment withsymptoms.

KYPROLIS.Advise This most commonly within Hypomagnesemia 71 (13.5) 2 (0.4) shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within Leukopenia 71 (13.5) 27 (5.1) 1 (0.2)0 a day of dosing. Advise patients to contact their physicians if they experience shortness of breath.

Leukopenia 71 (13.5) 27 (5.1) 1 (0.2) a day of dosing.

Advise patients to contact their physicians if they experience shortness of breath.

Counsel patients to avoid dehydration, since patients receiving KYPROLIS therapy may experience Pain in extremity 70 (13.3) 7 (1.3) 0 Counsel patients to avoid dehydration, patients receiving therapy may experience vomiting and/or diarrhea.

Instruct patientssince to seek medical adviceKYPROLIS if they experience symptoms Pain in extremity 7 (1.3) Pneumonia 67 70 (13.3) (12.7) 52 (9.9) 3 (0.6)0b vomiting and/or diarrhea. Instruct patients seek medical if they experience symptoms of dizziness, lightheadedness, or fainting spells.toCounsel femalesadvice of reproductive potential to use Pneumonia (12.7) 3 (0.6)b Aspartate aminotransferase increased 66 67 (12.5) 15 52 (2.9)(9.9) 1 (0.2) of dizziness, lightheadedness, faintingpregnancy spells. Counsel reproductive to use effective contraceptive measures toorprevent during females treatmentofwith KYPROLIS.potential Advise the Aspartate aminotransferase increased 66 66 (12.5) 1 (0.2) Dizziness (12.5) 5 15 (1.0)(2.9) 1 (0.2) effective contraceptive measures to prevent pregnancy during treatment with KYPROLIS. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately.

Dizziness (12.5) 5 (1.0) patient if she becomestreatment pregnantwhile during treatment, to contact herIf physician immediately.

Advise Hypoesthesia 64 66 (12.2) 3 (0.6) 01 (0.2) patients notthat to take KYPROLIS pregnant or breastfeeding. a patient wishes to restart Hypoesthesia 64 (12.2) 3 (0.6) patients notafter to take KYPROLIS treatment while pregnant or breastfeeding.

If aher patient wishesAdvise to restart breastfeeding treatment, advise her to discuss the appropriate timing with physician.

Anorexia 63 (12.0) 1 (0.2) 0 0 breastfeeding after advise her discuss thethey appropriate timingtaking with her physician.

Advise patients to discuss withtreatment, their physician any tomedication are currently prior to starting 63 (12.0) 1 (0.2) PainAnorexia 63 (12.0) 12 (2.3) 0 0 patientswith to KYPROLIS, discuss with their tophysician any new medication they are currently taking to starting treatment or prior starting any medication(s) during treatment withprior KYPROLIS. Pain 12 (2.3) Hyperglycemia 62 63 (12.0) (11.8) 16 (3.0) 3 (0.6)0 treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS. Hyperglycemia (11.8) 16 (3.0) Chest wall pain 60 62 (11.4) 3 (0.6) 03 (0.6) Chest wall pain (11.4) 3 (0.6) Hypercalcemia 58 60 (11.0) 13 (2.5) 8 (1.5)0 Hypercalcemia (11.0) 8 (1.5) Hypophosphatemia 55 58 (10.5) 24 13 (2.5) (4.6) 3 (0.6) Hypophosphatemia 55 (10.5) 24 (4.6) 3 (0.6) Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080 a b National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

One event was Grade 5 severity.

U.S.South San Francisco, CA 94080 Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 b One event was Grade 5 severity.

U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012

have been reported in Guinea, Liberia, Nigeria, and Sierra Leone since the outbreak was first reported in March 2014.

“There is an urgent need for a protective Ebola vaccine, and it is important to establish that a vaccine is safe and spurs the immune system to react in a way necessary to protect against infection,” said NIAID Director Anthony S. Fauci, MD. “The NIH is playing a key role in accelerating the development and testing of investigational Ebola vaccines.”

There is an urgent need for a protective Ebola vaccine, and it is important to establish that a vaccine is safe and spurs the immune system to react in a way necessary to protect against infection.

—Anthony S. Fauci, MD

The investigational vaccine now entering phase I trials was designed by Nancy J. Sullivan, PhD, Chief of the Biodefense Research Section in NIAID’s Vaccine Research Center (VRC). She worked in collaboration with researchers at the VRC, the U.S. Army Medical Research Institute of Infectious Diseases, and Okairos, a Swiss-Italian biotechnology company acquired by GSK in 2013.

The phase I clinical trial, called VRC 207, is being led by Principal Investigator Julie E. Ledgerwood, DO, Chief of the VRC’s clinical trials program, and will be conducted among 20 healthy adults ages 18 to 50 years.

In parallel, NIH has partnered with an international consortium to test the same NIAID/GSK monovalent vaccine candidate. The vaccine candidate will be tested among 60 healthy volunteers at the University of Oxford in England and among 40 healthy volunteers in Mali by the University of Maryland School of Medicine Center for Vaccine Development and its Center for Vaccine Development in Mali.

For more information about these early-stage Ebola vaccine clinical trials, see www.niaid.nih.gov/news/QA/ Pages/EbolaVaxQA.aspx n

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Director’s Corner

National Cancer Institute Launches the National Clinical Trials Network to Expedite Scientific Advances A Conversation With Jeffrey S. Abrams, MD

By Jo Cavallo

Jeffrey S. Abrams, MD

I

n March, the National Cancer Institute (NCI) transformed its Cooperative Group Program into the National Clinical Trials Network (NCTN).

Spurred by recommendations in the Institute of Medicine (IOM) 2010 report, A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program, which called for modernization of the clinical trials system to leverage rapidly evolving scientific innovations, the NCTN endeavors to deliver a more efficient and streamlined approach to developing clinical trials.

While the Cooperative Group clinical trials system, in place since 1950, has produced many advances in oncology care, the IOM and other expert committees reviewing the program concluded that the 10 decentralized organizations (nine adult groups and one pediatric group), each with its own operations and statistical centers, tumor banks, and other scientific support services, needed to be restructured to meet the changes taking place in oncologic science, especially in the improved understanding of tumor biology and the promise of precision medicine.

As a result, the 10 former Cooperative Groups have been consolidated into four adult groups and one pediatric group in the NCTN. The five research groups are SWOG, Alliance, NRG Oncology, ECOG-ACRIN, and the Children’s Oncology Group (COG). The system also includes the Canadian Collaborating Clinical Trials Network. The NCTN centralized functions include a Centralized Institutional Review Board, a Cancer Trials Support Unit, an Imaging and Radiation Oncology Core (IROC) Group, and a Common Data Management System that is hosted centrally.

Recently, the NCI announced four precision medicine initiatives that the NCTN is undertaking. Two of the initiatives, Lung-MAP (a multidrug, multiarm, biomarker-driven clinical trial for patients with advanced squamous cell lung cancer) and ALCHEMIST (a trial investigating whether targeted epidermal growth factor receptor [EGFR] and anaplastic lymphoma kinase [ALK] inhibitors improve survival for adenocarcinoma of the lung in the adjuvant setting), have already launched.

In addition, the Exceptional Responders Initiative (a retrospective study investigating why a minority of patients with solid tumors or lymphoma have either a complete response or a very good partial response to a specific therapy while a majority of similar patients do not) is launching this month, and the

trials system with the National Clinical Trials Network.

The main reason the NCI felt it was appropriate to make the change is that the types of trials being done in oncology were changing. The improvement in diagnostics especially occasioned us to look for a smaller number of groups that could screen patients across the country to find those with the molecular alterations in their tumors who would be the best fit for the types of targeted therapies that are currently under development.

In addition, there was sufficient evidence that the prior system was inefficient and that improvement would require us to centralize some of the functions that had been spread among many different groups so we could better use the resources that were available.

We will have to have some decrease in our patient enrollment to compensate for the new activities, but I expect that we will continue to do many important trials with the available funding. Moreover, by selecting our patients for treatment more appropriately using better diagnostic tools, it is likely that our trials will not need as many patients to prove the effectiveness of a new intervention.

—Jeffrey S. Abrams, MD

NCI Match trial (which will examine whether molecular markers can predict response to targeted therapies in patients with advanced cancer resistant to standard treatment) is launching either at the end of the year or the beginning of 2015.

The ASCO Post talked with Jeffrey S. Abrams, MD, Acting Director for Clinical Research and Associate Director of the Cancer Therapy Evaluation Program (CTEP) in the Division of Cancer Treatment and Diagnosis at the NCI, about the new clinical trials system.

He also addressed the concern among some oncology societies, including ASCO1 and members of the NCTN Working Group, that the consolidation of the 10 oncology groups into 5 will result in reduced funding and fewer trials.

Restructuring Rationale Please talk about why the NCI decided to replace the Cooperative Group clinical

From both operational and scientific vantage points, it was felt that only a major restructuring could meet the intended goals.

System Improvements How will the new system improve the design and results of NCI clinical trials?

Before, we had 10 groups with their own operation centers and tumor banks, and we were duplicating a lot of functions. In coalescing these activities into only four adult groups and one pediatric group, we gain both consistency and streamlining, all of which should result in greater efficiency in getting the trials mounted and conducted.

In addition, we recognized that the financial resources for clinical trials were not likely to increase in the near future.

The federal budget committed to clinical trials has been flat for many years, and therefore, we needed a prioritization

process whereby only the most important trials—those that we felt would really impact clinical practice and change the standard of care—were the ones conducted with federal support.

So on top of this infrastructure change, we also instituted a series of steering committees in all major cancer types, such as gastrointestinal, gynecologic, urologic, and childhood cancers, that oversee the trials conceived by the five different groups. The groups themselves generate the ideas for these trials, but then each steering committee reviews the trial concepts and evaluates them to see if they are high enough priority to be done in the NCTN. Another important new feature of the revised system is a change in incentives.

Previously, groups were rewarded for leading their own trials and having a full portfolio of trials in every disease. Now, the emphasis is changed. All trials that get through the prioritization process are put on a common menu that is available online via our Cancer Trials Support Unit. These trials are then open to all the groups in the network, not just the group that originated the idea. Groups are rewarded for participation in each other’s trials and no longer have to maintain an open trial in every cancer type.

Our hope is that this change will mean that all the groups will contribute to the accrual process and that important questions will be answered more quickly.

Complementary Systems How will the NCTN trials differ from industry-sponsored trials?

NCTN trials are not primarily focused on getting a specific drug to market. They tend to study what is the best treatment approach for a specific cancer.

Sometimes that focus does involve new drugs, but it also often involves how to combine drugs with radiation therapy and surgery or how to move new diagnostic techniques into the field. Those are the types of trials that this network will conduct. Although there clearly is some overlap with areas that industry is interested in, and we often partner with industry, the difference in emphasis tends to make the private and public systems very complementary.

In addition, we frequently collect a lot of blood and tumor specimens on

ASCOPost.com | SEPTEMBER 15, 2014

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Director’s Corner

NCTN trials so we can understand how to select for the best therapy, appreciate what causes resistance to treatment, and learn about toxicity, all of which will help us prepare for the next trial.

That isn’t to say that industry doesn’t do this as well, but the big difference is that in the public system, all the information that is gained in clinical studies is made available to researchers around the world, whereas in industry-sponsored trials the information that is made public is more limited.

Precision Medicine Trials How will the NCTN system produce greater efficiency than the prior system to advance knowledge about cancer and more effective therapies?

Perhaps the best example of how we hope to accomplish those goals is with the four precision medicine trials we have planned: Lung-MAP, ALCHEMIST, Exceptional Respond­ ers, and NCI MATCH. The Lung-MAP trial is taking advantage of the fact that we now have a network that can screen a large number of patients looking for a subset of lung cancer. We will then send their tumor tissue to be sequenced using nextgeneration sequencing of their tumor DNA, find those with the relevant genetic abnormalities, and in one single trial be able to enroll them to the appropriate treatment arm. This approach is much more efficient compared to having five separate trials.

NCTN gives the clinical trials system much more flexibility to work in an integrated way, to find patients who have specific genetic abnormalities and efficiently move them into what we believe will be the best trial for them.

The ALCHEMIST trial is also novel because it is investigating patients with early-stage adenocarcinoma of the lung with uncommon EGFR or ALK gene alterations to determine if treating them with targeted drugs can cure some of those patients. These gene alterations only represent 10% to 15% of this subset of patients with adenocarcinoma of the lung, and we have to screen a lot of patients to find those who have the genetic changes for this trial. Having this streamlined network will not only allow us to do that, but it will also allow us to capture important genetic information on the 85% or so of patients who do not have these gene mu-

tations, as all patients in the trial will undergo genome sequencing.

We intend to follow these patients for up to 5 years. Over time, we will see what happens to them in terms of who has a cancer recurrence and who doesn’t. At the time of relapse, we will again sequence their tumors to learn about changes in the genetic makeup, which should provide clues regarding how best to treat them.

The Exceptional Responders Initiative is an exciting retrospective study.

We are looking for at least 100 people whose tumors responded very well to a particular therapy, while the majority of patients with that tumor type did not. By sequencing the genes in the tumors of these exceptional responders, we hope to learn why patients had this exceptional response to a specific drug.

This trial should provide new leads that can be further investigated in new clinical trials.

The last of the first wave of precision medicine trials to open is NCI MATCH. This trial is unique in that NCI is working with over 15 pharmaceutical companies to bring their new, targeted agents into a multiarm, single phase II trial.

Adult patients with advanced solid tumors or lymphoma who have progression of their cancer on standard therapy are eligible. They will have a fresh biopsy of their tumor that will undergo DNA sequencing for a panel of selected genetic alterations. Genetic changes in the tumors, irrespective of histology, will be matched to specific agents that target the abnormality. NCI MATCH is a discovery trial in that we hope to find new leads that can then be followed up in larger, phase II trials.

Funding Gap One of the concerns expressed by the NCTN Working Group and ASCO is a 3-month gap in funding for community oncology clinics engaged in institute-funded research through the Community Clinical Oncology Program. Has the issue been resolved?

Yes. That problem was brought to the attention of Harold E. Varmus, MD [Director of the National Cancer Institute] and to others who run that program in the Division of Cancer Prevention. They realized that although it was never intended to have a 3-month gap in funding, the issuance of the new

Harold E. Varmus, MD

program application deadline resulted in that possibility. Once the problem was brought to our attention, we rapidly contacted all the sites involved and assured them that there would be funding to cover the gap period.

Budget Reduction Another concern is that NCTN faces a 40% reduction in its operating budget.

How will that funding decrease affect trials currently underway or new trials being planned? Are there plans to make up the funding deficit through private partnerships?

In 2013, the prior Cooperative Group system had a budget of $151 million from NCI resources, and the new NCTN has exactly the same amount—$151 million. As we went through the reorganization process, it was determined that the NCTN would benefit from several new components that the prior Cooperative Group system did not have. For example, the NCTN now has lead academic participating site grants, which include 30 grants to major cancer centers that provide a lot of intellectual leadership for the NCTN groups.

We also developed an integrated translational science award that we hadn’t had before, and those grants went to seven cancer centers that are going to work on biomarkers for NCTN trials.

In addition, we included a new imaging and radiation oncology center for quality control of NCTN trials, and we had not had that component funded at the current level before.

To fund these new components of the NCTN program, the group operation and statistical centers received a reduction in the proportion of the money that went to them. Because they have received somewhat lower funding in order to enable the existence of these new components, the Groups may have to do fewer trials and enroll fewer patients. However, it will not be anything like 40%.

For instance, in 2014 we are targeting the enrollment of about 19,000 patients, whereas in 2013 we had about 21,000 patients. We will have to have some decrease in our patient enrollment to compensate for the new activities, but I expect that we will continue to do many important trials with the available funding. Moreover, by selecting our patients for treatment more appropriately using better diagnostic tools, it is likely that our trials will not need as many patients to prove the effectiveness of a new intervention.

It remains to be seen if the NCI budget situation will allow us to enroll more patients or at least get back to enrolling the same number of patients in future years.

Private Partners Is there a plan to partner with private groups for additional funding?

Most definitely. The Lung-MAP trial, for example, is a partnership trial with the Friends of Cancer Research and Foundation Medicine, along with several major pharmaceutical partners. We have partnered with industry and philanthropic groups on many of our trials, not just recently, but in past years as well.

Moving forward, we intend to increase our collaborations with both industry and the advocacy community, as well as any philanthropic group that wants to help support cancer research.

Positive Signs What has been the reaction by the various stakeholders to the NCTN so far?

It’s a little too early to say how all this is going to work out. Sometimes people are very eager to get results, but the NCTN is brand new and only just received funding in March of this year.

So far we have been very pleased with the collaboration among the investigators. When you attend Cooperative Group meetings now, the researchers seem quite enthusiastic and collaborative, with many innovative trials coming forward, so those are all positive signs. n

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

Reference 1. Hudis CA: Cancer clinical trials, patients’ access to care threatened by NCI budget decisions: ASCO statement. Posted April 4, 2014. Available at www.asco.org.

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The ASCO Post | SEPTEMBER 15, 2014

PAGE 90

Journal Spotlight Breast Cancer

Adding Tomosynthesis to Digital Mammography Decreased Recall Rate, Increased Cancer Detection Rate in Breast Cancer Screening

By Matthew Stenger

I

n a large multicenter study reported in JAMA, Sarah M. Friedewald, MD, of the Advocate Lutheran General Hospital, Center for Advanced Care, Park Ridge, Illinois, and colleagues found that use of tomosynthesis plus digital mammography reduced the recall rate and increased the cancer detection rate in breast cancer screening compared with digital mammography alone.1 Tomosynthesis provides image acquisition from an x-ray source that moves over an arc of excursion and permits reconstruction into thin slices to

ing before and after introduction of tomosynthesis at 13 U.S. institutions over two periods. Period 1 consisted of 1 full year of screening with digital mammography alone that ended on the date of tomosynthesis introduction at each institution. Period 2 consisted of screening with tomosynthesis plus digital mammography until December 31, 2012. The start dates of period 2 ranged from March 2011 to October 2012. The average duration of period 2 was 17 months (range, 3–22 months).

For tomosynthesis, all 13 sites used

Addition of tomosynthesis to digital mammography was associated with a decrease in recall rate and an increase in cancer detection rate. Further studies are needed to assess the relationship to clinical outcomes.

—Sarah M. Friedewald, MD, and colleagues

minimize the effect of overlapping breast structures. The device can be used simultaneously with conventional digital mammography. Single-institution studies have indicated that tomosynthesis plus mammography increases cancer detection and reduces false-positive rates vs mammography alone.

Study Details This retrospective study compared performance of breast cancer screen-

the Selenia Dimensions device (Hologic), the only U.S. Food and Drug Administration–approved device at the start of the study. Outcome measures consisted of recall rate for additional imaging, biopsy rate, cancer detection rate, and positive predictive values for recall and biopsy. Outcomes were assessed using mixed models adjusting for site as a random effect.

Totals of 281,187 digital mammograms and 173,663 tomosynthesis/

Tomosynthesis Plus Digital Mammography ■■ The addition of tomosynthesis to digital mammography was associated with a decrease in recall rate, an increase in biopsy rate, and increases in cancer detection and invasive cancer detection rates.

■■ Positive predictive values for recall and biopsy were significantly improved with tomosynthesis/digital mammography.

digital mammograms were evaluated by 139 radiologists. The volume of examinations across institutions ranged from 4,801 to 53,181 for digital mammography alone and from 2,613 to 34,119 for tomosynthesis/digital mammography. Mean ages were 57.0 years in the digital mammography group and 56.2 years in the tomosynthesis/digital mammography group.

Recall, Biopsy, and Detection Rates Among women undergoing digital mammography alone, 29,726 were recalled, 5,056 underwent biopsy, and cancer was diagnosed in 1,207, including invasive cancer in 815 and ductal carcinoma in situ in 392.

Among women undergoing tomosynthesis/digital mammography, 15,541 were recalled, 3,285 underwent biopsy, and cancer was diagnosed in 950, including invasive cancer in 707 and ductal carcinoma in situ in 243.

Model-adjusted rates per 1,000 screens for digital mammography vs tomosynthesis/digital mammography were: 107 vs 91 for recalls (difference

Table 1: Model-Adjusted Rates per 1,000 Screens: Digital Mammography vs Tomosynthesis/Digital Mammography Digital Mammography vs Tomosynthesis/ Digital Mammography

Difference (CI)

Recalls

107 vs 91

−16 CI = −18 to −14, P < .001

Biopsies

18.1 vs 19.3

1.3, CI = 0.4 to 2.1, P = .004

Cancer detection

4.2 vs 5.4

1.2, CI = 0.8 to 1.6, P < .001

Invasive cancer detection

2.9 vs 4.1

1.2, CI = 0.8 to 1.6, P < .001)

Ductal carcinoma in situ detection

1.4 vs 1.4

0.0, CI = −0.2 to 0.2, P = .1

Positive Predictive Values Digital Mammography vs Tomosynthesis/ Digital Mammography

Difference (CI)

Recalls

4.3% vs 6.4%

2.1%, CI = 1.7%–2.5%, P < .001

Biopsies

24.2% vs 29.2%

5.0%, 95% CI = 3.0%–7.0%, P < .001

CI = confidence interval

= −16, 95% confidence interval [CI] = −18 to −14, P < .001); 18.1 vs 19.3 for biopsies (difference = 1.3, 95% CI = 0.4 to 2.1, P = .004), 4.2 vs 5.4 for cancer detection (difference = 1.2, 95% CI = 0.8 to 1.6, P < .001), 2.9 vs 4.1 for invasive cancer detection (difference = 1.2, 95% CI = 0.8 to 1.6, P < .001), and 1.4 vs 1.4 for ductal carcinoma in situ detection (difference = 0.0, 95% CI = −0.2 to 0.2, P = .95).

Changes per 1,000 screens by study site with tomosynthesis/digital mammography vs digital mammography ranged from −42 to 18 for recalls, −6.3 to 10.5 for biopsies, −1.5 to 3.7 for cancers detected, −0.9 to 3.0 for detection of invasive cancers, and −0.7 to 0.7 for detection of ductal carcinoma in situ.

Positive Predictive Values The positive predictive value for digital mammography vs tomosynthesis/ digital mammography was 4.3% vs 6.4% for recalls (difference = 2.1%, 95% CI = 1.7%–2.5%, P < .001) and 24.2% vs 29.2% for biopsies (difference = 5.0%, 95% CI = 3.0%–7.0%, P < .001). Changes in positive predictive value by study site with tomosynthesis/digital mammography vs digital mammography ranged from −3.2% to 4.8% for recalls and from −6.9% to 27.8% for biopsies.

The investigators concluded, “Addition of tomosynthesis to digital mammography was associated with a decrease in recall rate and an increase in cancer detection rate. Further studies are needed to assess the relationship to clinical outcomes.” n

Disclosure: The study was supported by a grant from the National Cancer Institute and

by Hologic. For full disclosures of the study authors, visit jama.jamanetwork.com.

Reference 1. Friedewald SM, Rafferty EA, Rose SL, et al: Breast cancer screening using tomosynthesis in combination with digital mammography. JAMA 311:24992507, 2014.

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 91

Perspective

Breast Cancer Screening Using Tomosynthesis in Combination With Digital Mammography

By Gary J. Whitman, MD

I

n a study reported in JAMA and reviewed in this issue of The ASCO Post, Friedewald and colleagues1 showed that the addition of tomosynthesis to digital mammography2 resulted in a decrease in the screening recall rate3 and an increase in the cancer detection rate.4,5 This retrospective analysis of screening mammography performance was conducted at 13 sites (8 nonacademic and 5 academic).

Hybrid Study Sites In this study, 454,850 examinations (281,187 digital mammography alone and 173,663 digital mammography combined with tomosynthesis) were evaluated. The introduction of tomosynthesis at the 13 sites was nonuniform. Two sites made a complete conversion for screening from digital mammography to digital mammography combined with ­tomosynthesis.

The other 11 sites maintained a hybrid environment, with some patients receiving digital mammography alone while the study patients underwent digital mammography combined with tomosynthesis. At the 11 sites with hybrid screening environments, the possibility of selection bias existed.

At the 11 hybrid sites, there were 245,985 concurrent cases with digital mammography alone during the same time period in which 173,663 screening examinations were performed with digital mammography combined with tomosynthesis. During that period, there was a statistically significant improvement in cancer detection of 0.6 cases per 1,000 examinations (P < .001) along with a decrease in the recall rate of 5.4 cases per 1,000 studies (P < .001) for the women who underwent digital mammography combined with tomosynthesis compared to digital mammography alone.

Recall Rate The recall rate for screening with digital mammography alone was 10.7%, compared to 9.1% for digital mammography combined with tomoDr. Whitman is Professor in the Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston.

synthesis (P < .001). The recall rate decreased for digital mammography combined with tomosynthesis compared to digital mammography alone at all but two sites—the site with the lowest tomosynthesis volume and the site with the fourth lowest tomosynthesis volume. These two low-volume sites also had the most and the second most radiologists interpreting the studies—20 radiologists at one site and 18 radiologists at the other site.

These findings suggest that there is a learning curve for interpreting tomosynthesis studies.

Cancer Detection The cancer detection rate was 4.2 cancers per 1,000 examinations for digital mammography and 5.4 cancers per

examinations with digital mammography alone and 0.55 cases per 1,000 examinations with digital mammography plus tomosynthesis. For invasive ductal carcinoma combined with invasive lobular carcinoma, the detection rate with digital mammography was 0.14 cases per 1,000 examinations. When tomosynthesis was added to digital mammography, the detection rate for invasive ductal carcinoma combined with invasive lobular carcinoma was 0.17 cases per 1,000 studies.

Twelve of 13 sites demonstrated an increased detection rate for invasive cancer with the addition of tomosynthesis. The single site that did not report an increased detection rate for cancer or invasive cancer with tomosynthesis had the highest number of

The increased invasive cancer detection rate with tomosynthesis is likely to be of great value in optimizing screening outcomes.

—Gary J. Whitman, MD

1,000 studies for digital mammography combined with tomosynthesis (P < .001). Twelve of the 13 sites showed increased cancer detection rates with the addition of tomosynthesis. Eleven of the 13 sites simultaneously increased cancer detection rates and decreased recall rates when tomosynthesis was added to digital mammography for breast cancer screening.

Histopathology When the cancers were classified according to histopathology, the invasive cancer detection rate was 2.9 cancers per 1,000 examinations for digital mammography alone and 4.1 cancers per 1,000 examinations for digital mammography combined with tomosynthesis. The invasive ductal carcinoma detection rate increased from 2.46 cases per 1,000 examinations with digital mammography to 3.27 cases per 1,000 when tomosynthesis was combined with digital mammography.

For invasive lobular carcinoma, the detection rate was 0.27 cases per 1,000

study radiologists (20) and the lowest number of tomosynthesis examinations (2,613).

The detection rate for ductal carcinoma in situ was 1.4 cases per 1,000 examinations for digital mammography combined with tomosynthesis and for digital mammography alone.

‘Win-Win’ With the addition of tomosynthesis, the investigators, in both academic and nonacademic settlings, recalled fewer patients yet found more cancers.

These findings are a real “win-win,” indicating that the relative yield for each recall increases with the introduction of tomosynthesis.

The positive predictive value for recall, the likelihood of cancer diagnoses in women recalled for additional imaging, increased from 4.3% to 6.4% with the addition of tomosynthesis.

Although the addition of tomosynthesis led to an increase in the biopsy rate (from 18.1 per 1,000 cases to 19.3 per 1,000 cases), it also led to a 5% increase

in the positive predictive value for biopsy, the proportion of cancers found in women undergoing biopsies based on screening-detected findings, from 24.2% to 29.2%.

This study showed that adding tomosynthesis to digital mammography leads to the detection of more invasive cancers without decreasing the detection rate for ductal carcinoma in situ. Tomosynthesis combined with digital mammography should allow for the identification of more subtle and/or obscured masses, which may be invasive cancers, without failing to identify suspicious calcifications, which may represent ductal carcinoma in situ.

The increased invasive cancer detection rate with tomosynthesis is likely to be of great value in optimizing screening outcomes, since the mortality reduction associated with mammographic screening is thought to be based on the identification and appropriate treatment of small, asymptomatic invasive cancers before they have had the opportunity to ­metastasize. n

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

References 1. Friedewald SM, Rafferty EA, Rose SL, et al: Breast cancer screening using tomosynthesis in combination with digital mammography. JAMA 311:2499-2507, 2014.

2. Pisano ED, Gastonis C, Hendrick E, et al: Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med 353:17731783, 2005.

3. Haas BM, Kalra V, Geisel J, et al: Comparison of tomosynthesis plus digital mammography and digital mammography alone for breast cancer screening. Radiology 269:694-700, 2013.

4. Ciatto S, Houssami N, Bernardi D, et al: Integration of 3D digital mammography with tomosynthesis for population breastcancer screening (STORM): A prospective comparison study. Lancet Oncol 14:583589, 2013.

5. Caumo F, Bernardi D, Ciatto S, et al: Incremental effect from integrating 3D-mammography (tomosynthesis) with 2D-mammography: increased breast cancer detection evident for screening centres in a population-based trial. Breast 23:76-80, 2014.

The ASCO Post | SEPTEMBER 15, 2014

PAGE 92

Journal Spotlight Breast Cancer

Study Finds Increased Breast Cancer Screening Costs in Medicare Population but No Increase in Cancer Detection

By Matthew Stenger

I

n a study of the use of breast cancer screening modalities in the Medicare population reported in Journal of the National Cancer Institute, Brigid K. Killelea, MD, MPH, FACS, and colleagues at Yale University School of Medicine, Yale Cancer Center, and Yale–New Haven Hospital, New Haven, Connecticut, found significant increases in use of digital image acquisition and computer-aided detection and significantly increased cost of screening between 2001–2002 and 2008–2009 but no difference in breast cancer incidence rates between the two time periods (of detection of early-stage or any-stage cancer during 2 years of folllow-up in the early and later cohorts).1

Overall, the use of screening mammography increased from 42.0% in the early cohort to 42.6% in the later cohort (P < .001). Large increases were observed in the use of digital image acquisition, from 2.0% to 29.8% (P <

In this large, population-based study we observed a 47% increase in percapita costs associated with breast cancer screening among Medicare beneficiaries from 2001 through 2009 without a statistically or clinically significant difference in the incidence of early-stage breast cancer.

—Brigid K. Killelea, MD, MPH, FACS, and colleagues

Study Details In the study, early (2001–2002) and late (2009–2009) cohorts of women aged ≥ 66 years without a history of breast cancer were derived from Medicare’s 5% random sample

.001), and the use of computer-aided detection, from 3.2% to 33.1% (P < .001), whereas the use of film screening mammography decreased from

Breast Cancer Screening Costs and Impact ■■ Use of digital image acquisition and computer-aided detection and screening-related costs increased significantly between 2001–2002 and 2008–2009.

■■ No significant increase in rate of detection of early-stage tumors was observed.

of beneficiaries who lived in a particular Surveillance, Epidemiology, and End Results (SEER) region. Each cohort was followed for 2 years, and women with incident breast cancer were identified.

In total, there were 137,150 women in the early cohort and 133,097 women in the later cohort. The early cohort had a younger mean age (76.0 vs 77.3 years, P < .001) and fewer comorbidities (≥ 3 comorbidities in 10.8% vs 15.6%, P < .001).

use of digital imaging increasing from 0.2% to 5.5% and use of computeraided detection increasing from 0.1% to 4.0% in this setting (P < .001 for both).

Breast ultrasound use increased from 4.0% to 4.9% and magnetic resonance

40.0% to 12.9% (P < .001).

Approximately one-third of women aged ≥ 75 years received screening mammography in both cohorts (32.4% vs 32.6%, P = .35), and the increases in use of digital image acquisition and computer-aided detection in these older women were similar to women under age 75.

Use of diagnostic mammography increased from 5.3% in the early cohort to 7.1% in the later cohort (P < .001), with

imaging use increased from 0.03% to 0.3% (P < .001 for both).

The biopsy rate decreased from 2.0% to 1.7% (P < .001). Use of other imaging techniques decreased from 1.8% to 1.5% (P < .001).

Cost Implications Screening-related cost per capita, including screening and workup procedures, increased from $76 in the early cohort to $112 in the later cohort (47.4% increase, P < .001).

The increase represents an absolute increase in Medicare spending from $666 million in the early period to $962 million in the later period (44% increase). The increased use of digital image acquisition and computer-aided detection contributed most to the increased total cost.

The cost of breast biopsy did not change over the study periods ($23 and $25, P = .75). Screening-related cost per capita increased from $101 to $150 in women aged 67 to 74 years

(50% increase, P < .001) and from $58 to 83$ in women aged ≥ 75 years (43% increase, P < .001).

Detection Rates There were no changes in cancer detection rates between the early and later cohorts overall or by disease stage. The overall incidence rates were 4.22 vs 4.30 per 1,000 person-years for any-stage breast cancer (adjusted rate ratio = 1.04, 95% confidence interval [CI] = 0.96–1.14), 2.45 vs 2.57/1,000 person-years for early stage (in situ and stage I) disease (adjusted rate ratio = 1.07, 95% CI = 0.96–1.20, P = .41), and 0.20 vs 0.23/1,000 personyears for late stage (stage IV) disease (adjusted rate ratio = 1.24, 95% CI = 0.85–1.82). There was no significant change in stage distribution or tumor size over time among the women diagnosed with breast cancer.

The investigators concluded: “In this large, population-based study we observed a 47% increase in per-capita costs associated with breast cancer screening among Medicare beneficiaries from 2001 through 2009 without a statistically or clinically significant difference in the incidence of early-stage breast cancer.”

Cary P. Gross, MD, of Yale University School of Medicine, is the corresponding author for the Journal of the National Cancer Institute article. n

Disclosure: The study was by the National Cancer Institute Comprehensive Cancer Center. disclosures of the study authors, oxfordjournals.org.

supported and Yale For full visit jnci.

Reference 1. Killelea BK, Long JB, Chagpar AB, et al: Evolution of breast cancer screening in the Medicare population: clinical and economic implications. J Natl Cancer Inst 106(8):dju159, 2014.

More on Breast Cancer Screening Costs See page 95 for a report on the editorial by Kerlikowske et al published with the Killelea et al report in the Journal of the National Cancer Institute.

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ASCOPost.com | SEPTEMBER 15, 2014

PAGE 95

Perspective

EXPERT POINT OF VIEW

I

n an accompanying editorial,1 Karla Kerlikowske, MD, of the University of California, San Francisco, and colleagues point out that while the finding of Killelea et al that digital mammography screening was not associated with downstaging of disease may not be surprising, given the similar accuracy of digital and film screening for cancer detection in older woman that has been observed

with film screening, and there is no convincing evidence to support use of computer-aided detection (which increased from 3.2% to 33.1% in the Killelea et al study).

As the commentators stated, “Thus, the transition to digital breast cancer screening in the US has increased screening mammography costs for possibly small or no health gains, resulting in screening mammog-

To be responsible advocates for high-quality medical care, our enthusiasm for new technologies should not replace strong, consistent evidence that the benefits of the new technology outweigh the harms in a clinically important way.

—Karla Kerlikowske, MD, and colleagues

elsewhere, the data are reassuring insofar as they suggest little evidence of increased harms with the shift to digital mammography.

They note that the study showed a small increase in diagnostic mammography and a small decrease in biopsy rates, suggesting that overdiagnosis has not been increased. However, they also emphasize that the increased costs associated with the use of digital mammography and computer-aided detection are troubling and require addressing if principles of high-quality care are to be upheld.

Reduced Cost Efficiency The commentators point out that the Killelea et al study adds to the literature indicating higher costs of digital mammography without clear added benefit in women aged ≥ 65 years.

Although some data suggest a small health gain at increased cost among women aged 50 to 79 years with biennial digital screening, other data indicate no overall benefit compared

raphy being less cost efficient than in the past.” This reduced cost efficiency has to be viewed in the context of the huge cost of mammography screening in the United States (estimated at $7.8 billion in 2010) and the fact that

overall numbers of screenings, falsepositives, and biopsies, as well as cases of overdiagnosis. The commentators state that breast imaging registries and organized screening programs are suited for use in evaluating riskbased strategies, given the risk factor data collected by these programs and the ability to link such data with outcomes.

Second, risk-based screening could also include strategies to discontinue screening in older women who are unlikely to benefit from screening. The commentators note that 55% of the Medicare patients in the Killelea et al study were aged ≥ 75 years and that > 40% had at least one comorbidity. However, there is no randomized trial evidence indicating a benefit of screening in women aged ≥70 years.

In this regard, the commentators cite findings of the Swedish TwoCountry trial, which showed no statistically significant reduction in breast cancer mortality among women aged 70 to 74 years screened every 24 to 33 months, a U.S. modeling study showing approximately two additional breast cancer deaths prevented per

Breast Cancer Screening and Cost ■■ The transition to digital mammography appears to reduce costefficiency of screening.

■■ Risk-based screening strategies may improve the overall performance of screening.

Medicare reimburses more for digital than film screening.

Risk-Based Screening Kerlikowske and colleagues suggest approaches to address this situation based on risk-based screening. First, the frequency of screening could be reduced using a risk-based approach in which low-risk women could stop screening or be screened at greater intervals, thus reducing the

1,000 women undergoing biennial screening from ages 70 to 74 years, and a recent study indicating that biennial vs annual screening did not increase risk of advanced-stage tumor incidence and reduced false-positive rates among women aged 66 to 89 years. They further point out that the benefit of screening is likely reduced among older women with moderate or severe comorbidities and limited life expectancy, whereas the harms

likely increase, since risk of overdiagnosis increases with age.

Thus, Dr. Kerlikowske and coauthors propose: “Risk-based screening that incorporates defined stopping ages based on breast cancer risk in combination with comorbidities and life expectancy may further improve the balance of benefits vs harms for older women, because screening would not be offered to elderly women with limited life expectancy who are unlikely to benefit.”

Conclusions The commentators concluded: “To be responsible advocates for highquality medical care, our enthusiasm for new technologies should not replace strong, consistent evidence that the benefits of the new technology outweigh the harms in a clinically important way. Once manufacturers demonstrate at least comparable performance, timely evaluation of emerging technologies using breast imaging registry risk factor and performance data can provide important comparative effectiveness evidence for guiding clinical applications.”

They note that efforts in this regard will be particularly important in evaluating whether tomosynthesis—“the newest breast cancer screening technology rapidly diffusing into community practice with minimal comparative effectiveness evidence”—provides any clinically important benefits over digital mammography. n

Disclosure: The work was supported

by National Cancer Institute-funded Breast Cancer Surveillance Consortium grants. The study authors reported no potential conflicts of interest.

Reference 1. Kerlikowske K, Hubbard R, Tosteson ANA: Higher mammography screening costs without appreciable clinical benefit: the case of digital mammography. J Natl Cancer Inst 2014; doi:10.1093/jnci/dju191.

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | SEPTEMBER 15, 2014

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Pioneers in Oncology Immunotherapy Research of James P. Allison, PhD, Has Led to a Paradigm Shift in the Treatment of Cancer

By Jo Cavallo

James P. Allison, PhD

J

ames P. Allison, PhD, has been bucking the status quo since he was a teenager growing up in the small agricultural town of Alice, Texas, in the 1950s and 1960s. He first butted heads with authority figures when he was in high school and learned that his biology class had omitted the teaching of evolution for religious reasons. He refused to take the class.

“I had the sense that trying to teach biology without Darwin was like trying to teach physics without Newton, and I said, ‘I’m not going to do it,’” said Dr. Allison. The incident caused such an uproar, the matter was taken up by the school board.

Eventually, a compromise was reached when a trusted school counselor suggested that Dr. Allison, then a senior, take a correspondence course in biology from The University of Texas. Although the incident was eventually settled amicably, the controversy did not make Dr. Allison popular with the other students or teachers. Studying alone in a classroom near the school gymnasium, he was often berated and taunted by coaches as he passed through the halls.

That sense of independence, dogged determination, and refusal to accept conventional wisdom would later lead Dr. Allison to scientific discoveries that have altered the treatment of cancer.

Early Influencers Born on August 7, 1948, to Albert and Constance Allison, Dr. Allison is the youngest of three brothers. While Dr. Allison credits his father, an eye, ear, nose, and throat specialist, with sparking an early interest in medicine, it was the influence of his 8th grade math teacher and his high school guidance counselor that steered him to a career in science.

“Growing up in a small rural town that

did not foster a lot of academic interest, I was really lucky to be inspired by these two people,” said Dr. Allison.

At the age of 15, Dr. Allison was accepted into a National Science Foundation–funded summer science-training program at The University of Texas at Austin (UT Austin) and graduated from high school the following year. Although he had planned to study medicine at UT Austin, a part-time job he got washing glassware in the college laboratory convinced him to switch to science.

“I realized that going the premed route meant memorizing a lot of information, and as a doctor, you can’t make mistakes—you have to know what to do,” said Dr. Allison. “As a scientist, you are supposed to make mistakes and hypothesize, then test the hypotheses. To me, that was a hell of a lot more fun than following algorithms, so I dropped premed. Plus, my grades in organic chemistry sucked,” he laughed.

Family History of Cancer Dr. Allison lost his mother to lymphoma when he was 11, followed by the deaths of her two brothers (one to lung cancer and the other to melanoma) a few years later. Although he maintained that the experience did not inspire him

Dr. Allison would lose another family member, his brother Mike, to prostate cancer in 2005, and received his own diagnosis of the disease that same year.

Rebel With a Cause After earning his bachelor’s degree in microbiology and his doctorate in biological sciences from UT Austin, Dr. Allison went to Scripps Clinic and Research Foundation near San Diego, for his postdoctoral fellowship. He returned to Texas the following year to take a faculty appointment at MD Anderson’s Science Park in Smithville, where he stayed for 8 years, studying the immune system.

In 1982, while working at The University of Texas System Cancer Center, Dr. Allison made a pivotal discovery that has become the cornerstone of his life’s work: he identified the T-cell antigen receptor, which allows T cells to recognize an unusual protein on the surface of another cell. Six years later, while a Professor in the Division of Immunology and Director of the Cancer Research Laboratory at the University of Berkeley in California, Dr. Allison demonstrated that the molecule CD28 is the “gas pedal” that T cells need for activation.

I was a basic scientist, a mouse guy, but I had the feeling that this type of therapy, which totally ignored the tumor cell and was completely reliant on the immune system, was a new approach to treating cancer.

—James P. Allison, PhD

to specialize in cancer research, he admits that witnessing the devastation wrought by radiation and chemotherapy later led him to consider immunotherapy as a much more effective and less toxic weapon against the disease.

“My mother had years of radiation therapy that left her skin burned and her body gaunt,” said Dr. Allison. “I then watched my uncle who had lung cancer waste away on chemotherapy. Another uncle who had melanoma refused therapy altogether because he had seen what happened to his sister and brother. So I was acutely aware of how ugly cancer therapy can be. As I got interested in immunology, I thought, ‘I bet we can use the immune system to treat cancer.’”

“Ron Schwartz, MD, PhD [Chief, Laboratory of Cellular and Molecular Immunology, and Chief, T-Cell Activation Section of the National Institutes of Health’s National Institute of Allergy and Infectious Diseases] and Marc ­Jenkins, PhD [Distinguished McKnight University Professor at the University of Minnesota Medical School’s Microbiology, Immunology, and Cancer Biology Program] had postulated that the T-cell antigen receptor signal was not sufficient to activate T cells. They needed costimulatory signals,” said Dr. Allison.

“I took clues from that and decided to test the notion, based on work by Jeff ­Ledbetter, PhD [Research Professor of Medicine, Division of Rheumatology at

the University of Washington Medicine] and Craig Thompson, MD [President and Chief Executive Officer at Memorial Sloan Kettering Cancer Center], that CD28 might be the cosignatory receptor. I found that it was.”

In 1996, Dr. Allison and another investigator, Jeffrey Bluestone, PhD [Executive Vice Chancellor and Provost at the University of California, San Francisco] identified CTLA-4 as an inhibitory checkpoint molecule, which restricted activated T-cell responses.

Dr. Allison then proposed that blocking CTLA-4 would enhance activation of T-cell responses against cancer, essentially taking the brake off the immune system, which it did.

While most researchers investigating cancer immunology were advocating vaccines to turn “on” T cells to drive antitumor immune responses, Dr. Allison was proposing the opposite—to block the “off ” signal. In murine studies of an antibody he developed against CTLA4, Dr. Allison found that 90% of the cancers in the treated mice disappeared.

That discovery led to a paradigm shift in immunotherapy research.

A human version of the antibody he used in his laboratory studies became ipilimumab (Yervoy), the first of a new class of drugs known as immune checkpoint inhibitors. In 2011, after a large randomized phase III trial of ipilimumab in patients with advanced melanoma showed a huge survival benefit—the first drug ever to do so—the U.S. Food and Drug Administration approved ipilimumab in the treatment of metastatic melanoma.

While statistics show that about 25% of patients with advanced-stage melanoma who took ipilimumab in clinical trials have lived 5 years or longer, more recent studies show prolonged immune responses and longer overall survival in some patients, especially when ipilimumab is combined with the investigational drug nivolumab. A study presented at last year’s ASCO Annual Meeting found that patients with advanced melanoma who were treated with a combination regimen of ipilimumab and nivolumab had a nearly 50% response survival rate.1

New Treatment Approach In 2004, Dr. Allison left Berkeley to become Chair of the Immunology Program and Director of the Ludwig

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Pioneers in Oncology Center for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center in New York, because he wanted to be involved in the human trials for ipilimumab being conducted at the cancer center—and gain credibility in the field.

“I was a basic scientist, a mouse guy, but I had the feeling that this type of therapy, which totally ignored the tumor cell and was completely reliant on the immune system, was a new approach to treating cancer. All of our mouse studies showed that the tumors grew before they regressed, because you are not treating the tumors, you are treating the immune system. I went to Memorial because I felt that if I didn’t insinuate myself into the process in an institution that had credibility, I would always be an observer and not a participant,” said Dr. Allison.

In 2012, he moved back to Texas to become Professor and Chair of the Department of Immunology, Executive Director of the Moon Shots Immunotherapy Platform, and Deputy Director of the David H. Koch Center for Applied Research of Genitourinary Cancers at The University of Texas MD Anderson Cancer Center. Dr. Allison and his colleagues are now investigating ipilimumab and other immune checkpoint inhibitors in the treatment

of melanoma, lymphoma, and lung, breast, gastric, kidney, and prostate cancers.

Dr. Allison has been recognized for his breakthrough research in cancer immunology with numerous awards. In 2013, Science magazine named cancer immunotherapy its Breakthrough of the Year, citing Dr. Allison’s work as crucial to immunotherapy’s rapid advancement, and The Economist honored him with its Innovations Award in Bioscience. Most recently, Dr. Allison received the SzentGyörgyi Prize, the Canada Gairdner International Award, the American Association for Cancer Research GHA Clowes Memorial Award, and the first Tang Prize for Biopharmaceutical Science, for opening “a new therapeutic era in medicine.”

Immunologist Turned Rock Star When Dr. Allison is not in the lab, he is playing harmonica and singing backup with The Checkpoints, a rock/blues band made up of other prominent immunologists and oncologists, including Thomas Gajewski, MD, PhD, Professor in the Department of Pathology at The University of Chicago, Rachel W. Humphrey, MD, Senior Vice President, Head of Immuno-Oncology at Astra-Zeneca,

James Allison performs with The Checkpoints.

Dirk Spitzer, PhD, Research Instructor of Surgery at Siteman Cancer Center, Pat Hwu, MD, Chair and Professor in the Department of Melanoma Medical Oncology at MD Anderson Cancer Center, and Keith Bahjat, PhD, Director, Laboratory of Immunologic Monitoring at Earle A. Chiles Research Institute.

In June, while the band members were in Chicago for ASCO’s Annual Meeting, they got together to play at the Society for Immunotherapy of Cancer’s 2014 Cancer Immunotherapy Fundraiser at the House of Blues. The event was sold out.

Dr. Allison’s love of music dates back to his postdoctoral days at the Scripps Clinic and Research Foundation in San Diego, when he played harmonica

with the Texas Honky Tonk Band at the Stingaree bar. The highlight of his music career came when country legend Willie Nelson appeared at the Stingaree and invited Dr. Allison to accompany him on “Blue Eyes Crying in the Rain,” a single from Nelson’s hit album The Red Headed Stranger.

“It was only that one song and that one night, but I’ll never forget it,” said Dr. Allison. n Reference 1. Wolchok JD, Kluger HM, Callahan MK, et al: Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients with advanced melanoma.

2013 ASCO Annual Meeting. Abstract 9012. Presented June 2, 2013.

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

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The ASCO Post | SEPTEMBER 15, 2014

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Announcements

UNC Lineberger Secures Three Major NCI Grants to Advance the Nation’s Clinical Trials Program

A

t the national level, clinical trials are seeing a lot of change. In an effort to increase efficiency and keep up with national changes in the types of clinical trials offered to cancer patients, the National Cancer Institute’s (NCI) National Clinical Trials Network (NCTN) is undergoing a major reorganization.

The new structure is meant to improve treatment for the more than 1.6 million Americans diagnosed with cancer each year and UNC Lineberger will be playing a major role in this transition.

into a network focused on experimental clinical trials, the NCI’s Experimental Therapeutics Clinical Trials Network. Led

by Claire Dees, MD, teaming with trialists at Duke and Washington University, UNC

Lineberger will conduct early-phase cancer clinical trials sponsored by the NCI to help speed the drug development process.

UNC Lineberger is one of five institutions across the country receiving a new

grant to measure biomarkers within the NCTN as an Integrated Translational Science Center (ITSC). The UNC ITSC will be spearheaded by Chuck Perou, MD, and Neil Hayes, MD. n

Leadership, Research in Drug Delivery, Genetic Sequencing The NCI awarded grants related to the new clinical trials infrastructure in the spring of 2014, and University of North Carolina (UNC) Lineberger secured three major new grants as a part of this initiative. “Receiving one of these

Ned Sharpless, MD

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Lisa Carey, MD

awards is an important accomplishment,” said UNC Lineberger Director Ned Sharpless, MD. “Receiving all three is truly remarkable.” Through these grants, UNC Lineberger will be providing scientific leadership into the development of the new network, will be working to accelerate drug delivery in early phase I trials, and will also be providing genetic sequencing in support of NCTN. As a part of the first grant, UNC Lineberger will serve as one of 30 NCI Lead Academic Participating Sites (LAPS) from across the country. Under the guidance of Lisa Carey, MD, UNC Lineberger will provide NCI with scientific leadership in the development and implementation of clinical trials.

The cancer center also secured entry

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Announcements

Moffitt Appoints Louis B. Harrison, MD, New Chair, Radiation Oncology

L

ouis B. Harrison, MD, has joined Moffitt Cancer Center in Tampa as Chair of the Department of Radiation Oncology, and Senior Member. Moffitt’s Radiation Oncology program includes faculty of cancer specialists who provide comprehensive

cancer care for tumors at all anatomical locations, as well as an array of clinical research trials aimed at improving outcomes by seeking more personalized approaches to care.

“Dr. Harrison is an internationally recognized and extensively pub-

lished expert in the areas of head and neck cancer, sarcomas, and intraoperative brachytherapy. His leadership will help provide our patients with the most innovative radiation oncology care,” said Douglas ­Letson, MD, Physician-in-Chief and Ex-

ecutive Vice President at Moffitt.

Dr. Harrison is a Fellow of the American Society for Radiation Oncology ­(ASTRO) and he has served ASTRO as a former Board Member, Chairman of the Board, and the Society’s President. Dr. Harrison has been a former President and Board Member of both the American Brachytherapy Society and the International Society for Intraoperative Radiation Therapy. He

Louis B. Harrison, MD

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currently serves on the Boards of the Radiation Oncology Institute and the Eastern division of the American Cancer Society.

“It is a true privilege to join one of America’s most respected cancer centers, and I believe Moffitt is poised to make important discoveries and contributions to cancer care and research.

I am looking forward to working with the faculty and staff at Moffitt to enhance the Radiation Oncology Program, and foster new discoveries and improvements to cancer care,” said Dr. Harrison.

Clinician, Administrator, Researcher Prior to joining Moffitt, Dr. Harrison served as the Physician-in-Chief for the Continuum Cancer Centers of New York and was the Gerald J. Friedman Chair and Chairman of Radiation Oncology at Beth Israel Medical Center and St. Luke’s and Roosevelt Hospitals of the Mount Sinai Health System. He was Professor of Radiation Oncology and Otolaryngology-Head and Neck Surgery at the Icahn School of Medicine at Mount Sinai.

Dr. Harrison is also the Senior Editor of the textbook Head and Neck Cancer: A Multidisciplinary Approach, now in its fourth edition. He is a co-editor of Intraoperative Irradiation: Techniques and Results, now in its second edition.

Dr. Harrison received his MD degree from the State University of New York- Downstate Medical Center and completed his residency in Radiation Oncology at Yale University School of Medicine. n

The ASCO Post | SEPTEMBER 15, 2014

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Clinical Trials Resource Guide

Ongoing Clinical Trials Actively Recruiting Patients With Intraocular Cancer Compiled by Jo Cavallo

T

he information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies of children and adults with intraocular cancers.

The studies include pilot, phase 0, phase I, phase II, and observational trials evaluating new combination therapies, vaccines, optical coherence tomography, molecular analysis of retinoblastoma, and radiation therapy in patients with newly diagnosed, advanced, and refractory disease.

All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

PILOT Study Type: Pilot study/interventoinal/nonrandomized Study Title: A Pilot Study of Intravenous Topotecan and Vincristine in Combination With Subconjunctival Carboplatin for Patients With a History of Bilateral Retinoblastoma and Refractory/Recurrent Intraocular Disease Study Sponsor and Collaborators: Children’s Hospital Medical Center, Cincinnati Purpose: To test subtenon carboplatin in combination with vincristine and topotecan intravenously to find a drug combination that may be effective against retinoblastoma that is recurrent or is resistant to other treatment Ages Eligible for Study: Up to 10 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To estimate the event-free survival, where an event is defined at the ocular level as the need for non-protocol therapy defined as additional nonprotocol chemotherapy, external beam radiation, or enucleation (time frame: at 1 year) Principal Investigator: James Geller, MD, Children’s Hospital Medical Center, Cincinnati, 513-636-6312, james. geller@cchmc.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00980551 Study Type: Interventional/nonrandomized Study Title: A Pilot Study Evaluat-

ing the Safety of Alternating Systemic Chemotherapy and Intra-Arterial Melphalan Chemotherapy in Children With Newly Diagnosed Advanced Intra-Ocular Retinoblastoma Study Sponsor and Collaborators: University of California, San Francisco Purpose: To test the safety of the treatment combination of alternating standard chemotherapy and another (melphalan) chemotherapy at different interval schedules Ages Eligible for Study: 4 months and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Adverse event evaluation for newly diagnosed advanced retinoblastoma treated with melphalan therapy and systemic chemotherapy (time frame: up to 2 years) Principal Investigator: Katherine Matthay, MD, University of California, San Francisco, 415-476-3831, matthayk@peds.ucsf.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02116959

PHASE 0 Study Type: Phase 0/interventional/nonrandomized Study Title: Anti-Angiogenic Therapy After Autologous Stem Cell Rescue (ASCR) for Relapsed and Refractory Pediatric Solid Tumors Study Sponsor and Collaborators: Washington University School of Medicine Purpose: To determine whether taking either of two low-dose drugs, metronomic cyclophosphamide and thalidomide, that would prevent new blood vessels from growing after stem cell transplant is feasible, and what the side effects of taking each of these drugs after autologous transplant might be Ages Eligible for Study: 1 to 21 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Safety (time frame: minimum of 2 years after initiation of study treatment); toxicity (time frame: minimum of 2 years after initiation of study treatment) Principal Investigator: Lisa Madden, MD, Washington University School of Medicine, 314-454-6018,

madden_l@kids.wustl.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01661400

PHASE I Study Type: Phase I/interventional/single-group assignment Study Title: Sirolimus in Combination With Metronomic Therapy in Children With Recurrent and Refractory Solid Tumors: A Phase I Study Study Sponsor and Collaborators: Emory University; Children’s Healthcare of Atlanta Purpose: This study proposes using sirolimus in combination with common chemotherapy drugs to treat patients with recurrent and refractory solid tumors. The study will investigate the highest dose of sirolimus that can be given orally with other oral chemotherapy drugs.

Ages Eligible for Study: Up to 30 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximum tolerated dose (time frame: 2 years after treatment starts) Principal Investigator: Muna Qayed, MD, Children’s Healthcare of Atlanta. Contact: Sindy Moon, 404-7851441, sindy.moon@choa.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT013311135

PHASE II Study Type: Phase II/interventional/randomized Study Title: A Randomized TwoArm Phase II Study of Trametinib Alone and in Combination With GSK2141795 in Patients With Advanced Uveal Melanoma Study Sponsor and Collaborators: National Cancer Institute Purpose: To investigate how well trametinib with or without Akt inhibitor GSK2141795 works in treating patients with metastatic uveal melanoma Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Time to progression (progression-free survival), defined from the date of randomiza-

tion to the date of documented progression or death per Response Evaluation Criteria in Solid Tumors (RECIST) (time frame: time from randomization to the earlier date of objective disease progression, assessed up to 12 months) Principal Investigator: Richard Carvajal, MD, Memorial Sloan Kettering Cancer Center, 646-888-4161, carvajar@mskcc.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01979523 Study Type: Phase II/interventional/randomized Study Title: A Phase II, Open-Label, Multicenter, Randomized Study of CDX-1401, a Dendritic Cell Targeting NY-ESO-1 Vaccine, in Patients With Malignant Melanoma Pre-treated With Recombinant CDX-301, a Recombinant Human Flt3 Ligand Study Sponsor and Collaborators: National Cancer Institute Purpose: To study how well DEC205/NY-ESO-1 fusion protein CDX1401 (CDX-1401) and neoantigenbased melanoma-poly-ICLC vaccine (poly-ICLC) vaccine therapy work when given with or without recombinant flt3 ligand (CDX-301) in treating patients with stage IIB-IV melanoma Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Immune T-cell response to NY-ESO-1 (time frame: up to 12 weeks after final vaccination) Principal Investigator: Nina Bhardwaj, MD, PhD, Mount Sinai Medical Center, 212-824-8427, nina.bhardwaj@mssm.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02129075 Study Type: Phase II/interventional/single-group assignment Study Title: A Phase II Pilot Trial of an Indoleamine 2,3, Dioxygenase-1 (IDO1) Inhibitor (INCB024360) Plus a Multipeptide Melanoma Vaccine (MELITAC 12.1) in Patients With Advanced Melanoma Study Sponsor and Collaborators: Fred Hutchinson Cancer Research Center; National Cancer Institute Purpose: To study how well

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Clinical Trials Resource Guide

INCB024360 (indoleamine 2,3-dioxygenase 1 [IDO1] inhibitor INCB024360) and vaccine therapy work in treating patients with stage IIIIV melanoma.

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Changes in the concentration and number of CD8+ and CD4+ specific T-cell immune responses by IFN-gamma ELISPOT (time frame: baseline to up to 16 weeks) Principal Investigator: Craig L. Slingluff, MD, Cancer Immunotherapy Trials Network, 434-924-1730 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01961115 Study Type: Phase II/interventional/single-group assignment Study Title: Phase II Study of Intrathecal I-3F8 in Patients With GD2-Expressing Central Nervous System and Leptomeningeal Neoplasms Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center Purpose: To study the side effects and how well iodine l 131 monoclonal antibody 3F8 works in treating patients with central nervous system cancer or leptomeningeal cancer Ages Eligible for Study: N/A Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Sixmonth overall survival (time frame: 6 months) Principal Investigator: Kim Kramer, MD, Memorial Sloan Kettering Cancer Center, 212-639-6410 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00445965 Study Type: Phase II/interventional/single-group assignment Study Title: An Open-label, Single Institution Phase II Study Using Radioactive yttrium90 Microsphere (SIRSpheres Microspheres) in Uveal Melanoma Patients With Hepatic Metastasis Study Sponsor and Collaborators: Thomas Jefferson University Purpose: To determine whether radiation provided locally to the liver tumor environment will demonstrate a response of tumor decline.

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No

Primary Outcome Measures: Clinical benefit rate of previously treated and naïve patients (time frame: 3 months post final treatment) Principal Investigator: Carin Gonsalves, MD, Thomas Jefferson University. Contact: Mary Ann Laudadio, RN, 215-955-9980, mary.ann.laudadio@jefferson.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01473004

Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To determine whether autologous Young TIL infused plus or minus the administration of high-dose IL-2 may result in clinical tumor regression in patients with metastatic ocular melanoma receiving a nonmyeloablative lymphoid depleting preparative regimen (time frame: 3 years) Principal Investigator: Udai S. Kammula, MD, National Cancer Institute, 301-435-8606, kammulau@mail. nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01814046

Study Type: Phase II/interventional/single-group assignment Study Title: Intra-arterial Chemotherapy for the Treatment of Intraocular Retinoblastoma Study Sponsor and Collaborators: Sidney Kimmel Comprehensive Cancer Center Purpose: To study whether chemotherapy delivered directly through the artery supplying the eye (ophthalmic artery) to patients with retinoblastoma is a safe and effective treatment alternative to conventional systemic chemotherapy, external beam radiation, and surgical removal of the eye Ages Eligible for Study: Up to 18 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Number of patients who complete therapy without the need for additional treatment, including systemic chemotherapy, external beam radiation, or enucleation (time frame: within the first 6 months after the initial treatment) Principal Investigator: Monica Pearl, MD, The Johns Hopkins Hospital, 410-955-8525, msmit135@jhmi.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01293539

Study Type: Phase II/interventional/single-group assignment Study Title: A Phase 2 Study of Vorinostat (NSC 701852) in Metastatic Uveal Melanoma Study Sponsor and Collaborators: National Cancer Institute Purpose: To study how well vorinostat works in treating patients with melanoma of the eye that has metastasized Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Overall response rate in patients with GNAQ/GNA11 mutant uveal melanoma, defined as the rate of complete and partial responses (time frame: up to 3 years) Principal Investigator: Richard Carvajal, MD, Memorial Sloan Kettering Cancer Center, 646-888-4161, carvajar@mskcc.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01587352

Study Type: Phase II/interventional/nonrandomized Study Title: Phase II Study in Patients With Metastatic Ocular Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of Autologous Tumor-Infiltrating Lymphocytes With or Without High Dose Aldesleukin Study Sponsor and Collaborators: National Cancer Institute Purpose: To determine if chemotherapy and white blood cell therapy is a safe and effective treatment for advanced ocular melanoma.

Ages Eligible for Study: 16 to 75 years

Study Type: Phase II/interventional/randomized Study Title: Randomized Phase II Study Comparing the MET Inhibitor Cabozantinib to Temozolomide/Dacarbazine in Ocular Melanoma Study Sponsor and Collaborators: National Cancer Institute Purpose: To investigate how well cabozantinib-s-malate works compared with temozolomide or dacarbazine in treating patients with melanoma of the eye Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Pro-

gression-free survival rate (time frame: at 4 months) Principal Investigator: Jason Luke, MD, Cancer and Leukemia Group B. Contact: NCI CTRP, 866-319-4357, ncictro@mail.nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01835145

OBSERVATIONAL Study Type: Observational Study Title: Characterization of Small Choroidal Tumors Using Functional Optical Coherence Tomography Study Sponsor and Collaborators: Oregon Health and Science University Purpose: To study whether mapping blood vessel patterns with optical coherence tomography (OCT) will help identify life-threatening choroidal tumors in their early stages and improve overall patient survival through early detection Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Blood vessel patterns in small choroidal tumors (time frame: 24 months) Principal Investigator: Alison Skalet, MD, PhD, Oregon Health and Science University. Contact Denny Romfh, 503-494-4351, romfhd@ohsu. edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01955915 Study Type: Observational Study Title: Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a Repository for Related Biological Studies Study Sponsor and Collaborators: National Cancer Institute Purpose: Laboratory investigators studying common childhood cancers are interested in developing a tissue repository to collect and store blood, serum, tissue, urine, or tumors of children who have cancer or adults who have common childhood cancers. The cancers include retinoblastoma.

Ages Eligible for Study: N/A Genders Eligible for Study: Both Accepts Health Volunteers: Yes Primary Outcome Measures: N/A Principal Investigator: Javed Khan, MD, National Cancer Institute, 301435-2937, khanjav@mail.nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01109394 n

Now Approved New Indication

(ofatumumab)

Injection, for intravenous infusion Indications ARZERRA® (ofatumumab) is indicated: • In combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate • For the treatment of patients with CLL refractory to fludarabine and alemtuzumab

Important Safety Information for ARZERRA WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)].

• Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA [see Warnings and Precautions (5.4)].

Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (eg, myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions.

Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment.

Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available.

Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication.

Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms

of myocardial ischemia. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment.

Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, ie, increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

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

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy.

In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment.

Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation.

First-line Treatment for CLL ARZERRA is now approved in combination with chlorambucil for previously untreated patients with CLL for whom fludarabinebased therapy is considered inappropriate.1 ARZERRA J-Code: J9302

i

To learn more, please visit www.ARZERRAhcp.com.

CLL=chronic lymphocytic leukemia.

Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis.

Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation.

Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.

Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied.

Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

Most Common Adverse Reactions In the previously untreated CLL clinical trial, the most common adverse reactions (≥10%, all grades) were infusion reactions (67% for ARZERRA plus chlorambucil vs 0% for chlorambucil) and neutropenia (27% vs 18%).

In the single-arm refractory CLL clinical trial, the most common adverse reactions (≥10%, all grades) were neutropenia, pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia.

Infections were the most common adverse reactions leading to drug discontinuation.

Laboratory Abnormalities In the previously untreated CLL clinical trial, post-baseline hematologic laboratory abnormalities (all grades) occurring with ≥5% incidence in patients receiving ARZERRA plus chlorambucil and also ≥2% more than patients receiving chlorambucil were leukopenia (67% for ARZERRA plus chlorambucil vs 28% for chlorambucil), neutropenia (66% vs 56%), and lymphopenia (52% vs 20%).

Reference: 1. ARZERRA (ofatumumab) [package insert].

Research Triangle Park, NC: GlaxoSmithKline; 2014.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for ARZERRA on the following pages.

www.GSKSource.com ©2014 GSK group of companies.

All rights reserved. Printed in USA. AZA438R0 May 2014

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; SEPTEMBER 15, 2014

PAGE 104

News

Gene Therapy Betters Chemotherapy Tolerance, Effectiveness in Small Glioblastoma Study

U

sing gene therapy and a combination of chemotherapy drugs, researchers at Fred Hutchinson Cancer Research Center have been able to enhance the tolerance and effectiveness

of medications used in treating glioblastoma while also protecting healthy cells from their toxic effects. The report, published this month in the Journal of Clinical Investigations, is based on

a study involving seven patients with glioblastoma who survived a median of 20 months, with one-third living up to 2 years.1 Hans-Peter Kiem, MD, PhD, a

Stem-Cell Transplant Researcher and Member of the Clinical Research Division at Fred Hutchinson Cancer Research Center, in Seattle and lead author Jennifer Adair, PhD, a Re-

BRIEF SUMMARY

discontinue ARZERRA andBRIEF any concomitant institute SUMMARY chemotherapy, discontinue and ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRAappropriate in patients whose HBVResumption of ARZERRA in patients whose HBV treatment. ÂŽ ARZERRAÂŽ (ofatumumab) Injection, for intravenous infusion reactivation resolves should be discussed with physicians expertise in be discussed with physicians with expertise in ARZERRA (ofatumumab) Injection, for intravenous infusion reactivationwith resolves should managing hepatitis B. InsufďŹ cient data exist regarding the hepatitis safety of B. resuming managing InsufďŹ cient data exist regarding the safety of resuming The following is a brief summary only; see full prescribing information, The following is a brief summary only; see full prescribing information, ARZERRA in patients who develop HBV reactivation.

(EPATITIS " 6IRUS ARZERRA in patients who develop HBV reactivation. (EPATITIS " 6IRUS including Boxed Warning, for complete product information. including Boxed Warning, for complete product information.

Infection Fatal infection due to hepatitis B in patients whoFatal haveinfection not beendue to hepatitis B in patients who have not been Infection WARNING: HEPATITIS B VIRUS REACTIVATIONWARNING: AND PROGRESSIVE infectedAND hasPROGRESSIVE been observed with ARZERRA. Monitor patients HEPATITIS B VIRUSpreviously REACTIVATION previously infected has been observed with ARZERRA. Monitor patients MULTIFOCAL LEUKOENCEPHALOPATHY for clinical and laboratory signs of hepatitis. 5.4for Progressive MULTIFOCAL LEUKOENCEPHALOPATHY clinical andMultifocal laboratory signs of hepatitis. 5.4 Progressive Multifocal s (EPATITIS " 6IRUS ("6 REACTIVATION CAN OCCUR IN PATIENTS ,EUKOENCEPHALOPATHY Progressive multifocal leukoencephalopathy (PML) s (EPATITIS " 6IRUS ("6 REACTIVATION CAN OCCUR IN PATIENTS ,EUKOENCEPHALOPATHY Progressive multifocal leukoencephalopathy (PML) ÂŽ receiving CD20-directed cytolytic antibodies, receiving including CD20-directed ARZERRAÂŽ, cytolytic resultingantibodies, in death has occurredARZERRA with ARZERRA. Consider in any including , resulting PML in death haspatient occurred with ARZERRA. Consider PML in any patient IN SOME CASES RESULTING IN FULMINANT HEPATITIS HEPATIC FAILURE

with new onset of or changes in pre-existing neurological signs or symptoms.

IN SOME CASES RESULTING IN FULMINANT HEPATITIS HEPATIC FAILURE

with new onset of or changes in pre-existing neurological signs or symptoms. and death [see Warnings and Precautions (5.2)].

If PML is suspected, discontinue ARZERRA and initiate evaluation fordiscontinue PML and death [see Warnings and Precautions (5.2)].

If PML is suspected, ARZERRA and initiate evaluation for PML s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY 0-, RESULTING including neurology consultation. 5.5 Tumor Lysis Syndrome Tumorconsultation. lysis s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY 0-, RESULTING including neurology 5.5 Tumor Lysis Syndrome Tumor lysis IN DEATH CAN OCCUR IN PATIENTS RECEIVING #$ DIRECTED syndrome (TLS), including the need for hospitalization, has(TLS), occurred in the need for hospitalization, has occurred in IN DEATH CAN OCCUR IN PATIENTS RECEIVING #$ DIRECTED syndrome including cytolytic antibodies, including ARZERRA [seecytolytic Warnings patients treated [see with ARZERRA. tumor burden high antibodies, including ARZERRA WarningsPatients with highpatients treatedand/or with ARZERRA. Patients with high tumor burden and/or high and Precautions (5.4)]. greater risk for developing and Precautions (5.4)]. circulating lymphocyte counts (>25 x 109/L) are at circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of prior to infusion of ARZERRA. For treatment of beginning 12 to 24 hours 1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE TLS, administer aggressive intravenous andadminister anti-hyperuricemic aggressive intravenous hydration and anti-hyperuricemic 0REVIOUSLY 5NTREATED #HRONIC ,YMPHOCYTIC ,EUKEMIA ARZERRA 0REVIOUSLY 5NTREATED #HRONIC ,YMPHOCYTIC ,EUKEMIA ARZERRA hydrationTLS, agents, correct electrolyte abnormalities, and monitor renal function. agents, correct electrolyte abnormalities, and monitor renal function. (ofatumumab) is indicated, in combination with (ofatumumab) chlorambucil, for the is indicated, in combination with chlorambucil, for the Severelymphocytic cytopenias,leukemia including neutropenia, thrombocytopenia, #YTOPENIAS Severe cytopenias, including neutropenia, thrombocytopenia, treatment of previously untreated patients with treatment chronic lymphocytic leukemia of previously untreated #YTOPENIAS patients with chronic and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and (CLL) for whom ďŹ&#x201A;udarabine-based therapy is considered inappropriate [see (CLL) for whom ďŹ&#x201A;udarabine-based therapy is considered inappropriate [see fatal neutropenic sepsis occurred in patientsfatal whoneutropenic received ARZERRA in occurred in patients who received ARZERRA in sepsis have Clinical Studies (14.1) of full prescribing information].

Refractory Clinical1.2 Studies (14.1) CLL of full prescribing information].

1.2 have Refractory CLL combination with with chlorambucil.

Gradeto3 or 4 late-onset neutropenia (onset at Grade 3 or 4 late-onset neutropenia (onset at combination with chlorambucil.

ARZERRA is indicated for the treatment of patients with CLL refractoryfor to the treatment ARZERRA is indicated of patients CLL refractory 42 days after(14.2) last treatment dose) and/or prolonged neutropenia least 42 days after last(not treatment dose) and/or prolonged neutropenia (not ďŹ&#x201A;udarabine and alemtuzumab [see Clinical Studies (14.2) ofand full alemtuzumab prescribing [seeleast ďŹ&#x201A;udarabine Clinical Studies of full prescribing resolved between 24 and 42 days after last treatment dose) were 24 reported resolved between and 42 days after last treatment dose) were reported information]. information]. in patients who received ARZERRA [see AdverseinReactions (6.1)].

MonitorARZERRA [see Adverse Reactions (6.1)]. Monitor patients who received complete blood counts at regular intervals during and after conclusion 4 CONTRAINDICATIONS complete blood counts of at regular intervals during and after conclusion of 4 CONTRAINDICATIONS therapy, and increase the frequency of monitoring in patients who develop therapy, and increase the frequency of monitoring in patients who develop None.

None.

Grade 3 or 4 cytopenias. 5.7 Immunizations The safety of 4immunization Grade 3 or cytopenias. 5.7 Immunizations The safety of immunization 5 WARNINGS AND PRECAUTIONS of ARZERRA 5 WARNINGS AND PRECAUTIONSwith live viral vaccines during or following administration with live viral vaccineshas during or following administration of ARZERRA has 5.1 Infusion Reactions ARZERRA can cause serious, including fatal, ARZERRAnot studied.

Doincluding not administer to studied. patients Do whonothave 5.1 Infusion Reactions canbeen cause serious, fatal, live viral vaccines not been administer live viral vaccines to patients who have infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, as bronchospasm, recently receiveddyspnea, ARZERRA. The ability to generate an immune response to The ability to generate an immune response to infusion reactions manifesting laryngeal edema, recently received ARZERRA. pulmonary edema, ďŹ&#x201A;ushing, hypertension, hypotension, syncope, any vaccine following syncope, administration of ARZERRA not been studied. pulmonary edema,cardiac ďŹ&#x201A;ushing, hypertension, hypotension, cardiac anyhas vaccine following administration of ARZERRA has not been studied. events (e.g., myocardial ischemia/infarction, acute coronary syndrome, ischemia/infarction, acute coronary syndrome, events (e.g., myocardial arrhythmia, bradycardia), back pain, abdominal arrhythmia, pain, pyrexia, rash, urticaria, 6 ADVERSE bradycardia), back pain, abdominalREACTIONS pain, pyrexia, rash, urticaria, 6 ADVERSE REACTIONS angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic The following serious adverse reactions are discussed in greater detailadverse in angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic The following serious reactions are discussed in greater detail in reactions. Infusion reactions occur more frequently with the ďŹ rst 2 reactions infusions.occurother of the reactions.

Infusion moresections frequently withlabeling: the ďŹ rst 2 infusions. other sections of the labeling: These reactions may result in temporary interruption withdrawal s )NFUSION 2EACTIONS [see Warnings (5.1)] Theseorreactions mayofresult in temporary interruption or withdrawal of and Precautions s )NFUSION 2EACTIONS [see Warnings and Precautions (5.1)] treatment [see Adverse Reactions (6.1)]. Premedicate with[see acetaminophen, (EPATITIS " 6IRUS 2EACTIVATION [see Warnings and Precautions (5.2)] treatment Adverse Reactions s (6.1)].

Premedicate with acetaminophen, s (EPATITIS " 6IRUS 2EACTIVATION [see Warnings and Precautions (5.2)] an antihistamine, and a corticosteroid [see Dosage and Administration s (EPATITIS " 6IRUS )NFECTION [see Warnings Precautions (5.3)] an antihistamine, and a(2.1, corticosteroid [see Dosage and Administration (2.1, ands (EPATITIS " 6IRUS )NFECTION [see Warnings and Precautions (5.3)] 2.4) of full prescribing information]. Infusion reactions occur despite s Infusion 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY [see Warnings and 2.4) of may full prescribing information]. reactions may occur despite s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY [see Warnings and premedication. Interrupt infusion with ARZERRApremedication. for infusion reactions of infusion withPrecautions (5.4)] Interrupt ARZERRA for infusion reactions of Precautions (5.4)] any severity. Institute medical management for severe infusion reactions s 4UMOR ,YSIS 3YNDROME [see Warnings and Precautions (5.5)] any severity.

Institute medical management for severe infusion reactions s 4UMOR ,YSIS 3YNDROME [see Warnings and Precautions (5.5)] including angina or other signs and symptoms ofincluding myocardial ischemia #YTOPENIAS [see Warnings and Precautions (5.6)] angina or other signs ands symptoms of myocardial ischemia s #YTOPENIAS [see Warnings and Precautions (5.6)] [see Dosage and Administration (2.3) of full prescribing information].

If an Previously Untreated CLL: The mostIfcommon adverse reactions (â&#x2030;Ľ10%) [see Dosage and Administration (2.3) of full prescribing information]. an Previously Untreated CLL: The most common adverse reactions (â&#x2030;Ľ10%) anaphylactic reaction occurs, immediately and permanently were infusion reactions anddiscontinue neutropenia (Table 1).

Refractory The and neutropenia (Table 1). Refractory CLL: The anaphylactic discontinue reaction occurs, immediately and permanently were infusion CLL: reactions ARZERRA and initiate appropriate medical treatment.

(EPATITIS " common adverse reactions (â&#x2030;Ľ10%) were neutropenia, pneumonia, ARZERRA and initiate appropriate most medical treatment.

(EPATITIS " most common adverse reactions (â&#x2030;Ľ10%) were neutropenia, pneumonia, Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases pyrexia, diarrhea, anemia, fatigue, dyspnea, rash,cough, nausea, bronchitis, Virus Reactivation Hepatitis B virus (HBV)cough, reactivation, in some cases pyrexia, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, resulting in fulminant hepatitis, hepatic failure, and death,inhas occurred in and upper respiratory tract 3). The serious resulting fulminant hepatitis, hepatic failure, and death, hasinfections occurred (Table in and most uppercommon respiratory tract infections (Table 3). The most common serious patients treated with ARZERRA. Cases have been reported in patients who adverse were infections pneumonia and sepsis), patients treated with ARZERRA. Cases havereactions been reported in patients(including who adverse reactions were infections (including pneumonia and sepsis), are hepatitis B surface antigen (HBsAg) positiveare andhepatitis also in patients who neutropenia, Infectionswho were the most common and adverse B surface antigen (HBsAg) positiveand andpyrexia. also in patients neutropenia, pyrexia. Infections were the most common adverse are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. reactions drug discontinuation. are HBsAg negative but are hepatitis B coreleading antibodyto(anti-HBc) positive. #LINICAL 4RIALS %XPERIENCE reactions leading to drug discontinuation. #LINICAL 4RIALS %XPERIENCE Reactivation also has occurred in patients who appear to have resolved Because who clinical trialstoare conducted varying conditions, Reactivation also has occurred in patients appear have resolvedunder widely Because clinical trials are conducted under widely varying conditions, hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B adverseanti-HBc reaction positive, rates observed in the clinical trials of a reaction drug cannot hepatitis B infection (i.e., HBsAg negative, and hepatitis B adverse ratesbeobserved in the clinical trials of a drug cannot be surface antibody [anti-HBs] positive). HBV reactivation is deďŹ ned an abruptpositive). directly compared with rates in clinical trialsdirectly of another drug and surface antibodyas[anti-HBs] HBV reactivation is deďŹ ned asthe an abrupt compared withmay rates in the clinical trials of another drug and may increase in HBV replication manifesting as a rapid increase in serum HBV manifesting not reďŹ&#x201A;ect rates observed in practice.

Untreated CLL: observed The increase in HBV replication as a the rapid increase in serum HBV Previously not reďŹ&#x201A;ect the rates in practice. Previously Untreated CLL: The DNA level or detection of HBsAg in a person whoDNA waslevel previously HBsAgof HBsAg insafety of ARZERRA evaluated in an open-label, parallel-arm, or detection a person who waswas previously HBsAg safety of ARZERRArandomized was evaluated in an open-label, parallel-arm, randomized negative and anti-HBc positive. Reactivation of HBV replication is oftenpositive. Reactivation trial (Studyof1)HBV in 444 patients iswith previously untreated CLL.1)Patients were with previously untreated CLL. Patients were negative and anti-HBc replication often trial (Study in 444 patients followed by hepatitis, i.e., increase in transaminase levelsbyand, in severe to receive infusion everyeither ARZERRA as an intravenous infusion every followed hepatitis, i.e., increaserandomized in transaminase levelseither and, ARZERRA in severe as an intravenous randomized to receive cases, increase in bilirubin levels, liver failure, and death.

Screeninall patients in combination with chlorambucil or chlorambucil as with a chlorambucil (n = 217) or chlorambucil as a cases, increase bilirubin levels, 28 liverdays failure, and death. Screen all patients(n = 217) 28 days in combination for HBV infection by measuring HBsAg and anti-HBc before initiating singleand agent (n = 227).

In initiating both arms, patients received chlorambucil for HBV infection by measuring HBsAg anti-HBc before single agent (n = 227). In both arms, patients received chlorambucil 2 schedule treatment with ARZERRA. For patients who showtreatment evidencewith of hepatitis B For patients 10 mg/m ARZERRA. who 2show hepatitis orallyevidence on Days of 1 to 7 everyB28 days. The infusion 10 mg/m orally on Days 1 to 7 every 28 days. The infusion schedule infection (HBsAg positive [regardless of antibodyinfection status] or HBsAgpositive negative (HBsAg [regardless of antibodywas status] or HBsAg negativeon Cyclefor1 ARZERRA for ARZERRA 300 mg administered Day 1, 1,000 wasmg 300 mg administered on Cycle 1 Day 1, 1,000 mg but anti-HBc positive), consult physicians with expertise in managing but anti-HBc positive), consult physicians with expertise managing administered on Cycle in 1 Day 8, and 1,000 mg administered 1 of1 Day 8, and 1,000 mg administered on Day 1 of administeredon onDay Cycle hepatitis B regarding monitoring and consideration for HBV antiviral therapy. hepatitis B regarding monitoring and consideration forcycles.

HBV antiviral therapy. subsequent 28-day The median numbersubsequent of cycles of 28-day ARZERRA cycles. The median number of cycles of ARZERRA Monitor patients with evidence of current or prior HBV infection clinical Monitor patientsfor with evidence of completed current or prior HBV for clinical was 6.

Theinfection data described in Table 1completed include relevant was 6.adverse The data described in Table 1 include relevant adverse and laboratory signs of hepatitis or HBV reactivation during andsigns for several and laboratory of hepatitis orreactions HBV reactivation anddays for several occurringduring up to 60 after the last dose of study medication; reactions occurring up to 60 days after the last dose of study medication; months following treatment with ARZERRA. HBVmonths reactivation has been following treatment with ARZERRA. HBV reactivation has been laboratoryTable Table 2 includes relevant hematologic abnormalities.

2 includes relevant hematologic laboratory abnormalities. reported for at least 12 months following completion of therapy.

In patients reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receivingwho ARZERRA, developimmediately reactivation of HBV while receiving ARZERRA, immediately (contâ&#x20AC;&#x2122;d)

(contâ&#x20AC;&#x2122;d)

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 105

News

searcher in Dr. Kiem’s Laboratory, expect the stem-cell protocol, once approved, could be used with other malignant solid tumors.

Phase II Study Planned Based on these results, the researchers are now soon planning to enroll patients in a Phase II clinical trial after

having to suspend treatment for a year because of a shortage of a key drug, O6-benzylguanine, or O6BG. The primary treatment for glioblastoma is temozolomide (Temodar), but approximately one-half of patients are resistant to temozolomide. Another drug, O6-benzylguanine, or O6BG, can counter the resistance and permit

temozolomide to effectively target the tumors. The combination of O6BG and temozolomide, however, kills bone-marrow cells yielding a potentially deadly side effect.

Conditioning a Key Component to Therapy Drs. Kiem and Adair developed

a method that inserts an engineered gene into the patient’s own cells, shielding them from the O6BG. This method facilitated more effective use of the combination temozolomide and O6BG. For example, while most patients might receive one or two cycles of chemotherapy, one patient continued on page 106

Table 1. Adverse Reactions With ≥5% Incidence in 1.

Patients Receiving receivedinall 12 infusions.

The median and age was years (range: 41 Table Adverse Reactions With and ≥5%55% Incidence Patients Receiving 55%63 received all 12 infusions.

The median age was 63 years (range: 41 ARZERRA Plus Chlorambucil and Also ≥2% More Than Plus Patients 86 years), 72% Than were Patients male, and 97% were white.

ARZERRA Chlorambucil andtoAlso ≥2% More to 86 years), 72% were male, and 97% were white.

Receiving Chlorambucil Receiving Chlorambucil Table 3. Incidence of All Adverse Reactions Occurring in ≥5% ofofPatients Table 3. Incidence All Adverse Reactions Occurring in ≥5% of Patients ARZERRA Plus ARZERRA Plus and in the Fludarabine- and Alemtuzumab-refractory and in theSubset Fludarabine- and Alemtuzumab-refractory Subset Chlorambucil Chlorambucil Chlorambucil Chlorambucil Fludarabine- and (N = 217) (N = 227) Fludarabine- and (N = 217) (N = 227) AlemtuzumabAlemtuzumabAll All All All refractory 4OTAL 0OPULATION refractory 4OTAL 0OPULATION Grades Grade ≥3 Grades Grade ≥3 (N = 59) (N =≥3 154) Grades Grade ≥3 Grades Grade (N = 59) (N = 154) Adverse Adverse Reactions % % Reactions % % % % % Grade All All % Grade Grade All Grade All ≥3 Grades ≥3 Adverse Grades0 ≥3 Grades ≥3 Grades Infusion reactionsa 67 10 Infusion 0reactionsa 0 67 Adverse10 0 % % % Reaction % Reaction % % % % Neutropenia 27 26 Neutropenia 18 14 27 26 18 14 Pneumoniaa 23 14 Pneumonia 25 a 15 23 14 25 15 Asthenia 8 <1 Asthenia5 0 8 <1 5 0 Pyrexia 20 3 25 5 Pyrexia 20 3 25 5 Headache 7 <1 Headache 3 0 7 <1 3 0 Cough 19 0 0 Cough19 19 0 19 0 Leukopenia 6 3 Leukopenia 2 <1 6 3 2 <1 Diarrhea 18 0 19 0 Diarrhea 18 0 19 0 b 6 0 Herpes simplex 4 <1 Herpes simplexb 6 0 4 <1 Anemia 16 5 17 8 Anemia 16 5 17 8 Lower respiratory tract 5 1 Lower respiratory 3 <1 tract 5 1 3 <1 Fatigue 15 0 15 0 Fatigue 15 0 15 0 infection infection Dyspnea 14 2 19 5 Dyspnea 14 2 19 5 Arthralgia 5 <1 Arthralgia3 0 5 <1 3 0 b 14 0 <1 5 Rash 0 3 a <1 a infusion or within Includes events which occurred on the day of an Includes events which occurred onBronchitis the day of an infusion or within11 24 hours of the end of an infusion and resulted 24 in an interruption or of an infusion and hours of the end resulted in an interruption 11 or Nausea 0 discontinuation of treatment. Infusion reactions discontinuation may include, butofare not treatment.

Infusion reactions may include, but are not respiratory tractpain, pruritus, 11 0 limited to, chills, dyspnea, flushing, hypotension,limited nausea, to,pain, chills,pruritus, dyspnea, flushing,Upper hypotension, nausea, infection pyrexia, rash, and urticaria. pyrexia, rash, and urticaria. b b Includes oral herpes, herpes, herpes virus infection, genital Includes oralherpes, herpes,and herpes, herpes virus peripheral infection, genital herpes,9 and Edema <1 herpes simplex. herpes simplex.

Back pain 8 1 Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring Chills 8 0 With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil 8 0 and Also ≥2% More Than Patients Receivingand Chlorambucil Also ≥2% More Than PatientsNasopharyngitis Receiving Chlorambucil

Upper abdominal pain

5

0 Upper abdominal 3 pain0

ARZERRA Plus Chlorambucil (N = 217)

8 8 Chlorambucil (N = 227)7

8

2

14

<1

17

2

19 Bronchitis

2

11

<1

19

2

12 Nausea

0

11

0

12

0

0 Upper 3respiratory tract infection

11

0

3

0

Edema8peripheral 2

9

<1

8

2

12 Back pain

2

8

1

12

2

Chills 10

0

8

0

10

0

0

8

0

8

0

10

8

8

10

10

8 Nasopharyngitis c Sepsis10

0

5 Urticaria

0

8

0

5

0

0

10 Insomnia

0

7

0

10

0

Grade All≥3 Grades Headache Grade ≥3 All Grades Grade ≥3 0 6 7 0 Headache 6 0 7 0 % % % % % Herpes zoster 6 1 7 2 Herpes zoster 6 1 7 2 Leukopenia 67 23 28 4 67 Leukopenia 23 28 4 Hyperhidrosis 5 0 5 0 Hyperhidrosis 5 0 5 0 Neutropenia 66 29 56 24 66 Neutropenia 29 56 24 Hypertension 5 0 8 0 Hypertension 5 0 8 0 Lymphopenia 52 29 20 7 52 Lymphopenia 29 20 7 Hypotension 5 0 3 0 Hypotension 5 0 3 0 Infusion Reactions: Overall, 67% of patients whoInfusion received ARZERRAOverall, in Reactions: 67% of patients who received ARZERRA in Muscle spasms 5 0 3 0 Muscle spasms 5 0 3 0 combination with chlorambucil experienced onecombination or more symptoms of with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal).(10% Infusion 5 2 3 2 infusion reactions were Grade Sinusitis 3 or greater; none were fatal). Infusion Sinusitis 5 2 3 2 reactions that were either Grade 3 or greater, serious, or led treatment reactions thattowere either Grade 3 or greater, serious, or led to treatment Tachycardia 5 <1 7 2 Tachycardia 5 <1 7 2 interruption or discontinuation occurred most frequently during Cycle 1 (56% occurred most frequently during Cycle 1 (56% interruption or discontinuation a a on Day 1 [6% were Grade 3 or greater] and 23%ononDay Day1 8[6% [3%were wereGrade Grade3 3or greater] and 23% on Day 8lung [3%infection, were Grade Includes pneumonia, lobar3 pneumonia, andpneumonia, lung infection, lobar pneumonia, and Includes or greater]) and decreased with subsequent infusions.

Infusion or greater]) andreactions decreasedledwith subsequent infusions. Infusion reactions led bronchopneumonia. bronchopneumonia. b to discontinuation of treatment in 3% of patients. adverse of events to Serious discontinuation treatment in 3% of patients. adverseand events Includes rash,Serious rash macular, rash vesicular.b Includes rash, rash macular, and rash vesicular. c of patients. Neutropenia: Overall, 3% c and septic shock. of infusion reactions occurred in 2% of patients.ofNeutropenia: Overall,occurred 3% infusion reactions in 2% Includes sepsis, neutropenic sepsis, bacteremia, Includes sepsis, neutropenic sepsis, bacteremia, and septic shock. of patients had neutropenia as a serious adverseofevent, reported up to patients had neutropenia as a serious adverse event, reported up to Infusion Reactions: Infusion reactions occurred in 44% patients onInfusion the reactions occurred in 44% of patients on the InfusionofReactions: 60 days after the last dose. One patient died with sepsis 60neutropenic days after the last and dose. One patient died with neutropenic sepsis and day of the first infusion (300 mg), 29% on the day of the second infusion day of the first infusion (300 mg), 29% on the day of the second infusion agranulocytosis. Prolonged neutropenia occurred in 6% of patients receivingneutropenia occurred in 6% of patients receiving agranulocytosis.

Prolonged (2,000 mg), and less frequently during subsequent infusions.

Infections: A (2,000 mg), and less frequently during subsequent infusions. Infections: A ARZERRA in combination with chlorambucil compared within 4% of patientswith chlorambucil ARZERRA combination compared with 4% of patients total of 108 patients (70%) experienced bacterial,total viral,ofor108 fungal infections.

Aexperienced bacterial, viral, or fungal infections. A patients (70%) receiving chlorambucil. Late-onset neutropenia receiving occurred chlorambucil. in 6% of patients Late-onset neutropenia occurred in 6% of patients total of 45 patients (29%) experienced Grade 3 ortotal greater of which of 45infections, patients (29%) experienced Grade 3 or greater infections, of which receiving ARZERRA in combination with chlorambucil compared within 1% receiving ARZERRA combination with chlorambucil compared with 1% 19 (12%) were fatal. The proportion of fatal infections in thewere fludarabine19 (12%) fatal. Theand proportion of fatal infections in the fludarabine- and of patients receiving chlorambucil alone. Refractory CLL: The safety of of patients receiving chlorambucil alone. Refractory CLL: The safety of alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with monotherapy with ARZERRA was evaluated in 181 patients with or was evaluated monotherapy withrelapsed ARZERRA in 181 patients with relapsed or normal neutrophil counts at baseline, 45 (42%) developed Grade 3 counts or greater normal neutrophil at baseline, 45 (42%) developed Grade 3 or greater refractory CLL in 2 open-label, non-randomized,refractory single-arm studies.

In these non-randomized, CLL in 2 open-label, single-arm studies. In these neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Nineteen Some patients (18%) developed Grade 4 neutropenia. Some patients studies, ARZERRA was administered at 2,000 mg beginning with the second studies, ARZERRA was administered at 2,000 mg beginning with the second experienced new onset Grade 4 neutropenia >2 weeks in duration. experienced new onset Grade 4 neutropenia >2 weeks in duration. dose for 11 doses (Study 2 [n = 154]) or 3 dosesdose (Study 3 [ndoses = 27]).

The data for 11 (Study 2 [n = 154]) or 3 doses (Study 3 [n = 27]). The data 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic described in Table 3 and other sections below are derived in from 1543 patients described Table and other sections below are derived from 154 patients proteins such as ofatumumab. Serum samples from moresuch thanas 300 patients Serum samples from more than 300 patients proteins ofatumumab. in Study 2. All patients received 2,000 mg weekly from the second dose in Study 2. All patients received 2,000 mg weekly from the second dose with CLL were tested during and after treatment with for antibodies ARZERRA. CLL were to tested during and after treatment for antibodies to ARZERRA. onward. Ninety percent of patients received at least 8 infusions of ARZERRA onward.

Ninety percent of patients received at least 8 infusions of ARZERRA All Grades %

Grade ≥3 %

Chlorambucil (N = 227)

Sepsisc ARZERRA Plus Urticaria Chlorambucil (N = 217) Insomnia

Rashb17

All Grades %

(cont’d)

(cont’d)

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; SEPTEMBER 15, 2014

PAGE 106

Announcements

Drew Pinsky, MD, Elected to Prostate Cancer Foundation Board of Directors

T

he Prostate Cancer Foundation has announced that Drew Pinsky, MD, has been elected to the Foundationâ&#x20AC;&#x2122;s Board of Directors. Dr. Pinsky, a cancer survivor, is a Practicing Physician and a Member of the Staff of Huntington Memorial Hospi-

tal in Pasadena, California. He is also Assistant Clinical Professor of Psychiatry at the Keck University of Southern California School of Medicine.

In addition to his medical career, Dr. Pinsky is also a multimedia personality having starred in a number of

television and radio broadcasts as well as in online podcasts. â&#x20AC;&#x153;As one of approximately 16 million prostate cancer survivors worldwide, Drew brings personal perspectives and counsel on a broad scope of critical issues important to our mission to Drew Pinsky, MD

There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and speciďŹ city, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading. 0OSTMARKETING %XPERIENCE The following adverse reactions have been identiďŹ ed during post-approval use of ARZERRA. 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. Infusion-related Cardiac Events: Cardiac arrest. Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda.

7 DRUG INTERACTIONS Coadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or wellcontrolled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity.

Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential beneďŹ t to the mother justiďŹ es the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older.

Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see Adverse Reactions (6.1)]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients [see Clinical Studies (14.1) of full prescribing information]. In refractory CLL, clinical studies of ARZERRA did not include sufďŹ cient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 2ENAL )MPAIRMENT No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information].

(EPATIC )MPAIRMENT No formal studies of ARZERRA in patients with hepatic impairment have been conducted.

10 OVERDOSAGE No data are available regarding overdosage with ARZERRA. 13 NONCLINICAL TOXICOLOGY #ARCINOGENESIS -UTAGENESIS )MPAIRMENT OF &ERTILITY No carcinogenicity or mutagenicity studies of ofatumumab have been conducted.

In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

2EPRODUCTIVE AND $EVELOPMENTAL 4OXICOLOGY Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the maximum human dose (2,000 mg) of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the ďŹ nal dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15% to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared with control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared with the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared with control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared with the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological signiďŹ cance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals.

17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: s 3IGNS AND SYMPTOMS OF INFUSION REACTIONS INCLUDING FEVER CHILLS RASH

or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1), Adverse Reactions (6.1)] s 3YMPTOMS OF HEPATITIS INCLUDING WORSENING FATIGUE OR YELLOW DISCOLORATION of skin or eyes [see Warnings and Precautions (5.2, 5.3)] s .EW NEUROLOGICAL SYMPTOMS SUCH AS CONFUSION DIZZINESS OR LOSS OF balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.4)] s "LEEDING EASY BRUISING PETECHIAE PALLOR WORSENING WEAKNESS OR FATIGUE [see Warnings and Precautions (5.6)] s 3IGNS OF INFECTIONS INCLUDING FEVER AND COUGH [see Warnings and Precautions (5.6), Adverse Reactions (6.1)] s 0REGNANCY OR NURSING [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: s -ONITORING AND POSSIBLE NEED FOR TREATMENT IF THEY HAVE A HISTORY of hepatitis B infection (based on the blood test) [see Warnings and Precautions (5.2)] s 0ERIODIC MONITORING FOR BLOOD COUNTS [see Warnings and Precautions (5.6)] s !VOIDING VACCINATION WITH LIVE VIRAL VACCINES [see Warnings and Precautions (5.7)] ARZERRA is a registered trademark of the GSK group of companies.

Manufactured by: GLAXO GROUP LIMITED Brentford, Middlesex, TW8 9GS, United Kingdom U.S. License 1809 Distributed by:

improve and save lives from prostate cancer,â&#x20AC;? said Jonathan W. Simons, MD, President and CEO of the Prostate Cancer Foundation. â&#x20AC;&#x153;After my personal battle with prostate cancer, I decided to join forces with [Prostate Cancer Foundation] to help spread the word about its researchersâ&#x20AC;&#x2122; latest life-saving breakthroughs,â&#x20AC;? said Dr. Pinsky. â&#x20AC;&#x153;[The Foundationâ&#x20AC;&#x2122;s] commitment to curing prostate cancer has accelerated discoveries that will ultimately benefit all cancers. Iâ&#x20AC;&#x2122;m honored that I have been asked to serve on the Board.â&#x20AC;?

Dr. Pinsky received his undergraduate degree from Amherst College and his MD from the University of California, School of Medicine. He is a diplomat of the American Board of Addiction Medicine and the American Board of Internal Medicine and is a Fellow with the American College of Physicians. n

Gene Therapy continued from page 105

in the study received nine cycles of chemotherapy. Â The researchers also added an extra step to the treatment, conditioning the patients with an additional chemotherapy drug, carmustine, before giving the gene-modified blood cells. â&#x20AC;&#x153;The drug helped the patientsâ&#x20AC;&#x2122; bodies accept and use the gene-modified blood cells, but also treated any residual brain tumor,â&#x20AC;? Dr. Adair said. â&#x20AC;&#x153;The gene therapy might not have worked without the conditioning.â&#x20AC;? n

Disclosure: Drs. Kiem and Adair reported no potential conflicts of interest.

GlaxoSmithKline Research Triangle Park, NC 27709 Š2014, the GSK group of companies. All rights reserved.

Revised: 04/2014 ARZ:8BRS Š2014 GSK group of companies.

All rights reserved. Printed in USA. AZA438R0 May 2014

Reference 1. Adair JE, Johnston SK, Mrugala MM, et al: Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. J Clin Invest 124(9):40824092, 2014.

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 107

Journal Spotlight Technology

Using Electronic Health Records to Improve Communication With Patients

By Charlotte Bath

C

linicians may argue that electronic health records (EHRs) interfere with the patient-physician relationship, and patients may complain about “distracted doctors,” too busy with computer screens to make eye contact, but according to Thomas W. LeBlanc, MD, MA, of Duke University School of Medicine and Duke Clinical Research Institute, Durham, North Carolina, and colleagues, “one thing is certain: the EHR in the examination room is here to stay.” Having conceded that point, the physician authors of an article published online by the Journal of Oncology Practice, noted that their goal is “to provide evidencebased suggestions to help busy clinicians integrate the electronic health record into their workflow in a way that is constructive for communication and the patient-clinician relationship.”1

‘Six Ingredients for Success’ In comparison with other healthcare settings, “communication in oncology is often even more high-stakes, involving complex dilemmas, emotional content, clinical uncertainty, and life-limiting illness,” the researchers wrote. They offered “six ingredients for success,” which were “extrapolated from the substantial evidence on highquality patient-centered communication, to promote the successful integration of the EHR into the oncology clinic.”

1. “Position yourself for dual access, to the EHR and to the patient.”

The computer screen shouldn’t be a barrier between the clinician and patient, but should serve as a bridge or a “conduit for information flow, and an

opportunity for more active patient participation.” Proper positioning allows the patient to view the screen along with the clinician.

2. “Ask permission or acknowledge that you will use the EHR.” Explain that the computer is there to

help you “use the computer in a less disruptive manner, can save time, and may even improve patient satisfaction with a visit,” the researchers stated.

6. “Demonstrate Internet resources that might contribute to patient activation.” Encourage patients to use

One thing is certain: the [electronic health record] in the examination room is here to stay.

—Thomas W. LeBlanc, MD, and colleagues

accurately document the patient’s visit and that you will be entering information while talking to the patient.

“Few, if any, patients will decline, but asking their permission helps to position the computer more positively as an integral component of their care,” the researchers wrote. Avoid making apologies for the computer or the EHR; apologies are generally counterproductive.

3. “Use the EHR as a teaching tool.” Using the computer to show trends in laboratory results or radiographic images “can be a powerful way to integrate the EHR into patient care,” the authors asserted.

4. “Preserve nonverbal contact with the patient.” Make periodic eye contact with the patient and stay alert to the patient’s nonverbal cues.

5. “Organize what you want to accomplish before the visit.” This can

Six Ingredients for Success 1. Position yourself for dual access, to the EHR and to the patient.

2. Ask permission or acknowledge that you will use the EHR. 3. Use the EHR as a teaching tool.

4. Preserve nonverbal contact with the patient.

5. Organize what you want to accomplish before the visit.

6. Demontrate Internet resources that might contribute to patient activation.

Internet resources to fact check on their own and be prepared to show patients useful online resources.

“Clinicians must be attuned to the fact that the computer will amplify pre-existing positive and negative communication behaviors; thus, conscious attention to communication strategies around the computer is important,” the authors concluded.

Use of Patient Portals Increasing Cancer patients, particularly younger patients, are increasingly using Webbased of electronic portals to access their personal health records, according to retrospective analysis of enrollment and use of the MyChart portal among patients seen at The University of Texas Southwestern Medical Center. This study by David E. Gerber, MD, of the Harold C. Simmons Cancer Center at UT Southwestern, and colleagues was also published online by the Journal of Oncology Practice.2 The investigators looked at use of the portal by 6,495 patients between 2007 and 2012.

According to the investigators, “it appears that portal use by patients with cancer clearly exceeds that reported in other populations.” In addition, over the 6-year period of the

analysis, patient enrollment increased fivefold, and total log-ins increased more than 10-fold.

The portal was most commonly used to view test results, accounting for 37% of all portal actions. “The interpretation of such data by individuals without formal medical training outside the context of a health care encounter raises a number of questions,” the authors acknowledged. These concerns include distress and anxiety about the clinical significance of test results. Although the portal includes an electronic health reference library to help patients interpret data, “it was used rarely by patients in our study, accounting for only 0.5% of MyChart actions,” the researchers ­reported.

Other common uses of the portal include viewing and responding to clinic messages (29%), and sending medical advice requests (6.4%), which allows patients to send messages directly to providers and clinic staff. More than 30% of these requests were sent during nonclinic hours, and the investigators voiced concern about delays in urgent medical attention if time-sensitive messages are not seen promptly by the medical team. Although the portal instructions warn patients not to use the medical advice function for urgent messages, there is “a growing societal expectation that text messaging provides realtime communication,” and patients may rely on the portal rather than call the medical center for services after normal business hours. n

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

References 1. LeBlanc TW, Back AL, Danis M, et al: Electronic Health Records (EHRs) in the oncology clinic: How clinician interaction with EHRs can improve communication with the patient. J Oncol Pract. July 15, 2014 (early release online).

2. Gerber DE, Laccetti AL, Chen B, et al: Predictors and intensity of online access to electronic medical records among patients with cancer. J Oncol Pract. July 15, 2014 (early release online).

The ASCO Post | SEPTEMBER 15, 2014

PAGE 108

Health-Care Policy

Delivering Cancer Care in Low-Income Countries

By Ronald Piana

I

n wealthy industrialized nations like the United States, escalating costs of cancer care have put the term “cost-effective care” on the forefront of health-care policy discussions. However, the cost issues we wrestle with in our $3 trillion health-care system are vague abstractions for much of the world’s cancer population. According to the World Bank, approximately 1.5 billion people live on less than a dollar a day, and in the world’s poorest areas, particularly Africa, delivering oncology care is often an overwhelming challenge in the financial triaging of a country’s limited resources.

To give our readers a better understanding of how resource-challenged areas can develop high-quality cancer delivery systems, The ASCO Post recently spoke with Lawrence N. Shulman, MD, Chief of Staff and Director of the Center for Global Cancer Medicine, Boston. Dr. Shulman is a Senior Advisor for Partners In Health, an organization that concentrates its cancer care efforts in Rwanda, Malawi, and Haiti.

Specifically, Dr. Shulman has been part of an ongoing partnership to bring oncology services to Rwanda, which is the most densely populated country in subSaharan Africa.

Low- vs Middle-Income Countries Dr. Shulman said that the incremental efforts to create a cancer care infra-

structure in Rwanda could be seen as a model for other resource-challenged areas. “However, an important distinction often lost in these discussions is the difference between low-income countries such as Rwanda and Haiti, and middleincome countries like Mexico or Brazil.

out that Brazil has a very good national cancer institute in the nation’s largest city, San Paolo. “The challenge in a place like Brazil is delivering their high-quality care from the cities to much of the outlying population, especially in rural areas,” said Dr. Shulman.

Rwandan health professionals, not volunteers from Dana-Farber, run the cancer care delivery system at the Butaro Cancer Center. The goal of this international partnership is to establish the in-country capacity to train physicians, nurses, community health workers, and lab technicians so that eventually Rwandan cancer services become less and less dependent on international partners.

—Lawrence N. Shulman, MD

Understanding this distinction has a lot to do with how we plan to build a caredelivery model,” stressed Dr. Shulman.

He added, “Those two income groups are often lumped together, but the issues and challenges they face are quite different.”

He explained that in middle-income countries there is often in-country medical expertise in cancer care. He pointed

Kids on the Cancer ward at Butaro—all receiving active chemotherapy.

He continued, “However, in a lowincome country like Rwanda, there is very little cancer care infrastructure. So the challenge is building a delivery system from the ground up, rather than capitalizing on an existing ­system.”

Dr. Shulman said that it’s important to note that in very poor countries such as Rwanda, the only way cancer

patients can avail themselves of care is if it is provided for free; virtually any cost becomes prohibitive to the access of cancer services for most of the population.

“Given this harsh fiscal reality, one of the basic principles in our partnership is that we care for every patient who comes to the door of the Butaro Cancer Center located in rural northern Rwanda, which we opened in partnership with the Ministry of Health of Rwanda in July 2012,” he said.

Dr. Shulman stressed that building partnerships is a key component within the larger cancer care development plan. “In Rwanda, for instance, we need to partner with the local Ministry of Health and the local health-care providers. Remember, this is not Dana-Farber or Partners In Health going in and unilaterally setting up a cancer care system. Instead, we’ve established a collaborative effort between our resources and those in Rwanda to create a working foundation that we build on,” he said.

“Moreover, Rwandan health professionals, not volunteers from Dana-Farber, run the cancer care delivery system at the Butaro Cancer Center. The goal of this international partnership is to establish the in-country capacity to train physicians, nurses, community health workers, and lab technicians so that eventually Rwandan cancer services becontinued on page 110

Dr. Lawrence Shulman, and Trish Kriger, Executive Director of the Jeff Gordon Children’s Foundation, with Tushime at her home. Tushime was the first cancer patient we treated in Rwanda, at the time of this photo, 5 years after successful treatment for rhabdomyosarcoma of the right face.

The ASCO Post | SEPTEMBER 15, 2014

PAGE 110

Cancer Care in Low-Income Countries continued from page 108

come less and less dependent on international partners—in this case, DanaFarber,” he continued.

Value Is a Subjective Metric In the United States, the oncology community is involved in an ongoing discussion about the complex concept of deriving value in cancer care. Resource-challenged areas such as Rwanda also need to derive value from cost, but the metrics that determine value are very different. With such limited access to resources, difficult decisions need to be made about which patients to treat and what treatments to use.

“For instance, Rwanda had inadequate pathology capacity, which severely hampered our ability to diagnose and treat patients,” said Dr. Shulman. “So together with our Rwandan partners, we built a highly functional pathology lab in Butaro. There was also no in-country access to chemotherapy drugs, and we were able to get much-needed drugs as donations or purchase them ourselves and bring them into the country. We also made some careful decisions about what cancers we thought we could effectively treat, given the assets at hand.

And for each of those cancers, we developed very specific protocols that outlined how we’d evaluate, treat, and follow the patient [see sidebar].”

Dr. Shulman explained that the decision-making process about how to best allocate resources resulted in a protocol prioritization report, which evaluated cancers to treat on a “value = benefit/ cost scale.” All of the protocols were vetted through the Ministry of Health and adopted as national treatment guidelines.

“Ironically, we’re just beginning to adopt this protocol standardization in the United States, with so-called pathways. But in the Rwandan experience, where you do not have an on-site oncologist, this pathway care model is necessary for the delivery of consistently good care,” said Dr. Shulman,

adding, “the protocol pathway system used at the Butaro Cancer Center is ‘tele­supported’ by staff at Dana-Farber.”

Dr. Shulman emphasized that the care models being set up in Rwanda are developed in a very different environment than those seen in the United States. “We know most of the challenges going in, but we also have to deal with situations that we hadn’t anticipated. In that regard, what we’re doing is sort of a research experiment. In other words, our hypothesis is about the delivery of cancer care, but then we have to prospectively measure what’s been accomplished. Not approaching it in that manner would be irresponsible,” said Dr. Shulman.

“To that end,” he continued, “we have a prospective database used to monitor all of our patients, with information ranging from dosing to toxicity.

This way we can accurately measure outcomes, typically survival.”

Since the Butaro Cancer Center was dedicated and opened in 2012, Dr. Shulman said that they’ve seen more than 2,000 patients. “There have been more cancer patients than expected, so it’s been a challenge to manage the volume. We see patients from across Rwanda, and more than 80% of our patients treated in this rural hospital are from outside the dis-

Rwandan physician on the pediatric cancer ward at the Butaro Cancer Center of Excellence.

trict. Some patients are even coming from neighboring countries such as Uganda and Burundi. And no matter where they come from, or how poor they are, we care for them at our center,” said Dr. Shulman.

The College of Medicine and Health Sciences at the University of Rwanda in Butare has designated the Butaro Cancer Center as the national center for oncology training. “We’re beginning to train full-time physicians, residents, and medical students in on-

Prioritizing Cancer Care

I

n Rwanda, there is basically no chemotherapy available through government purchasing. The Partners in Health/Dana-Farber partnership supplies all the standard-of-care chemotherapy regimens for the cancer patients at the Butaro Cancer Center of Excellence, explained Lawrence N. Shulman, MD, Chief of Staff and Director of the Center for Global Cancer Medicine, Boston, and Senior Advisor for Partners in Health.

“We have prioritized cancers where we can make an impact in overall survival—early-stage breast cancer, early-stage cervical cancer, Hodgkin lymphoma, large B-cell lymphoma, acute lymphoblastic leukemia, Wilms tumor,” said Dr. Shulman. “For cancers where we cannot significantly improve survival, we offer palliation—pancreatic cancer, for instance.”

He continued, “There are written pathways similar to those used in the United States for all of the diseases we treat, which run from diagnostics, to treatment, to follow-up care—all aspects of the continuum of care. So it is more than guidelines for the chemotherapy regimens, but rather, for overall care.” n

cology, and we also have a formalized national oncology nursing program,” said Dr. Shulman.

Palliative Care Initiative Lack of palliative care has long been a difficult problem in resource-challenged areas. Dr. Shulman addressed that crucial issue. “There is a national palliative care plan in the works that is supported by the Ministry of Health and headed by a Rwandan physician, Christian R. Ntizimira, MD, a palliative care expert who practices at Kibagabaga Hospital. Dr. Ntizimira traveled to the U.S. for palliative care training. Several experts from our area have worked in Rwanda to help move their palliative care initiative forward. We’re also working very hard on bringing opiates, both oral and parenteral, to our patients at Butaro. It’s an ongoing process, which is part of the larger effort to establish a high-quality cancer care delivery system in a very challenged environment.”

Dr. Shulman, along with others physicians from Dana-Farber Cancer Institute, will be traveling to Rwanda in September.

The ASCO Post will continue to follow Dr. Shulman’s important work at the Butaro Cancer Center. n Disclosure: Dr. Schulman reported no potential conflicts of interest.

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 111

FDA Update

FDA Grants Priority Review to Lanreotide Injection for Gastroenteropancreatic Neuroendocrine Tumors

T

he U.S. Food and Drug Administration (FDA) has accepted and granted priority review to Ipsen’s supplemental New Drug Application (sNDA) for the somatostatin analog lanreotide (Somatuline Depot) 120 mg injection in the treatment of gastroenteropancreatic neuroendocrine tumors.

The FDA designates priority review status to drug candidates that have the potential to offer a significant improvement in treatment compared to currently approved options. A decision is expected in early 2015.

In the United States, lanreotide is indicated for the long-term treatment

gression or death (hazard ratio = 0.47, 95% confidence interval = 0.30–0.73).

The most common adverse reactions (incidence > 5%) were diarrhea (37%), cholelithiasis (20%), abdomi-

Now

OAK of patients with acromegaly who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. The active substance in the drug is lanreotide acetate, a somatostatin analog that inhibits the secretion of several endocrine, exocrine, and paracrine amines and peptides.

CLARINET Trial The regulatory submission was supported by the results of the investigational phase III CLARINET study, which demonstrated the antitumor effect of lanreotide in the treatment of patients with gastroenteropancreatic neuroendocrine tumors, and which was recently published in The New England Journal of Medicine.1 The randomized, double-blind, placebo-controlled, multinational trial enrolled 204 patients from 48 centers across 14 countries with well or moderately differentiated nonfunctioning enteropancreatic neuroendocrine tumors and a proliferation index of < 10%.

Patients were randomly assigned to receive an extended-release aqueous gel formulation of lanreotide or placebo.

The primary endpoint was time to either disease progression or death.

Patients treated with lanreotide experienced significantly prolonged progression-free survival compared with the placebo group (not reached vs 18.0 months). At 96 weeks, the estimated rates of progression-free survival were 65.1% for the lanreotide group vs 33% for the placebo group, representing a 53% reduction in risk of disease pro-

nal pain (19%), nausea (11%), and injection-site reaction (9%), constipation (8%), flatulence (7%), headache (7%), arthralgia (7%), vomiting (7%), and loose stools (6%). n

Reference 1. Caplin ME, Pavel M, Cwikla JB, et al: Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371:224-233, 2014.

Enrolling

A Randomized Phase III Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Failed Platinum Therapy (NCT02008227, Study ID GO28915)

MPDL3280A1 Patients with locally advanced or metastatic NSCLC who have failed platinum-containing chemotherapy

(an engineered anti-PDL1 antibody)

N=850

Randomized 1:1

Docetaxel

Primary Endpoint:

Secondary Endpoints:

• Objective survival

• Safety: incidence of adverse events • Overall response rate • Progression-free survival • Duration of response

Key Inclusion Criteria 2:

Key Exclusion Criteria 2:

• Locally advanced or metastatic NSCLC • • • •

• History of autoimmune disease

(stage IIIB, stage IV, or recurrent) Representative FFPE tumor specimens Disease progression during or following platinum-containing treatment regimen Measurable disease, defined by RECIST v1.1 ECOG performance status of 0-1

• Active hepatitis B or hepatitis C • Prior treatment with docetaxel, CD137 agonists,

anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

For more information Visit: clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp

Call: Genentech Trial Information Support Line: 1-888-662-6728 (US only)

E-mail: global.rochegenentechtrials@roche.com

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002588200 Printed in USA.

The ASCO Post | SEPTEMBER 15, 2014

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Future of Oncology Technology

Potential of Liquid Biopsies in Detecting Cancer and Establishing Prognosis A Conversation With Massimo Cristofanilli, MD, FACP

By Jo Cavallo

Massimo Cristofanilli, MD, FACP

T

ests in development to detect circulating tumor cells that escape from solid tumors and travel through the blood, spreading cancer to new sites, may serve as an alternative to conventional tissue biopsy for early cancer diagnosis and gene-expression analysis over the next decade. According to Massimo Cristofanilli, MD, FACP, Director of the Jefferson Breast Care Center and Deputy Director of Translational Research at the Kimmel Cancer Center at Thomas Jefferson University and Hospitals in Philadelphia, blood tests called “liquid biopsies” will provide oncologists with more accurate information of the cancer’s biology, its aggressiveness, and whether treatment is working than information currently gleaned from tissue biopsy analysis.

“Tissue biopsies have been disappointing because right now they are not helping to cure patients. There must be some limitation in the tissue analysis and the information we get from the tissue,” said Dr. Cristofanilli. “It may be that we are missing an additional piece of information that comes from the blood.”

In 2004, Dr. Cristofanilli published a study1 showing that breast cancer patients with more than five circulating tumor cells in the blood had more aggressive forms of the disease and significantly shorter progression-free survival (2.7 vs 7 months) and overall survival (10.1 vs > 18 months) than women with fewer than five circulating tumor cells per blood draw. In addition, the presence of circulating tumor cells more accurately predicted a patient’s prognosis than either the site of metastatic disease or the tumor’s estrogen receptor status.

Currently, the only circulating tumor cell test approved by the U.S. Food and Drug Administration to monitor disease progression in patients with

metastatic breast, prostate, or colorectal cancer is CellSearch. The test’s drawback is that it only counts circulating tumor cells and cannot capture them, which would allow oncologists to monitor treatment effectiveness. However, newer tests are in development that will allow cells to be both counted and sequenced as biomarkers for use in personalized treatment.

The ASCO Post talked with Dr. ­Cristofanilli about the accuracy of liquid biopsies in detecting and analyzing cancer, their potential use as a tool for cancer screening in healthy people, and how they can provide accurate prognostic information in patients with recurrent disease.

Real-Time Evaluation How accurate are liquid biopsies in detecting malignant cells in the peripheral blood of patients with cancer?

The information is very accurate.

When you look at the blood of patients with cancer it gives you a real-time evaluation and deeper understanding of not only the disease biology based on modification of the genes, but also the metastatic process and how that process modifies with treatment.

The circulating tumor cell test has been available for about 10 years. In

tient’s disease and other factors, including the patient’s immune system before and during treatment. We will be able to detect disease progression without using imaging tests, which have been essentially guiding our treatment decisions and monitoring response for years.

Convenience Factor In terms of its value in cancer care, would a liquid biopsy be not only more informative than a tissue biopsy, but also more convenient for the patient?

It definitely would be easier on the patient. I suspect it would also be easier on the health-care system, because instead of having to do many imaging studies to track cancer progression and treatment effectiveness, we would have a biologic way to monitor the disease at a less expensive cost.

Sequencing Technologies How would liquid biopsy be used to sequence circulating tumor cells in the peripheral blood?

In addition to being able to detect circulating cancer cells, we will be able to detect and monitor immune cells, such as circulating cancer-associated macrophage-like cells or specific subsets of lymphocytes that can indicate a more aggressive disease. Another ex-

The bottom line is that the blood has everything that you need to know to understand disease biology, select treatment, and predict outcome.

—Massimo Cristofanilli, MD, FACP

retrospect, I think this was a very innovative concept for which we can now imagine that solid tumors also have a liquid phase allowing for detection and enumeration, and quantification of cancer cells in the blood—a totally different environment for those tumors.

The enumeration actually provides information about the disease outcome.

Every time a patient undergoes a liquid biopsy, the number of circulating tumor cells found in the blood reflects what’s going to happen to the patient in the following month or years.

Over the next 5 to 10 years, we are going to develop a number of different sensitive circulating tumor cell technologies with which we won’t have to access the tumor tissue any longer, and we will have a chance to be informed about the pa-

ample is if a patient with breast cancer is estrogen receptor–positive and receiving endocrine therapy, we will be able to detect the number of circulating tumor cells and see whether that patient harbors a PIK3CA mutation, suggesting more sensitivity to certain targeted therapies. Then we can monitor the patient over time while she is receiving treatment, see if the cancer cells are disappearing and if another mutation appears, and determine the predominant mechanism of resistance.

Alternatively, the lack of circulating tumor cell detection—and of an actionable mutation—might suggest that we could simply use a less toxic endocrine therapy. Currently, we have to serially biopsy the tissue over time to get this information. Also, if the patient

has a disease that cannot be measured through a tissue biopsy, we would have to use a sequence of positron-emission tomography/computed tomography scans or other imaging to see the state of the cancer.

These tests might not be necessary if you have a very sensitive blood test that allows you to measure microscopic or minimal residual disease. The real challenge is to be able to obtain such information in all patients with advanced disease. In this regard, I think the future is in the integration of different bloodbased detection methods. Circulating tumor cells obviously have the advantages we’ve highlighted, but current methods do not detect tumor cells in 100% of patients and, more importantly, the detection of very few cancer cells limits the ability to do a genomic analysis and find a mutation.

If you also use DNA sequencing technologies to analyze circulating free DNA, you might have a complete understanding of what the tumor representation is within the blood. The circulating tumor cells may reflect more of the stem cell–like cells, the cells that are responsible for the new metastases, and the DNA circulating cells may be reflecting the bulk of the metastatic tumor.

The bottom line is that the blood has everything that you need to know to understand disease biology, select treatment, and predict outcome.

Screening Potential Eventually, could liquid biopsy become part of routine cancer screening in healthy people? And what is the prognostic value of such a screening test—would you be able to determine whether the circulating cancer cells will progress to aggressive cancer or are safe to leave untreated?

In terms of screening healthy people, we are not at that point yet. Liquid biopsy analyses would have to be sensitive enough to detect when the tumor is really releasing cancer cells. We may imagine that the process of cancer development from in situ to invasive disease could be associated with the activation of innate immunity and such changes might be detected in the blood before they show up on an imaging scan. Another possibility could be the detection of products of tumor metabolism related to the cancer. continued on page 113

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 113

Perspective

Sequencing Analysis of Tumor DNA: Is It All in the Plasma?

By Britta Weigelt, PhD, and Jorge S. Reis-Filho, MD, PhD, FRCPath

M

assively parallel sequencing analyses have demonstrated that most of the common malignancies display relatively complex repertoires of somatic genetic alterations, that the number of highly recurrent mutations is limited, and that a large number of genes is mutated in a small minority of tumors from a given cancer type.1 In addition, there is evidence to demonstrate that a substantial proportion of tumors are composed of multiple clones that in addition to the mutations present in all cells (the founder genetic events), have mutations restricted to some populations of cancer cells.2 This intratumor genetic heterogeneity has also been documented by differences in the mutations found in anatomically distinct biopsies of a cancer3 or between biopsies of the primary tumor and of its metastatic lesions.4 Importantly, some of the mutations present in minor populations of tumor cells within a Dr. Weigelt is Assistant Member in the Department of Pathology at Memorial Sloan Kettering Cancer Center, and Dr. Reis-Filho is a Member in the Department of Pathology at Memorial Sloan Kettering Cancer Center, New York.

ctDNA is an undeniably appealing source of tumor material and may prove instrumental for the realization of the potentials of precision medicine.

—Britta Weigelt, PhD, and Jorge S. Reis-Filho, MD, PhD, FRCPath

Analyzing Circulating Tumor DNA to Monitor Disease

cancer have been shown to mediate resistance to specific therapies.

Blood-Borne Biomarkers Although the presence of circulating DNA in plasma has long been known, circulating cell-free plasma DNA (cf DNA) is detected in normal individuals, and its measure is of limited utility in oncology. With the development of highly sensitive sequencing technologies, there has

Massimo Cristofanilli, MD, FACP

Current Use

continued from page 112

How are you using liquid biopsies in your clinical practice?

Any patient who comes to my clinic with metastatic breast cancer can be evaluated with a number of tests, including imaging studies for staging, tissue biomarkers, and circulating tumor cells, so we can talk with the patient about her options and what the prognostic outcome looks like. Obviously, we try to be precise, and at the same time, we want to educate the patient.

Unfortunately, our approach to metastatic breast cancer has been to provide treatment recommendations even before understanding the implications of such a diagnosis.

We should be able to tell patients ev-

In terms of the prognostic value of circulating tumor cells, more data are needed to determine the accuracy of such an approach. The data suggest that if we are able to detect circulating tumor cells along with circulating macrophages, we will have the ability to predict both prognosis and what happens when the disease becomes resistant to treatment and likely to develop metastasis.

But what do you do with that information once you have the biology attached to it? Can you use secondary adjuvant therapy, for example, or is it safe to continue to monitor the cancer?

More research needs to be done to tell us how to act on this information.

also metastatic lesions and minimal residual disease.5-7 Sequencing analysis of ctDNA has been envisaged as a means to overcome the challenges posed by intratumor and interlesion genetic heterogeneity. Evidence suggests that massively parallel sequencing analysis of ctDNA from patients with advanced disease allows for the identification of the entire constellation of somatic mutations found in cancer cells, either from the primary tumor or from metastatic lesions.4,6-8

been renewed interest in this bloodborne biomarker, as it may constitute a minimally invasive source of tumor material that can be employed for sequencing analyses (ie, “liquid biopsies”). Circulating tumor DNA (ctDNA) in plasma comprises a fraction of cf DNA, and is believed to be shed in the bloodstream by cancer cells through apoptosis, necroptosis, or secretion (eg, exosomes) not only from the primary tumor, but erything they need to know about the state of their cancer, particularly when you are having a sensitive conversation about the prognosis of metastatic disease. If I know that the patient has a survival median of 30 months or more vs someone who has 12 months, I think the patient should have that information for a number of reasons. Either the treatment will likely not be effective and the patient needs to decide what to do, or there may be numerous options with which there is a possibility of long-term control. By itself, this makes having information about circulating tumor cells very useful. I have patients who want to know their circulating tumor cell level and want the test run every 3 months to see if there are any changes, because

Although ctDNA levels have been shown to be detectable in the majority of patients with advanced disease—in particular, those with bladder cancer, colorectal cancer, gastroesophageal cancer, pancreatic cancer, breast cancer, and melanoma6—only a small minority of patients with gliomas have been reported to have detectable levels of ctDNA in plasma.6 Hence, ctDNA detection may only be useful for patients with specific tumor types.

Given that ctDNA levels correlate with tumor burden, its detection in patients with early-stage cancers continued on page 114

they think this information is helpful in managing their life, and why not?

Once a patient becomes metastatic and has to deal with the devastating news that her disease is terminal, she wants to know exactly what else can be done and how to cope with the reality of her situation. I think we now have the technology to help us help our patients better understand their prognosis. n

Disclosure: Dr. Cristofanilli is on the clinical advisory board and a consultant for Cynvenio, a cancer diagnostics company based in Los Angeles.

Reference 1. Cristofanilli M, Budd T, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781-791, 2004.

The ASCO Post | SEPTEMBER 15, 2014

PAGE 114

Perspective

Sequencing Analysis of Tumor DNA continued from page 113

has proven to be more challenging.9 By the same token, as variations in ­ctDNA levels are associated with variations in tumor burden, studies investigating whether ctDNA levels could be employed for disease monitoring have revealed that this approach may offer a substantial lead time over traditional methods for the detection of metastatic disease.4,6-8 Numerous challenges remain for the translation of the immense potential of this approach into benefit for cancer patients. Current technologies that allow for the identification of the entire repertoire of mutations in a cancer have a sensitivity of approximately 1%. As the amount of ctDNA in cf DNA varies (and is often low in patients with low tumor burden), de novo discovery of mutations by plasma DNA analysis is not trivial.5 The sequencing techniques currently available for the detection of known or “hotspot” mutations, how-

ever, offer incredibly high levels of sensitivity. In fact, there is evidence to suggest that these techniques may be useful for disease monitoring in cases where the primary tumor has been previously subjected to sequencing or for patients with tumor types characterized by the presence of highly recurrent mutations, as well as for the identification of emerging mutations already known to result in therapy resistance.

Importantly, however, for the expeditious implementation of ctDNA analysis as a clinical tool, it will be essential to learn from experience with the translation of circulating tumor cell enumeration5 and molecular characterization10 into biomarkers and from previous high-throughput genetic analyses of tumors for clinical decision-making.

ctDNA Analysis in Clinical Decision-Making

References 1. Kandoth C, McLellan MD, Vandin F, et al: Mutational landscape and significance across 12 major cancer types. Nature 502:333-339, 2013.

2. Burrell RA, McGranahan N, Bartek J, et al: The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501:338-345, 2013.

3. Gerlinger M, Rowan AJ, Horswell S, et al: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883892, 2012.

4. De Mattos-Arruda L, Weigelt B, Cortes J, et al: Capturing intra-tumor ge-

ctDNA is an undeniably appealing source of tumor material and may prove instrumental for the realization of the potentials of precision medicine. Whether sequencing of ctDNA will render tumor biopsies redundant remains to be determined, particularly because of the strong association between ctDNA yield and disease burden and the technologic and bioinformatic developments required for de novo discovery of mutations based solely on ctDNA analysis.

Disclosure: Drs. Weigelt and Reis-Filho reported no potential conflicts of interest.

netic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: A proof-of-principle. Ann Oncol 25:1729-1735, 2014.

5. Bidard FC, Weigelt B, Reis-Filho JS: Going with the flow: From circulating tumor cells to DNA. Sci Transl Med 5:207ps14, 2013.

6. Bettegowda C, Sausen M, Leary RJ, et al: Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224ra24, 2014.

7. Dawson SJ, Tsui DW, Murtaza M, et al: Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368:1199-1209, 2013.

8. Murtaza M, Dawson SJ, Tsui DW, et al: Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497:108112, 2013.

9. Beaver JA, Jelovac D, Balukrishna S, et al: Detection of cancer DNA in plasma of patients with early-stage breast cancer.

Clin Cancer Res 20:2643-2650, 2014.

10. Krebs MG, Metcalf RL, Carter L, et al: Molecular analysis of circulating tumour cells-biology and biomarkers. Nat Rev Clin Oncol 11:129-144, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post

Sarah M. Friedewald, MD, and Gary J. Whitman, MD, on tomosynthesis in breast cancer screening see page 90 and 91

Antonis C. Antoniou, PhD, and Judy E. Garber, MD, MPH, on PALB2 mutations and breast cancer risk see pages 47 and 52

Jeffrey S. Abrams, MD, on the National Clinical Trials Network see page 86

Kenneth J. Pienta, MD, on cancer cell metabolism see page 152

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 115

2014-2015 Oncology Meetings September Celebrating 100 Years of Retinoblastoma Center in New York: 1914-2014 September 18-19 • New York, New York For more information: www.mskcc.org/events/cme Palliative Medicine and Supportive Oncology 2014 – The 17th International Symposium September 18-20 • Henderson, Nevada For more information: www.clevelandclinicmeded.com Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: www.aonnonline.org

European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress

18th SIS World Congress on Breast Healthcare October 16-19 • Orlando, Florida For more information: www2.kenes.com/sis/Pages/Home. aspx

2nd International Conference on Hematology & Blood Disorders September 29–October 1 • Linthicum, Maryland For more information: omicsgroup.com/hematologyblood-disorders-conference-2014/ index.php

2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org

Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29-October 2 • Cambridge, Massachusetts For more information: steelelab.mgh.harvard.edu

16th World Congress of Psycho-Oncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: www.cutaneousmalignancies.com

14th Annual Conference of SIOG October 23-25 • Lisbon, Portugal For more information: www.siog.org

20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/ home/programs/physicians

October

NCCN 9th Annual Congress: Hematologic Malignancies™ September 19-20 • New York, New York For more information: www.nccn.org/professionals/meetings/ hematological/ Cancer Survivorship Conference September 19-20 • Houston, Texas For more information: www.mdanderson.org/educationand-research/education-and-training/ schools-and-programs/cmeconference-management/conferences/ index.html Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr.org/home/scientists/ meetings--workshops/specialconferences/advances-in-melanomafrom-biology-to-therapy.aspx

2014-2015

ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org

American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

Atlanta Lung Cancer Symposium October 18 • Atlanta, Georgia For more information: www.phillipsgilmore.com/alcs2014

11th Annual Meeting of the International Society of Gastrointestinal Oncology (ISGIO) October 23-24 • Arlington, Virginia For more information: www.isgio.org

International Cancer Imaging Society Meeting and 14th Annual Teaching Course October 9-11 • Heidelberg, Germany For more information: www.icimagingsociety. org.uk/index. cfm?task=meetings&meetingid=37 11th Meeting of the European Association of NeuroOncology (EANO) October 9-12 • Turin, Italy For more information: www.eano.eu/mee_welcome.php

ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston, Massachusetts For more information: www.palliative.asco.org

2nd Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: cme.baptisthealth.net/ breastcancer/pages/index.aspx

11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org

2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org 3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org continued on page 116

The ASCO Post | SEPTEMBER 15, 2014

PAGE 116

2014-2015 Oncology Meetings continued from page 115

Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail. aspx/80028747 CNS Anticancer Drug Discovery/ Development Conference November 12-13 • Miami Beach, Florida For more information: www.soc-neuro-onc.org Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: www.mayo.edu/cme/surgicalspecialties-2014s306 19th Annual Meeting of the Society for Neuro-Oncology November 13-16 • Miami Beach, Florida For more information: www.soc-neuro-onc.org/ EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org ESMO Symposium on Immuno-Oncology November 21-22 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ Immuno-Oncology-2014

European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl

2014-2015

ASH Annual Meeting and Exposition December 6-9 • San Francisco, California For more information: hematology.org

RSNA 2014: Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

December American Association for Cancer Research: Tumor Immunology December 1-4 • Orlando, Florida For more information: www.aacr.org Society of Urologic Oncology 15th Annual Meeting December 3-5 • Bethesda, Maryland For more information: http://suonet. org/meetings/2014/default.aspx UICC World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org 24th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists December 5-7 • Vienna, Austria For more information: iasgo2014.org

SAVE THE DATE

NP FOR s AN YOU D PAR s

37th Annual San Antonio Breast Cancer Symposium December 9-13 • San Antonio, Texas For more information: www.sabcs.org

January 2015 Melanoma 2015: 25th Annual Cutaneous Malignancy Update January 10-11 • San Diego, California For more information: www.scripps.org/events/melanomaannual-cutaneous-malignancyupdate-january-10-2015 Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org 11th Annual Clinical Breakthroughs and Challenges in Hematologic Malignancies January 17 • Lake Buena Vista, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

February

October 30TH – November 2ND Loews Royal Pacific Hotel at Universal Orlando, FL

A CE/CME/CEU Conference for Advanced Practitioners in Oncology

apsho.org/jadprolive

2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11-15 • San Diego, California For more information: www.asbmt.org

5th International Conference on Innovative Approaches in Head & Neck Oncology February 12-14 • Nice, France For more information: www.estro.org/congresses-meetings/ items/5th-ichno The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 19-21 • San Diego, California For more information: www.imedex.com/anti-angiogenesisand-immune-therapies/ Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org 6th Current Concepts in the Management of Thyroid and Parathyroid Neoplasms February 26-28 • Houston, Texas For more information: www.mdanderson.org 32nd Annual Miami Breast Cancer Conference® February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/32nd-Annual-MiamiBreast-Cancer-Conference

March 13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers March 5-8 • Orlando, Florida For more information: www.aacr.org 16th European Congress: Perspectives in Lung Cancer March 6-7 • Torino, Italy For more information: www.imedex.com/lung-cancercongress-europe/index.asp

continued on page 125

The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1,2

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

as a single agent

overall response rate1 overall response rate1

76 54%

% (95% CI: 62, 87)

median duration of response1

(95% CI: 40, 67)

median duration of response1

10.5 5.6

months

(95% CI: 7, 15)

months

(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 MAP-kinase signaling and increased cell proliferation in BRAF wild-type 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.

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1 Major efficacy outcome: Investigator-assessed response rate1 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

60

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible.

Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

50 40 30 20 10 0

9%

4

%

Complete Response

Partial Response

TAFINLAR as a single agent (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. Retinal detachments resulting from MEKINIST are often

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1 Efficacy outcome: Investigator-assessed median duration of response1

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months Months TAFINLAR as a single agent (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1 • 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 – 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

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1.

If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent.

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

®

(dabrafenib) 50 mg, 75 mg capsules

®

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

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 Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al.

N Engl J Med. 2012;367:1694-1703.

TAFINLARMEKINISTHCP.com TAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved.

Printed in USA. MEL156R0 July 2014

®

(dabrafenib) 50 mg, 75 mg capsules

®

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

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 Adverse Reactions Gradesa 3 and 4 Gradesa 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 45 0 43 Rashc Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

0

8

2

0

2

0

0

9

2

0

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.

Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute.

Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness.

Gastrointestinal Disorders: Stomatitis, pancreatitis.

General Disorders and Administration Site Conditions: Asthenia.

Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.

Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

b

All All All Grades Grades Grades Grades 3 and 4 Grades 3 and 4 Grades 3 and 4a Tests Hematology Leukopenia 62 5 46 4 21 0 Lymphopenia 55 22 59 19 40 6 Neutropenia 55 13 37 2 9 2 Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0 Liver Function Tests Increased AST 60 5 54 0 15 0 Increased alkaline 60 2 67 6 26 2 phosphatase Increased ALT 42 4 35 4 11 0 Hyperbilirubinemia 15 0 7 4 0 0 Chemistry Hyperglycemia 58 5 67 6 49 2 Increased GGT 56 11 54 17 38 2 Hyponatremia 55 11 48 15 36 2 Hypoalbuminemia 53 0 43 2 23 0 Hypophosphatemia 47 5 41 11 40 0 Hypokalemia 29 2 15 2 23 6 Increased creatinine 24 5 20 2 9 0 Hypomagnesemia 18 2 2 0 6 0 Hyperkalemia 18 0 22 0 15 4 Hypercalcemia 15 0 19 2 4 0 Hypocalcemia 13 0 20 0 9 0 a 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.

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 © 2014 GSK group of companies.

All rights reserved. Printed in USA. MEL156R0 July 2014

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2014-2015 Oncology Meetings continued from page 116

Advances in the Management of Multiple Myeloma March 6-7 • Saint Petersburg, Florida For more information: http://moffitt. org/for-physicians-healthcareprofessionals/conferences/ conferences Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial SloanKettering Cancer Center March 6-9 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse Advanced Prostate Cancer Consensus Conference March 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

State-of-the-Art Neuro-Oncology Conference: 3rd Annual Meeting March 19-20 • Clearwater Beach, Florida For more information: http://moffitt. org/for-physicians-healthcareprofessionals/conferences/ conferences 21st Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 19-21 • Stevenson, Washington For more information: www.ohsu.edu/bbb Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/ EORTC-EANO-ESMO 2015 March 27-28 • Istanbul, Turkey For more information: www.ecco-org.eu/Events/EORTC_ EANO_ESMO-2015

NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp 8th Annual Interdisciplinary Prostate Cancer Congress™ March 14 • New York, New York For more information: http:// www.gotoper.com/conferences/ ipcc/meetings/8th-AnnualInterdisciplinary-Prostate-CancerCongress American Society of Preventive Oncology (ASPO) Annual Meeting March 15-17 • Birmingham, Alabama For more information: http://aspo.org/annual-meeting ACCC 41st Annual National Meeting March 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ calendar.asp

2014-2015

ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: http://www.esmo.org/Conferences/ ELCC-2015-Lung-Cancer American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org ONS 40th Annual Congress April 23–26 • Orlando, Florida For more information: www.ons.org/conferences/ congress-2015 3rd ESTRO Forum April 23-28 • Barcelona, Spain For more information: http://www.estro.org/congressesmeetings/items/3rd-estro-forum

May The 28th Annual Meeting of the American Society of Pediatric Hematology/Oncology May 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/content/ annualmeeting.html

46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

June International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/ 2015 Clinical Update: 21st Century Prevention of HPV-Associated Cancer June 5-7 • Baltimore, Maryland For more information: www.asccp. org/Education/2015-21st-CenturyPrevention-of-HPV-Associated-Cancer Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org The International Society of Ocular Oncology (ISOO) Meeting June 16-19 • Paris, France For more information: http://www.isoo.org Anticancer Drug Action and Resistance: from Cancer Biology to the Clinic June 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015 MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July

April American Brachytherapy Society Annual Meeting April 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index.cfm

American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org

Hematologic Malignancies: New Therapies and the Evolving Role of Transplant April 10-11 • Chicago, Illinois For more information: www.mayo.edu/cme/hematologyand-oncology-2015r919

ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28–August 1 • Washington, DC For more information: http://www.apos-society.org/ professionals/meetings-ed/ annualconference.aspx Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

The ASCO Post | SEPTEMBER 15, 2014

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Book Review

Cancer Frontier: Bringing the New Sciences to an Old School

By Ronald Piana

C

ancer seems to have an endless supply of people who want to write about it. Why not? It’s an intriguing subject of life and death and struggle and hope, one that touches virtually every person of a certain age.

However, the bookshelves are filled with cancer survivorship books, so to stand out, an author must have an especially compelling story.

Likewise, books detailing scientific advances in the battle against cancer also abound. Then there’s Siddhartha Mukherjee’s Pulitzer Prize winning tome, The Emperor of All Maladies, which offers a biography of cancer, beginning in 1947 as Dr. Sidney Farber began his earnest research and treatment of childhood leukemia. Vying to make its place in this crowded field

Bookmark Title: On the Cancer Frontier: One Man, One Disease, and a Medical Revolution Authors: Paul A. Marks, MD, and James Sterngold Publisher: PublicAffairs, New York Publication date: March 11, 2014 Price: $26.99; Hardcover, 272 pages

is a new book by noted cell biologist and President Emeritus of Memorial Sloan Kettering Cancer Center, Paul A. Marks, MD, titled On the Cancer Frontier: One Man, One Disease, and a Medical Revolution.

Career in Cancer Written with journalist James Sterngold, Dr. Marks tells an autobiographical account of his career in cancer, beginning in his third year at the College of Physicians and Surgeons, Columbia University Medical School, New York. Dr. Marks recalls his early days on rotation in the pediatrics ward.

A teenage girl diagnosed with lymphoma had captivated him with her buoyant spirit and will to live. Then came the experience shared among all young oncologists. “One day, my young cancer patient just seemed to fall asleep as she slipped into a coma and then passed away. I asked myself, was this really the best my profession had to offer?” Dr. Marks offered.

Dr. Marks continues his opening chapter reviewing background science and some historical inflection points in cancer care. Here the reader will also learn that Dr. Marks was an early skeptic about the war metaphor used to rally the scientific troops after President Nixon signed the National Cancer Act into law in 1971. By then, Dr. Marks was Dean of Columbia’s medical school. He wrote, “Wars are won and lost; this is a contest with our inner mature, our inner mechanisms. We can, in time, control them, but not ‘defeat’ them.”

So concerned about what he felt was the wrongheaded obsession with a cure, he wrote a letter to the Chairman of the President’s Cancer Panel, boldly expressing his worry. “It was an impulsive gesture … but that letter altered my career and, perhaps, helped influence the direction the ‘war’ would take.”

Science and Politics In On the Cancer Frontier, Dr. Marks seeks to enrich the reader with the history of cancer care as seen through the experiences of an eminent oncologist,

well-traveled and well-versed in both the science of cancer, false hopes and all, and the politics in the hierarchy of the oncology world. The book is also written to inform but not intimidate the lay reader.

To that end, the book succeeds, largely due to the skill of journalist James Sterngold who keeps proper pacing between the expository and the anecdotal.

Since this book is lay public–friendly, what does it offer readers of The ASCO Post and others in the professional oncology community? On the cancer science front, there’s not a lot of information that will be of interest. But that gripe is small, because the true value of this book lies in the telling of stories that oncologists, especially those just entering the field, will find enlightening and fun to read.

For instance, Dr. Marks is passionate about absolute honesty in every aspect of oncology. He neatly describes a time when his passion boiled over at an informal gathering of researchers at Columbia University. “A faculty member had tried to impress us with what I believed were exaggerated data from experiments in gene expression. It seemed to me that he was on a big ego trip, so I challenged him.

As the argument grew heated, I reached out, grabbing him by both arms, shaking him, and demanding that he stop massaging the data—an episode reported some years later, to my embarrassment, in the New York Times Sunday Magazine, in a cover story about my leadership of Memorial Sloan Kettering.”

Agent of Change Given his stature as a leader and agent of change in the history of Memorial Sloan Kettering, the reader will anticipate reaching the point in the book when, in 1980, Dr. Marks becomes the first President and CEO of a unified—previously, Memorial Hospital and Sloan-Kettering Institute—Memorial Sloan Kettering Cancer Center. It’s worth the wait.

Dr. Marks gives a fly-on-the-wall description of meetings with Memorial’s then Chairman of the Board, Laurance Rockefeller, whose father, Nelson

Rockefeller, was an original patron of the institution. By now, Dr. Marks had already turned down a leadership role at The University of Texas MD Anderson Cancer Center and was itching for a challenging opportunity. During a cocktail party at the Rockefellers’ suite, Laurance Rockefeller confided in Dr. Marks while showing him his art collection that included Renoir, Matisse, Picasso, and other masters.

Rockefeller whispered, “You don’t realize it, I don’t even think Mary [his wife] realizes it, but all these paintings are copies. I had the originals copied so we could place them in museums. Each copy is exactly one inch larger than the original, so they wouldn’t be confused.”

After Dr. Marks takes the position, the rest, as they say, is history. In chapter 12, one of the book’s strongest sections, Dr. Marks brings the reader into an exciting and rewarding part of Memorial Sloan Kettering’s history. The title says it all: “Enlisting a Major New Ally—the Cancer Patient.” This is when Memorial takes a lead in palliative care, bringing in Kathleen M. Foley, MD; psycho-oncology, enlisting the pioneer, Jimmie C. Holland, MD; and eventually, integrative oncology, with another pioneer, Barrie R. Cassileth, MS, PhD. This section will make every reader feel good about those on the front lines of cancer care.

Closing Notes The book ends with the chapters “Cancer Screening as a Way of Life,” which is certain to receive its share of criticism from those who are skeptical of some of the modalities touted by Dr. Marks, and finally, “The Next Leap,” which may leave readers, at least those knowledgeable in health-care policy, a bit disappointed. Much of it is rehashed information that can easily be challenged.

That said, Dr. Marks and Mr. Sternberg set out to inform and entertain.

Mission accomplished. This is a worthwhile book that should make its mark in the increasingly popular area of cancer care history. n

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PAGE 127

Reflections

I Work for You

By James O. Armitage, MD marrow transplant, an autologous procedure, using his own stem cells.

He was in remission for a brief period, and the disease recurred. This time it was very aggressive. He had huge

tumor masses on his back and lots of cancer cells circulating in his blood. At the time, MCL patients—some 6% of all non-Hodgkin cases—survived perhaps 3 years.

As it turned out, he had a matched sibling donor, a brother. An allogeneic stem cell transplant was a possibility, though in my view, it was an exceedcontinued on page 128

For Your Patients James O. Armitage, MD

The following essay by James O. Armitage, MD, is excerpted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was co-edited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon .com and at thebigcasino.org.

New Cancer Survivorship Guide This Resource Helps Patients Transition Into Life After Active Treatment Has Finished

Going back to work For many people, returning to a full-time work schedule is a sign both to themselves and the world of getting back to “normal.” Working can provide opportunities to reconnect with colleagues and friends, focus on something other than cancer, get involved in interesting and challenging projects, and start settling back into a regular routine and lifestyle.

However, transitioning back into the workforce may feel overwhelming at times.

T

he first thing I say to a new patient: “You need to know who works for whom around here. I work for you. Not the other way around.”

I’ve spent more than 30 years as a researcher at the University of Nebraska Medical Center, specializing in lymphomas. In 1983, I founded the Center’s Bone Marrow and Transplant Program. Today, it’s one of the busiest in the world, with more than 4,000 transplant procedures performed. Despite the numbers, so many of these patients have stayed with me because of who they are or what they’ve taught me.

In the 1990s, a successful businessman in his mid-50s was diagnosed with mantle cell lymphoma (MCL), one of the rarest forms of non-Hodgkin lymphoma. In fact, we’d just figured out there was such a thing when he showed up. He’d had chemotherapy, went into remission, but soon relapsed. I gave him an alternate form of chemotherapy that put him into remission, and did a bone

Dr. Armitage is the Joe Shapiro Professor of Medicine at the University of Nebraska Medical Center, Omaha. “I Work for You” is excerpted from The Big Casino with permission from the book’s publishers, Stan Winokur, MD, and Vincent Coppola.

Additional essays from The Big Casino will be published in future issues of The ASCO Post.

Every survivor’s work situation is different. Many people with cancer who took time off for treatment return to work afterwards, while many others may have worked throughout treatment. Still others may not be able to return to work because of long-term side effects. Your decisions about work will likely depend on your financial resources, health insurance, the type of work you do, and the nature of your recovery.

Cancer Survivorship Trusted Information About Life After Treatment From the American Society of Clinical Oncology

PLANNING YOUR RETURN For survivors who cut back on their hours or stopped working, the first step is to talk with your doctor about whether you are ready to return to work. The timing depends on the type of cancer and treatment you had and the type of job you perform. If your job is stressful or physically demanding, you may need to wait longer before returning to work. Ongoing treatment or side effects, such as fatigue, may also cause delays.

Once you know it’s okay to return to work, a good next step is to set up a telephone or in-person meeting with your human resources department to discuss transition plans.

Ask whether your employer has a formal “return-to-work” or disability management program. You may also want to discuss the possibility of flexible work arrangements, such as part-time hours, partial or full-time telecommuting, job sharing, reassignment to another position, leave time for doctor visits, or periodic work breaks to take medications 24

ASCO Answers

Trusted information about coping with psychological, physical, sexual, reproductive, financial, and work-related challenges Descriptions of the rehabilitation and support services available to help the transition into everyday life A blank treatment summary and follow-up care plan patients and providers can fill out together

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and contact members of your health care team. These are all considered reasonable accommodations under the Americans with Disabilities Act (ADA).

Before granting a reasonable accommodation, your employer may request documentation that verifies your limitations, such as fatigue, chronic pain, and cognitive difficulties, which are classified as disabilities under the ADA. However, employers are not allowed to ask for your medical records.

An employer may deny a request if the accommodation would cause an “undue hardship,” such as being too difficult or expensive to implement. However, an employer is required to determine if there is an easier or less costly accommodation that can be made to meet your needs.

Other things to consider to make your transition back to work smoother include: • Planning to take small breaks throughout the day to help maintain your energy level • Using lists and reminders or setting meeting and task alarms on your office e-mail system • Scheduling frequent meetings with your manager to talk about the transition and make any necessary changes or adjustments

TALKING WITH COWORKERS It’s your decision when and how to tell coworkers about your cancer experience, if you even decide to talk about it at all. However, if you have been absent for a while or your

The ASCO Post | SEPTEMBER 15, 2014

PAGE 128

Reflections I Work for You

Taking Care of People, Not Diseases

continued from page 127

ingly long shot. We had a long talk.

“I feel really good about this,” he told me.

“I don’t think it’s a great idea,” I said.

“You have other medical issues. There’s the possibility of graft-vs-host disease.

You’re older than I think is safe to do it.”

What I didn’t say, but I was definitely thinking: It’d be easier to smother you with a pillow. He’d die and it would be a bad death.

“Nope, I feel right about this,” he insisted. “I’m going to do it!”

I believe a physician gives his or her best advice. If a patient wants to do something that’s not illegal or immoral, the physician is obligated to do it. If not, he needs to refer the patient elsewhere. The first thing I say to a new patient: “You need to know who works for whom around here. I work for you.

Not the other way around.”

So we went ahead. And it was the smoothest allogeneic transplant ever.

He never had graft-vs-host disease and promptly went into complete remission. This was about 18 years ago. We became good friends, but that didn’t stop him from sending me these little notes: “You know, Jim, it’s now been 5,814 days since my transplant….”

You never know about these things. Thinking you know the future and what’s always best for your patients isn’t a safe thing for physicians to be doing.

In my lifetime, we’ve gone from not understanding lymphoma very much at all to understanding it a lot. Progress has been incremental, but it turns out lymphomas are among the cancers most responsive to therapy. So my patients almost always get better and very often are cured. I can’t help but remember the ones who didn’t make it. One year later, or 10 years later, and it could have turned out differently.

After medical school, I spent 2 years in private practice in Omaha. I learned that physicians are supposed to take the patient’s side. I came to appreciate what

to undergo unpleasant tests to figure out where it is, you’re going to have unpleasant treatments that can have long-term effects, and then after you’re well, you’re going to spend each day worrying if the thing is going to come back and kill you.

This is not a great deal.

The line I take is, “If it’s such a great deal, he can have it!” It’s wise to remember the patient’s position when we talk to them. We take care of people, not diseases.

Living Life to the Fullest I was born in Hollywood, but grew up in the Midwest, in Kearney, Nebraska, probably one of the few people in

It’s wise to remember the patient’s position when we talk to them. We take care of people, not diseases.

—James O. Armitage, MD

helped referring physicians—what they considered friendly and unfriendly in a research program. Doctors are just like everybody else. There are nice ones and less nice ones, smarter ones and less smart ones. You treat people the way you’d like to be treated.

Before a patient gets to me, they’ve seen other physicians. Maybe they’ve heard, “How lucky you are to have gotten Hodgkin!” I’m very anti-that. What they meant was, “Isn’t it great you don’t have pancreatic cancer?” True. If you have to choose between the two, Hodgkin is much, much better, but you’re still going

the United States who can make that claim. My dad was a postal worker. As a kid, I spent a lot of time with a bunch of illnesses, one of which might have been tuberculosis. When I was 12, one of my grade-school classmates, a boy named David, died of leukemia. I guess these things influenced me, although at various times I wanted to be a biologist, a game warden, and a chemist.

I’ve mentioned the amazing advances we’ve made in treating lymphoma, but the truth is, things never advance fast enough if you have a patient who can’t be fixed with what you know right now.

A few years back, a man from Boston— maybe the smartest person I’ve ever known—showed up. He had all sorts of important friends; a famous actor/comedian accompanied him on his first visit.

He’d been referred to me because we were one of the first to do bone marrow transplants. He had this bad kind of lymphoma—peripheral T-cell—that’s rare and doesn’t respond well to treatment.

He seemed a good candidate for a transplant. I gave him chemotherapy; it wasn’t successful. Another approach using radiation did put him into remission. I did a transplant and he had unbelievably hard complications. He had terrible toxicity; his skin fell off like a burn.

He survived, but it was touch and go.

Three months after the transplant, the lymphoma returned. At this point, he was losing his enthusiasm for my ideas.

I was too. We finally tried interferon, which seemed the best of our choices and one he could imagine taking. He went into remission in 2 or 3 weeks.

Here’s this ultra-successful, incredibly rich, driven guy, who worked 80 hours a week. He’d spend part of the week working in Europe, then fly back: an amazingly intense person. In retrospect, he was well for 5 years. He fell in love, got married, and did the things he wanted to do.

His disease returned and he decided he didn’t want to pursue more therapy.

I really do believe he lived more in the 5 years after diagnosis than his 50-odd years before.

I think he would say that. n

Coming in Future Issues of The ASCO Post Coverage of the 2014 Breast Cancer Symposium held September 4-6, 2014, in San Francisco, including: ■■ A study assessing the impact of Angelina Jolie’s preventive double mastectomy on genetic testing referrals at one academic cancer center (Abstract 44).

■■ A randomized study evaluating the effect of reminder letters from family physicians on screening mammography return rates among women overdue for screening (Abstract 1).

■■ Findings from a survey evaluating the factors associated with a preference for contralateral preventive mastectomy (Abstract 71).

■■ Results from an analysis of locoregional recurrence rates in patients with breast cancer after treatment with neoadjuvant (preoperative) chemotherapy (Abstract 61).

■■ A comparison of 30-day complications after double vs single mastectomy with immediate breast reconstruction (Abstract 62).

Visit ASCOPost.com to view the complete contents of The ASCO Post.

ASCOPost.com | SEPTEMBER 15, 2014

PAGE 129

Awards

ASTRO Awards Seven Physicians a Total of $675,000 to Fund Radiation Oncology-Specific Studies

T

he American Society for Radiation Oncology (ASTRO) presented seven physicians a total of $675,000 in awards and grants to advance radiation oncology research. The awards will fund studies in radiation and cancer biology, radiation physics, translational research, outcomes/health services research, and comparative effectiveness research within radiation oncology. Recipients were recognized at ASTRO’s 56th Annual Meeting earlier this month in San Francisco.

“High-quality research is essential to advancing radiation oncology and to providing the best possible treatments for our patients,” said ASTRO Chair Colleen A.F. Lawton, MD, FASTRO. “ASTRO is proud to support these seven outstanding researchers in their work to improve radiation oncology and cancer care.”

Junior Faculty Career Research Training The ASTRO Junior Faculty Career Research Training Award provides $100,000 annually for 2 years to two winners ($200,000 to each recipient) to support the careers of promising junior faculty by offering them the opportunity for dedicated time to work on research projects in radiation oncology,

ing to determine if phar macolog ical ascorbate can be used to modulate chemoradiation sensitivity in nonsmall cell lung cancer and therefore be utilized to improve Bryan Allen, MD, PhD outcomes in lung cancer treatment.

• Stephen Shiao, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles. Dr. Shiao is researching the mechanisms by which blocking interleukin (IL)-4, a cytokine that controls the development of macrophages that suppress an ongoing immune response, enhances solid tumor response to radiation therapy.

Residents/Fellows in Radiation Oncology Research The ASTRO Residents/Fellows in Radiation Oncology Research Seed Grant awards $25,000 for 1-year projects to residents and fellows who are planning to pursue careers focusing on basic science or clinical research in radiation oncology services.

The three 2014 grant recipients are: • Zachary Morris, MD, PhD, of the University of Wisconsin Hos-

High-quality research is essential to advancing radiation oncology and to providing the best possible treatments for our patients.

—Colleen A.F. Lawton, MD, FASTRO

biology, physics, or outcomes/health services. Recipients must be board-eligible physicians, physicists in radiation oncology or radiobiologists within the first 3 years of their junior faculty appointment.

The two 2014 ASTRO Junior Faculty Career Research Training Award recipients are: • Bryan Allen, MD, PhD, of the University of Iowa Hospitals and Clinics in Iowa City. Dr. Allen is work-

pitals and Clinics in Madison. Dr. Morris is comparing the efficacy of combinations of radiation, a tumor-specific antibody that elicits antibody-dependent, cell-mediated cytotoxicity, and a checkpoint inhibitor with respect to the control of local, distant (non-radiated) and reintroduced sites of disease to evaluate the immune response to these treatments. Previous research suggests radiation may comple-

Stephen Shiao, MD, PhD

Zachary Morris, MD, PhD

Tu Dan, MD

Todd Aguilera, MD, PhD

Benjamin Smith, MD

James Murphy, MD, MS

ment immunotherapies by enhancing the immune susceptibility of tumor cells.

• Tu Dan, MD, of Thomas Jefferson University in Philadelphia. Dr. Dan is examining the inhibition of miR-21, an oncogenic microRNA, to overcome treatment resistance and to sensitize tumors to DNAdamaging agents in radioresistant breast cancer.

• Todd Aguilera, MD, PhD, of Stanford University Cancer Center in Stanford. Dr. Aguilera is investigating why tumor immunity often does not occur in a checkpoint blockade setting and is evaluating the Abscopal Effect of radiation that, when combined with radiation, can lead to immune responses in untreated tumors.

Comparative Effectiveness Research The ASTRO/ROI Comparative Effectiveness Research Award provides $50,000 annually for 2 years to two researchers ($100,000 to each recipient) who will conduct comparative effectiveness research examining radiation oncology treatment. At the time the award begins awardees are board-

certified or board-eligible physicians in radiation oncology and are focused on academic radiation oncology. The two 2014 recipients are: • Benjamin Smith, MD, of The University of Texas MD Anderson Cancer Center in Houston. Dr. Smith is working to improve and personalize the selection of local therapy in older women with localized, estrogen receptor–positive breast cancer by comparing quality of life outcomes for patients treated with four local therapy options: lumpectomy with whole breast irradiation, lumpectomy with brachytherapy, mastectomy without radiation, and lumpectomy with endocrine therapy alone.

• James Murphy, MD, MS, of the University of California, San Diego. Dr. Murphy is examining the patterns of hypofractionated breast radiation, studying the comparative effectiveness and assessing the patient or provider characteristics associated with the use of hypofractionated vs standard fractionated radiation therapy.

For more information about ASTRO-supported grants and awards, visit www.astro.org/grants. n

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Integrative Oncology

The Role of Music Therapy in Cancer Care

By Karen Popkin, LCAT, MT-BC, HPMT

M

usic therapy, an established adjuvant to standard cancer care, is offered in a growing number of cancer centers throughout the United States and internationally. Defined by the American Music Therapy Association (AMTA) as “the evidence-based use of music interventions to accomplish individual goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program,”1 music therapy has a well-established place in integrative oncology.

Music therapy aims to support the coping strategies of patients who experience a range of physical, psychological, emotional, and spiritual suffering.

Music therapists create a milieu within which the cancer patient can engage with the therapist. Goals may include promotion of wellness, stress management, pain alleviation, expression of feelings, memory enhancement, improved communication, and enabling of physical rehabilitation.

Once a rarely offered therapy, both the profession and therapeutic intervention have grown substantially. In the United States, 30 of 41 National Cancer Institute–designated Comprehensive Cancer Centers offer music therapy for patients, and many community cancer centers do as well.

Professional organizations and training programs exist throughout the world. In 2011, the AMTA reported that its members live in 30 countries and six continents around the globe.

The World Federation of Music Therapy has regional liaisons representing professionals and training programs across North America, Europe, Australia/New Zealand, South East Asia, South Africa, the Western Pacific, Eastern Mediterranean, and Latin America.2 In her newly published book, “Survivorship: Living Well During and After Cancer,” Barrie Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York, offers valuable insights for cancer patients and families on a wide spectrum of integrative cancer treatment approaches, including music therapy.3

Ms. Popkin is Manager of the Music Therapy Program in the Integrative Medicine Service, at Memorial Sloan-Kettering Cancer Center, New York.

Some excerpts on music therapy are included on these pages.

Music Therapy at Memorial Sloan Kettering At Memorial Sloan Kettering Cancer Center, the Music Therapy program, supported by a grant from Gabrielle’s Angels Foundation for Cancer Research, serves pediatric and adult inpatients and their families. Therapists who are boardcertified by the Certification Board for Music Therapists and licensed by New York State work with patients at bedside and in small groups, customizing interventions designed to address the needs of each patient. An integral part of the Integrative Medicine Service, the program was established in the year 2000 and has maintained a continuously active presence since that time.

to improve mood4,5 and reduce anxiety and pain.6-8 Techniques for individual sessions vary according to the needs, abilities and preferences of the patient.

Environmental music therapy is provided in various areas within the hospital, such as the Post Anesthesia Care Unit and the Pre-Surgical Unit, offering a powerful way to influence the hospital environment, as patients cope with stressors surrounding surgery and recovery. Staff members also describe a sense of personal benefit from the environmental music therapy, citing stress reduction as helpful to job performance.

A recent important extension of the Memorial Sloan Kettering music therapy program is the Rising Voices Chorus.

This is the first North American chapter of Something to Sing About, a global network of choirs for cancer survivors.

As researchers continue to integrate neuroscientific findings on how music impacts the human brain, we may see more studies examining biomechanisms in music therapy as well as new situations in which music therapy can play a role in the care of patients with cancer.

—Karen Popkin, LCAT, MT-BC, HPMT

This inpatient music therapy program provides physical, emotional, psychological, and spiritual benefit, applying the various elements of music, which include rhythm, melody, tone, harmony, and lyrics. The therapy helps ease patients’ fear and anxiety, enhances creative expression, helps manage symptoms, and promotes relaxation and comfort. Available to hospitalized patients of all ages, music therapists work throughout Memorial Sloan Kettering’s inpatient areas to help restore a critical sense of control over mind and body at a time of paramount uncertainty. Music therapists often serve in an interdisciplinary capacity, working in tandem with physical therapists, occupational therapists, social workers, and chaplains.

Bedside visits are a primary feature of the program. Sessions for patients who are in isolation for extended periods of time, such as those undergoing hematopoietic stem cell transplantation, report that music therapy helps

The group meets regularly to provide survivors the opportunity to experience the aesthetic pleasure, social bonding, group support, and community service benefits of group singing.

Music therapy referrals often request support and comfort care for end-of-life Music therapists connect with their patients through sound and song, rather than words. As musicians who are also trained counselors, they typically bring portable instruments to the bedside, allowing patients to participate in playing, singing or writing songs.

This type of therapy often benefits both the patient and his or her family. It can reduce anxiety, depression, and pain, as well as encourage communication.

—From Cassileth B: Suvivorship: Living Well During and After Cancer, p 147.3

From the family of a patient following her death: The music that you brought to Mom during her hospital stays gave her some of the most joyful moments she was able to experience in her final weeks, even when she was in terrible pain and distress. We cannot thank you enough for that gift, and for the meaningful time we were able to share as a family while you played and sang to her. Please know that you have our everlasting gratitude for the pleasure you brought to Mom. —From Cassileth B: Suvivorship: Living Well During and After Cancer, p 132.3

patients. Family members frequently benefit from this intervention as well, at a time when it can be most difficult to attain a sense of peace and calm. The music therapist may include music that is spiritually relevant to the patient, and can facilitate the participation of family when appropriate.

Music Therapy vs Environmental Music Although there is growing recognition of how music affects cognition, mood, and physical energy or motivation to move, some studies do not clearly define the difference between music therapy and environmental music. A major distinction is that in the former, a music therapist assesses the needs of the individual patient, enters into an interpersonal therapeutic relationship, and adjusts music interventions in real time according to patient needs. These important components are absent with environmental music, which can benefit many patients at once.

In the case of environmental music, sometimes called “music medicine,” the patient typically is offered a passive listening experience with recorded material, usually preselected by health-care providers. An opportunity for the patient to reflect and explore the meaning of the music does not occur. The music method applied is a matter of great importance when reviewing the literature.

Some of the most important music therapy studies in oncology are briefly summarized below.

Clinical Research Music therapy researchers are increasingly turning their attention to best practices, such as the randomized

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Integrative Oncology trial reported earlier this year from a group at Indiana University.9 The study tested a specific music therapy intervention, Therapeutic Music Video (TMV), which is designed to improve resilience in adolescent and young adult patients undergoing stem cell transplantation.

A total of 113 patients aged 11 to 24 undergoing stem cell transplantation When used with typical antiemetic medications, music therapy may help to further reduce nausea and vomiting from chemotherapy. At the very least, it can relieve stress and reduce blood pressure, lower heart rate, and promote general well-being. Even something as simple as music can be very powerful.

—From Cassileth B: Suvivorship: Living Well During and After Cancer, pp 156-157.3

for cancer were randomly assigned to a TMV intervention group or a control group that received audiobooks.

Participants completed six sessions over 3 weeks. The TMV group demonstrated significantly better measures of courageous coping, social integration, and family environment. Study results support the use of a music-based intervention delivered by a music therapist to help adolescents and young adults positively cope with high-risk, highintensity cancer treatments.

Investigators in Southern Taiwan studied the effects of music therapy and verbal relaxation on anxiety in outpatients receiving chemotherapy.10 They randomly assigned 98 patients to three groups: music therapy, verbally guided relaxation, and standard care. Efficacy was measured using the Spielberger State-Trait Anxiety Instrument, Emotional Visual Analog Scale, and three biobehavioral indicators (skin temperature, heart rate, and consciousness level) measured during and after chemotherapy. The researchers found that music therapy had a greater positive effect on postchemotherapy anxiety than did verbal relaxation or control groups.

Patients with high baseline anxiety receiving music therapy had a greater drop in postchemotherapy anxiety than

did those with a predefined “normal” state of anxiety in a subset analysis.

Palliative care teams frequently include music therapists as part of a multidisciplinary approach to the treatment of pain. Researchers at University Hospitals–Case Medical Center found that a single music therapy intervention incorporating therapistguided relaxation and live music effectively lowered pain in palliative care patients.11 In this study, 200 inpatients were randomly assigned to standard care with vs without music therapy.

Pain was assessed using a numeric rating scale as the primary outcome and the Functional Pain Scale as a secondary outcome. The Face, Legs, Activity, Cry, Consolability (FLACC) scale also was applied as a secondary outcome. Significantly greater decreases in both pain measure scores were seen in the music therapy group; scores did not differ between study groups per the third scale.

The above examples demonstrate the ability of music therapy to be used in a variety of oncologic investigational settings. More research will enable better understanding of biomechanisms, Music therapy harnesses the power of music to uplift our moods and arouse our emotions. It involves performing, creating, or listening to music to encourage healing and promote a general sense of well-being. Patients listen to or perform music with the guidance of a professional music therapist.

The therapist can help to develop lyrics, improvise with the patient, or simply provide technical and emotional support. The practice can enhance relaxation, creativity, pleasure, and self-expression while helping to reduce pain and feelings of isolation. Music therapy is provided by musicians who received training, typically graduate training, in the use of music (rather than only words) as therapy. It is especially helpful in a hospital setting.

—From Cassileth B: Suvivorship: Living Well During and After Cancer, pp 120-121.3

Learn More About

Herbs, Botanicals, & Other Products

GUEST EDITOR

I

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.

The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and maintains a free website—About Herbs (www.

Barrie R. Cassileth, MS, PhD mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 269 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.

In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http://itunes.apple.com/us/app/ about-herbs/id554267162?mt=8. dosage, and clinical indications that may be especially amenable to music therapy. Finally, as researchers continue to integrate neuroscientific findings on how music impacts the human brain, we may see more studies examining biomechanisms in music therapy as well as new situations in which music therapy can play a role in the care of patients with cancer. n Disclosure: Ms. Popkin reported no potential conflicts of interest.

References 1. American Music Therapy Association: Profile of the 2011 Membership. A Snapshot of the Music Therapy Profession, p 10. Available at www.musictherapy.org/ assets/1/7/statprofile11.pdf.

Accessed August 26, 2014.

2. World Federation of Music Therapy: Regional information. Available at www.musictherapyworld.net/WFMT/Regional_Information.html. Accessed August 26, 2014.

3. Cassileth B: Suvivorship: Living Well During and After Cancer. Ann Arbor, Michigan; Spry Publishing; 2014.

4. Ratcliff CG, Prinsloo S, Richardson M, et al: Music therapy for patients who have undergone hematopoietic stem cell transplant. Evid Based Complement Alternat Med 2014:742941, 2014.G 5. Cassileth BR, Vickers AJ, Magill LA: Music therapy for mood disturbance during hospitalization for autologous stem cell transplantation: A randomized

controlled trial. Cancer 98:2723-2729, 2003.

6. Nguyen TN, Nilsson S, Hellstrom AL, et al: Music therapy to reduce pain and anxiety in children with cancer undergoing lumbar puncture: A randomized clinical trial. J Ped Oncol Nursing 27:146155, 2010.

7. Bradt J, Dileo C, Grocke D, et al: Music interventions for improving psychological and physical outcomes in cancer patients. Cochrane Database Syst Rev (8) CD006911, 2011.

8. Shabanloei R, Golchin M, Esfahani A, et al: Effects of music therapy on pain and anxiety in patients undergoing bone marrow biopsy and aspiration. AORN J 91:746-751, 2010.

9. Robb SL, Burns DS, Stegenga KA, et al: Randomized clinical trial of therapeutic music video intervention for resilience outcomes in adolescents/young adults undergoing hematopoietic stem cell transplant: A report from the Children’s Oncology Group. Cancer 120:909917, 2014.

10. Lin MF, Hsieh YJ, Hsu YY, et al: A randomised controlled trial of the effect of music therapy and verbal relaxation on chemotherapy-induced anxiety. J Clin Nursing 20:988-999, 2011.

11. Gutgsell KJ, Schluchter M, Margevicius S, et al: Music therapy reduces pain in palliative care patients: A randomized controlled trial. J Pain Symptom Manage 45:822-831, 2013.

Visit the free About Herbs website at

www.mskcc.org/aboutherbs

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

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR)

100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20% 0%

ORR 7.4% (n=8) POMALYST (n=108)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

POMALYST + low-dose dex (n=113)

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

Study design: A phase 2, multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy

For more information visit www.pomalyst.com/hcp or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning 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 • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of 2 reliable methods of contraception POMALYST is only available through a restricted distribution program called POMALYST REMS™.

VENOUS THROMBOEMBOLISM • Deep venous thrombosis (DVT) and pulmonary embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. 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.

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

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

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

Venous Thromboembolism • Deep venous thrombosis (DVT) and pulmonary embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of 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 Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced Grade 3/4 dizziness, and 3% of patients experienced Grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.

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

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

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.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction.

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

DRUG INTERACTIONS Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 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 greater than or equal to 65 years of age

were more likely than patients less than or equal to 65 years of age to experience pneumonia.

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

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS on following pages.

POMALYST® is a registered trademark of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation. © 2014 Celgene Corporation 07/14 US-POM120033a(2)

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Appointments

Arizona Health Science Center Appoints Rick Kittles, PhD, Director of New Division of Population Genetics

R

ick Kittles, PhD, a national leader on cancer health disparities and the role of genes and environment in disease, and a pioneer in DNA testing to trace the ancestry of African Ameri-

cans, has been appointed Director of the new Division of Population Genetics, part of the new Center for Applied Genetics at the Arizona Health Sciences Center at the University of Arizona.

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full Prescribing Information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy.

POMALYST is a thalidomide analogue.

Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.

• Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)].

POMALYST is only available through a restricted distribution program called POMALYST REMS™ [see Warnings and Precautions (5.2)].

Venous Thromboembolism • Deep venous thrombosis (DVT) and pulmonary embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression.

POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)].

POMALYST may be taken with water. Inform patients not to break, chew, or open the capsules.

POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

2.2 Dose Adjustments for Toxicities Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities 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

Dose Modification

• For each subsequent drop <500 per mcL • Return to more than or equal to 500 per mcL

Interrupt POMALYST treatment Resume POMALYST treatment at 1 mg less than the previous dose

Thrombocytopenia • Platelets <25,000 per mcL

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

• Platelets return to >50,000 per mcL

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

• For each subsequent drop <25,000 per mcL • Return to more than or equal to 50,000 per mcL

Interrupt POMALYST treatment Resume POMALYST treatment at 1 mg less than previous dose

ANC, absolute neutrophil count.

For other Grade 3 or 4 toxicities, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion.

To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL and the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 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) and Clinical Pharmacology (12.3)].

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)].

the Division of Health Promotion Sciences at the University of Arizona Mel and Enid Zuckerman College of Public Health. He is also a member of the University of Arizona Cancer Cen-

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. 5.2 POMALYST REMS™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements.

• Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)].

• Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST, and comply with REMS requirements.

Further information about the POMALYST REMS program is available www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.

5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (VTEs) (venous thromboembolism) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

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

Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Dr. Kittles also has been appointed Professor in the Department of Surgery, Division of Urology at the University of Arizona College of MediT:7” appointment in cine, Tuscon, a joint

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Appointments

ter and the Center’s Cancer Prevention and Control Program.

Dr. Kittles joined the University of Arizona in July.

Population Genetics, Cancer Genomics, Health Disparities “We are thrilled to welcome Dr. Kittles to the University of Arizona,” said

T:7” Rick Kittles, PhD

treatment cycles was 5. Sixty-three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty-seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%.

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)].

Tables 2, 3, and 4 summarize all treatment-emergent adverse reactions reported for the POMALYST + Low-dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug related and those that reflect the patient’s underlying disease.

In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Low-dose Dex (n=112), all patients had at least one treatment-emergent adverse reaction.

Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%).

Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low-dose Dex (99/112).

Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia (6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%).

Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low-dose Dex (69/112).

5.5 Hypersensitivity Reactions Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

5.6 Dizziness and Confusional State In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced Grade 3/4 dizziness, and 3% of patients experienced Grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and to not take other medications that may cause dizziness or confusional state without adequate medical advice.

5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of Grade 3 or higher neuropathy adverse reactions reported.

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

5.9 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 Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Clinical Trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low-dose Dexamethasone (Low-dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of

Dr. Garcia added. “Dr. Kittles will provide critical leadership in our efforts to advance precision health approaches to population health outcomes, the development of personalized diagnostics and therapeutics in complex diseases, and the development of well-phenotyped racially and ethnically diverse patient groups for genomic study.”n

Serious Adverse Reactions in ≥2 patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: Constipation (1%, 3%); Blood and lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and labyrinth disorders: Vertigo Hepatobiliary disorders: Hyperbilirubinemia Infections and infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis Investigations: Alanine aminotransferase increased Metabolism and nutritional disorders: Hyperkalemia Renal and urinary disorders: Urinary retention Reproductive system and breast disorders: Pelvic pain Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease 6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with POMALYST: Pancytopenia, tumor lysis syndrome. 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 (eg, ciprofloxacin and fluvoxamine) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 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.

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5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%.

Joe G.N. “Skip” Garcia, MD, UA Senior Vice President for Health Sciences and Interim Dean of the University of Arizona College of Medicine, Tuscon. His leadership will be critical to our efforts to establish a multi-campus (Tucson and Phoenix) and statewide network focused on population genetics, cancer genomics, and the reduction of health disparities,”

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Awards

ASTRO Honors Jasan Zimmerman With 2014 Survivor Circle Award

T

he American Society for Radiation Oncology (ASTRO) presented the 2014 Survivor Circle Award to San Francisco Bay Area resident and cancer survivor Jasan Zimmerman during ASTRO’s 56th

Annual Meeting held recently in San Francisco. The Survivor Circle Award recognizes a cancer survivor who lives in the ASTRO Annual Meeting host city and who has dedicated his or her time and energy in service and supCYP1A2 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)]

advocacy world,” Mr. Zimmerman said.

“The benefits of volunteering are twofold for me: every time I share my story, it helps me come to terms with and accept my experiences a little more, and externally, I can see positive changes in

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.

contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.

8.3 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, 41% were aged 65 years and older, while 12% were aged 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients aged greater than or equal to 65 years were more likely to experience pneumonia than patients aged less than or equal to 65 years.

8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy.

Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 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

8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

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.

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.

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)].

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Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue.

Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented, and mortality at or shortly after birth has been reported in about 40% of infants.

Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-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

port of their local community.

“Volunteering was always a part of my life, instilled in me by my parents, so when I was finally comfortable enough to share my story, it was easy to find T:7” volunteer opportunities in the cancer

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Awards

the lives of other people based on the work that I have done, whether directly or indirectly.”

Neuroblastoma at 6 Months, Thyroid Cancer at 15 Years, and Recurrence at 21 Years Mr. Zimmerman was diagnosed in 1976, at 6 months old, with neuroblas-

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-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements, and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)].

• POMALYST is available only from pharmacies that are certified in POMALYST REMS. Provide patients with the telephone number and Web site for information on how to obtain the product.

Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment [see Venous Thromboembolism (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 Hematologic Toxicities (5.4)].

Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID® [see Hypersensitivity Reaction (5.5)].

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 Dizziness and Confusional State (5.6)].

cal Center in Rancho Mirage. He experienced a recurrence of thyroid cancer in 1997 at age 21 and underwent radiation therapy at the University of California Irvine Medical Center. In 2004, after Mr. Zimmerman finished graduate school and moved to the Bay Area, he felt like something was missing in his life. He read about a local support 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 Neuropathy (5.7)].

Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown [see Risk of Second Primary Malignancies (5.8)].

Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warning and Precautions (5.9)].

Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day.

• POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

• The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water.

• Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed.

Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)].

Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID®, and THALOMID® are registered trademarks of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation.

Pat. http://www.celgene.com/therapies © 2005-2014 Celgene Corporation All rights reserved.

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group in the paper and decided to attend. During those meetings, he met other group members who were involved in advocacy for cancer patients, and he realized that he had experiences and knowledge to share as a pediatric and young adult cancer survivor.

“I never had a conscious ‘moment of inspiration,’ but slowly, I became more and more involved in advocating for the psychosocial support of pediatric and young adult cancer survivors,” Mr. Zimmerman said. “I don’t want people to have the negative experiences that I had when I was sick, such as depression, anger, and being treated as a child instead of as a young adult who could make my own decisions. I really enjoy helping people and connecting them with resources that can make their lives easier.”

Volunteer Activities Mr. Zimmerman has volunteered in multiple events and programs for cancer survivors and children and young adults with cancer. These have included serving as a member of the Palo Alto Medical Foundation Cancer Patient Advisory Council since 2010; and since 2012, a member of the planning committee for Courageous Kids, an annual American Cancer Society. Mr. Zimmerman has also served as a Super Advocate for the National Coalition for Cancer Survivorship from 2008 to 2011 and a Patient Services Committee member for Cancer CAREpoint in San Jose from 2011 to 2013. He has also reviewed cancer research grants for the Congressionally Directed Medical Research Program and spoken about survivorship to various groups, including the Palo Alto Medical Foundation, Relay for Life, and Stupid Cancer’s 2014 OMG! Cancer Summit for Young Adults.

“Volunteering has helped me learn about resources that impact my own survivorship, like seeking out a treatment summary and survivorship care plan. I’ve met lots of great people who have educated and mentored me, and I’m so grateful for their support, care, and leadership.”

“ASTRO is honored to present Mr. Zimmerman with the 2014 Survivor Circle Award,” said Bruce G. Haffty, MD, FASTRO, President of ASTRO’s Board of Directors. “His dedication to helping other cancer survivors and his willingness to share his story with so many others, particularly other pediatric and young adult cancer survivors, are an inspiration. He is an excellent example of the importance of caring for and supporting our patients—from diagnosis through survivorship.”n T:10”

• 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)].

toma of the left neck. The tumor was removed, and he was treated with upper mantle radiation therapy at Loma Linda University Medical Center. In 1991, at age 15, Mr. Zimmerman was then diagnosed with thyroid cancer and had a thyroidectomy at the University of California Irvine Medical Center and radiation therapyT:7” at Eisenhower Medi-

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Patient’s Corner

Breast Cancer Has Led Me to Careers in Activism and Filmmaking An experimental bone marrow transplant 23 years ago saved my life.

I’ve been giving back to the cancer community ever since.

By Barbara Masry, as told to Jo Cavallo

T

he last thing I expected to find when I returned home after a summer vacation celebrating my 50th birthday was a letter from my gynecologist saying the routine mammogram I had before I left found suspicious-looking calcifications in my right breast and that I should see a surgeon right away. Being an optimistic person, I was sure the calcifications were benign. But when the biopsy showed invasive ductal carcinoma that had spread to nine lymph nodes, I was terrified.

I started meeting with different oncologists to get their opinions on my best course of treatment. Several pulled out pads and pencils to calculate my odds of survival and said my 5-year overall survival rate was about 50%.

One oncologist was so glib in her assessment of my chances for survival I felt doomed.

Surviving Cancer The year was 1991, a time when intensive chemotherapy with autologous bone marrow transplantation was considered a promising new approach in the treatment of breast cancer, and many of the oncologists I consulted recommended the experimental procedure as part of a clinical trial. I read about the potential longterm health risks of the treatment, including heart disease from the highdose chemotherapy and even death, and I was devastated.

Finally, I found an oncologist who assured me I was young enough to withstand the aggressive therapy and even gave me the names of several patients who had successfully undergone

the procedure. After talking with them, I gathered up my courage and agreed to the transplant. I wanted to do everything I could to live.

I had a lumpectomy, followed by four rounds of high-dose CAF chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil) and then the transplant. After the transplant, I had several rounds of radiation and was prescribed tamoxifen for 5 years.

The therapy was successful, and

other women going through treatment and survivorship.

An early childhood teacher by profession, I changed the focus of my life after my diagnosis. I became an activist with the National Breast Cancer Coalition, lobbying Congress for more research funding. I also launched the Great Neck Breast Cancer Coalition in my community on Long Island, New York, to raise awareness of the disease, encourage funding for research, and

Although great strides have been made in increasing survival rates in breast cancer, more needs to be done.

I remain committed to advocating for greater breast cancer awareness, increased research funding, and improving access to quality health care and patient navigation.

—Barbara Masry

23 years later I remain cancer-free. Although I have some late effects from the chemotherapy, including an enlarged heart and atrial fibrillation, I’m able to pursue an active lifestyle and I’m grateful to be alive.

Changing the Course of My Life Twenty-three years ago, the words “breast cancer” were spoken in hushed tones and rarely in public, and stigma and fear surrounding the disease were profound. After my experience with breast cancer, I was determined to help

promote healthier lifestyles. In a circuitous way, having breast cancer also led me to a career in filmmaking.

When I was diagnosed with breast cancer I was fortunate to have good health insurance and the luxury of getting multiple opinions from leading oncologists to ensure I would receive the highest-quality medical care and the best shot at survival. A young woman I met at the hospital wasn’t so lucky. Because she didn’t have health insurance and couldn’t afford a mammogram, her breast cancer diagnosis

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

had been delayed. By the time the cancer was discovered, it had metastasized, and she later died from her ­illness.

That experience led me to write a screenplay titled A Wake-up Call, which describes the experiences of two women in the aftermath of breast cancer and the inequity of the health care they receive. A movie is currently in development.

Making a Difference Of course, I would have preferred never to have had cancer, but the disease has taught me about the fragility of life and the importance of giving back.

Since the formation of the Great Neck Breast Cancer Coalition more than 2 decades ago, many women in the community have learned about screening mammograms, the importance of diet and exercise, promising new therapies, and the avoidance of potential environmental toxins to reduce the risk of the disease.

Although great strides have been made in increasing survival rates in breast cancer, more needs to be done.

I remain committed to advocating for greater breast cancer awareness, increased research funding, and improving access to quality heath care and patient navigation, to assist medically underserved patients attempting to navigate their way through the complex medical maze until a cure is found. n Barbara Masry is an activist, screenwriter, and film producer living in Great Neck, New York.

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

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In the News Genetics/Genomics

News of Mutations in PALB2 Gene Raising Risk of Breast Cancer Offers Opportunity to Explain Limits of Genetic Testing

By Charlotte Bath

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he response among patients to news reports about mutations in a gene known as PALB2 raising the risk of breast cancer “has been predictable,” Theodora Ross, MD, PhD, wrote in The New York Times.1 As an example, Dr. Ross, Director of the Cancer Genetics Program at The University of Texas Southwestern Medical Center in Dallas, cited one patient who called to make an appointment for a whole-genome scan.

In an interview with The ASCO Post, Dr. Ross said that several other patients called to see if their genetic testing had included PALB2 and if not, whether it should have.

While the response from patients may have been expected, Dr. Ross did not expect the response to her New York Times article, explaining the current limitations of genetic testing and the futility of germ-line whole-genome sequencing as a means of assessing breast cancer risk. She received “hundreds of emails from people saying, ‘Thank you. Somebody needed to say this.’”

Having said that, Dr. Ross went on to explain the value of genetic testing for specific known mutations, particularly among patients with family his-

Looking at the pace of research on a year-to-year basis can be very frustrating, but if you look back 20 years and then look at where we are now, the difference is unbelievable. Think about how many lives have been saved just based on what we know about Lynch syndrome–associated MMR genes and the hereditary breast and ovarian cancer–associated BRCA genes.

—Theodora Ross, MD, PhD

tories of certain cancers. These would include mutations in BRCA1 and BRCA2 and now PALB2, known to increase the risk of breast cancer, and the mismatch repair genes responsible for Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC).

Screening for PALB2 Mutations “Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect

both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers,” Antoniou et al reported in The New England Journal of Medicine.2 That study involved 362 members of 154 families with loss-of-function mutations PALB2. This included 311 women (229 with breast cancer), as well as 51 men (7 with breast cancer).

Expect Questions From Patients

“C

onscientious doctors are unlikely to say yes to a patient’s request for full genome sequencing,” Theodora Ross, MD, PhD, wrote in The New York Times.1 Dr. Ross, Director of the Cancer Genetics Program at the University of Texas Southwestern Medical Center in Dallas, was writing about the current limitations of genetic testing and the futility of germline sequencing as a means of assessing breast cancer risk.

The issue of genetic testing was in the news following publication of a study in The New England Journal of Medicine demonstrating that mutations in the PALB2 gene increased the risk of breast cancer and that risk might overlap with the risk for those with BRCA2 mutations.2

‘Luxury Purchase’ So how can physicians discourage patients from seeking whole-

genome sequencing? “They can say, ‘If you have the money, you can pay for it, but it is going to cost you $23,000.’” That would include the roughly $2,000 to get the data and many thousands more to have it interpreted, and may in fact be a lowball estimate.

“Insurance companies don’t and shouldn’t pay for this,” Dr. Ross said, “because it’s currently a luxury purchase,” with results raising more questions than can be answered. She advised physicians to make sure patients understand that they might find out they have conditions like Huntington’s disease.

Stored Data “There is so much more research to do, but I would predict that ultimately people will undergo genome sequencing and the data will be stored, and then when new genes

come up and we discover their link to cancer or some neurodegenerative syndrome, you can just go to the stored data and see if the ‘new’ gene is mutated,” Dr. Ross said.

For now, there are multigene panels that can screen for mutations in BRCA1, BRCA2, and several other genes like PALB2 and help provide women with estimates of their breast cancer risk. Also contributing greatly to those estimates, Dr. Ross stressed, is the “low-tech” family history. n

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

References 1. Ross T: Cancer and the secret of your genes. New York Times, August 16, 2014.

2. Antoniou AC, Casadei S, Heikkinen D, et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506, 2014.

“The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age,” the researchers reported. “Because of the widespread availability of multigene panels and whole-exome sequencing, screening for inherited loss-of-function mutations in PALB2 has begun to enter clinical practice,” the authors added.

Such screening has already begun at the Cancer Genetics Program that Dr. Ross directs. “Some argue that the panels are premature, but I would say that the paper in The New England Journal of Medicine helped. What was so beautiful about the paper was the large number of families with this mutation that have early-onset cancers.”

As more screening is done, “we are going to collect more and more of this kind of much-needed data,” Dr. Ross said.

Genetic Screening: An Ongoing Process “Genetic testing is a process for many patients, not a one-time event,” Dr. Ross noted in the Times article.

Patients “need to know that, because when their family history changes, they’ve got to let us know,” Dr. Ross stated. In addition, when changes in the clinical research area, such as the PALB2 study, move an aspect of genetic testing from the research into the practical arena, there might be a need to reconnect with a patient.

“That is why we always tell patients to recontact us in a few years,” Dr. Ross emphasized. She realizes, however, that some patients may be lax about calling back. “Physicians can be the worst patients about checking in, indicating that it is not just lack of information that blocks a reconnection. Emotional issues reflected in denial and practial issues such as inconvenience may interfere for many patients,” she said.

“In the coming weeks, in light of the report on PALB2, as well as the emergence of sophisticated tests that can now analyze many cancer genes at one continued on page 142

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In the News PALB2 Mutations continued from page 141

time, we’ll advise some former patients who tested negative for BRCA or other specific genes to return for more genetic counseling and potentially further testing,” Dr. Ross wrote in the Times.

The article itself has prompted calls from patients, as have talks Dr. Ross has presented at survivor groups and other meetings.

For now, patients are not being individually contacted, but “there are some of those mystery patients that we think we should probably call,” Dr. Ross said. By mystery patients, she means women who have a strong family history of breast and ovarian cancer or have had these cancers themselves but haven’t been found to carry any predicted mutations. “We would have expected that they had a BRCA1 or BRCA2 mutation. They don’t have it, but they clearly have this high risk. There is something genetic, but what is it? We need to discover what it is.”

Who Gets Tested?

Genetic testing “is becoming more mainstream,” Dr. Ross said, but “demographics make a big difference,” with underrepresentation of African American and Hispanic populations.

Women seeking genetic testing for breast cancer gene mutations may be prompted by something they have read, a realization or reminder of a family history of breast cancer, or a referral by their primary care physician. About half of the patients already have cancer and are referred by their oncologist.

The University of Texas Southwestern Medical Center has initiated a family history of cancer questionnaire that is embedded into mammogram screening. “The technicians essentially can flag somebody who has a family history, and we are able to pick up some BRCA mutations,” Dr. Ross explained.

Patients who are found by genetic testing to have a BRCA and/or, for example, PALB2 or RAD51C mutation are referred to a breast surgeon and to a gynecologic surgeon for consultation concerning removal of the breasts and ovaries, respectively, Dr. Ross explained.

“Among people with BRCA mutations, if they elect to do breast screening, then they embark on frequent clinical exams as well as alternating breast magnetic resonance imaging and mammograms every 6 months,” she added. “So it really depends on their personal choice.”

There are also some patients who seek genetic testing for breast cancer genetic mutations but do not have cancer or a family history of breast cancer. Those patients might still be candidates for testing based on their age or other factors. This would include ovarian cancer, no matter what their family history, Dr. Ross said.

Several organizations, including the National Comprehensive Cancer Network (NCCN), have issued guidelines for genetic testing to determine cancer risk. “We follow the NCCN guidelines, and other relevant guidelines, as do insurance companies,” Dr. Ross noted.

Using Genetic Information for Prevention “We can now use genetic information to prevent breast, ovarian, and colon cancer in many patients,” Dr. Ross wrote in the Times article. She expanded on this in the interview with The ASCO Post. “In the case of Lynch syndrome, if patients have yearly colonoscopies where suspicious polyps are removed, the estimated lifetime for these patients is normal, because most deadly colon cancers [in these patients] have been prevented with polypectomies,” Dr. Ross stated.

For patients with a high genetic risk

‘Everybody Has a Mutation or More’

W

hile genome sequencing is not currently recommended or widely used because of its high cost and paucity of meaningful, actionable results, some patients wouldn’t want it even if it were free and useful, ­Theodora Ross, MD, PhD, Director of the Cancer Genetics Program at the University of Texas Southwestern Medical Center in Dallas, told The ASCO Post. Part of the reason for that is worry about discrimination and insurance.

“There are nondiscrimination clauses with respect to genetic information and health insurance, but not life insurance or long-term care insurance.

There is a lot of fear around that,” Dr. Ross said.

That might change, she commented. “I think insurance companies are going to start realizing that everybody has a mutation or more, predisposing them to something else. If somebody learns about their genetic inheritance, it could signal the insurance company that the patient takes care of him or herself. It could correlate with exercise or limited alcohol intake. Someday there may be discrimination against those who don’t care to learn about their genetic inheritance.”

She also predicted that with more companies entering the field of genetic testing, more genes being tested, and more information being reported, “there are going to be more mistakes. So even though the U.S. Food and Drug Administration is saying it is going to start regulating these laboratories for clinical outcomes, it is going to be a bit of a mess. We can’t assume that the genetic tests we are getting are accurate enough.” n of breast cancer, “if you take out the ovaries and remove the breasts, they will have normal risk,” Dr. Ross noted.

“Some people choose not to do that, understandably, and that is where the issue of family history is so important.

Because if you have a 30% cancer risk, it may be less urgent to take the preventive action of prophylactic surgeries,” she continued.

Patience With the Pace of Research “We need to have patience with the pace of research,” Dr. Ross advised. She understands why people get impatient with the pace of clinical translation, for example, when a gene that increases cancer risk has been identified, but it is unclear what to do with that knowledge. “We know that there is some risk, but we are not exactly sure how high a risk,” she said.

“PALB2 was called a low-penetrant

gene for a long time, and it frequently is not, based on the data reported in The New England Journal of Medicine.”

“Looking at the pace of research on a year-to-year basis can be very frustrating,” she acknowledged, “but if you look back 20 years and then look at where we are now, the difference is unbelievable. Think about how many lives have been saved just based on what we know about Lynch syndrome–associated MMR genes and the hereditary breast and ovarian cancer–associated BRCA genes.” n

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

References 1. Ross T: Cancer and the secret of your genes. New York Times, August 16, 2014.

2. Antoniou AC, Casadei S, Heikkinen D, et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506, 2014.

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Ongoing Molecular Research in the Science of Oncology BIOMARKERS TRIM44 Amplification in Esophagogastric, Breast Tumors May Be Marker for mTOR Inhibitor Therapy TRIM44 family overexpression is associated with carcinogenesis, and TRIM44 has been identified as a prognostic gene. In a study reported in Journal of the National Cancer Institute, Ong and colleagues attempted to identify therapeutic strategies for patients with TRIM44 overexpression.

Genomic and transcriptomic data from 1,932 epithelial cancers, 1,980 breast cancers, and 163 esophagogastric cancers were analyzed to identify genomic alteration associated with TRIM44 overexpression. The driver gene status of TRIM44 was determined using a small interfering RNA (siRNA) screen of the 11p13 amplicon. It was found that TRIM44 overexpression resulted from genomic amplification in 16.1% of epithelial cancers, including 8.1% of esophagogastric cancers and 6.1% of breast cancers.

Computer simulation analysis showed a link between TRIM44 and mTOR signaling. Support for this link was provided by the finding of a reduction in mTOR signaling after siRNA knockdown of TRIM44 in cell lines and co-localization of TRIM44 and p-mTOR in patient samples.

Studies in vitro showed that the mTOR inhibitor everolimus (Afinitor) decreased cell viability in two TRIM44-amplified cells lines by 88% and 70% compared with 35% in a control cell line. These findings were confirmed in xenograft models.

The investigators concluded, “Genomic amplification drives TRIM44 overexpression in [esophagogastric cancers and breast cancers]. Targeting the mTOR pathway provides a potential therapeutic option for TRIM44-amplified tumors.”

Ong C-AJ, et al: J Natl Cancer Inst. April 28, 2014 (early release online).

Extracellular Matrix Stiffness Promotes Malignant Progression Via PTEN-Reducing Effect of Micro-RNA Tissue mechanics are altered in tumor progression, although many of the mechanisms underlying the changes remain unclear. In a study reported in Nature Medicine, Mouw and colleagues found that increased tissue extracellular matrix stiffness modulated microRNA expression to promote tumor progression via integrin activation of beta-catenin and MYC. In human and mouse tissue, increased matrix stiffness was shown to induce increased expression of miR-18a; this resulted in a decrease in levels of the tumor suppressor PTEN both as a direct effect and as an indirect effect mediated by a reduction in homeobox A9 (HOXA9) levels.

In human breast tumor tissue, extracellular matrix stiffness was significantly correlated with miR-18a expression, with expression being highest in basal-like breast tumors with the lowest levels of PTEN and HOXA9. High levels of miR-18a expression were predictive of poor prognosis in patients with luminal breast cancers.

The instigators concluded, “Our findings identify a mechanically regulated

microRNA circuit that can promote malignancy and suggest potential prognostic roles for HOXA9 and miR-18a levels in stratifying patients with luminal breast cancers.”

Mouw JK, et al: Nature Med 20:360367, 2014.

Potential Marker for Response to Anti-EGFR Therapy in KRAS Wild-Type Metastatic Colorectal Cancer As reported in Clinical Cancer Research, Manceau and colleagues attempted to identify microRNAs that can predict response to anti-EGFR therapy in wild-type KRAS metastatic colorectal cancer patients.

Initial screening of 1,145 microRNAs in fresh frozen tumor samples from chemotherapy-refractory metastatic colorectal cancer patients who were treated with anti-EGFR therapy showed a significant association between has-miR-131-3p expression and progression-free survival.

Studies in vitro identified a total of 47 genes regulated by hsa-miR-31-3p. Statistical models based on has-miR-1313p expression discriminated high vs low risk of progression in both fresh frozen and formalin-fixed paraffin embedded (FFPE) samples.

The models were confirmed in a validation cohort for both fresh frozen (hazard ratio [HR] = 4.1, P < .04) and FFPE samples (HR = 2.44, P = .028). The percentage of variation in RECIST responses in the validation cohort was significantly associated with both level of hsa-miR-313p expression (r2 = 0.49, P = .0035) and risk status based on expression level (P = .02). The investigators constructed and validated nomograms to predict progression-free survival based on hsa-miR-313p expression level.

The investigators concluded, “HsamiR-31-3p appears to be a new [metastatic colorectal cancer] biomarker whose expression level allows for the identification of patients with wild-type KRAS [metastatic colorectal cancer] who are more likely to respond to anti-EGFR therapy.”

Manceau G, et al: Clin Cancer Res 20:3338-3347, 2014.

MECHANISMS OF ACTION Tissue Microenvironment Affects Activity of PTEN in Leukemia ©Charles Saxon/The New Yorker Collection/www.cartoonbank.com

The tumor suppressor PTEN, which is underexpressed in many cancers, dephosphorylates phosphatidylinositol

(3,4,5)-triphosphate and thus inhibits activity of phosphatidylinositol 3-kinases involved in growth factor and survival factor signaling through effectors such as Akt and mTOR. As reported in Nature, Miething and colleagues assessed whether continuous PTEN inactivation is necessary to maintain malignancy.

Using an RNA interference-based transgenic mouse model in which PTEN can be regulated by tetracycline in a timeand tissue-specific manner, they found that PTEN knockdown resulted in disseminated T-cell acute lymphoblastic leukemia in the hematopoietic compartment. Reactivation of PTEN resulted in reduced dissemination but had little effect on tumor load in the hematopoietic organs. Disease infiltration into the intestine was shown to be dependent on CCR9 Gprotein-coupled receptor signaling, and this signaling was found to be amplified

by PTEN loss.

The investigators concluded, “Our results suggest that in the absence of PTEN, G-protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.”

Miething C, et al: Nature 509:402-406, 2014.

ONCOGENESIS Overexpression of Sirt7 Is Associated With Tumorigenesis and Poor Prognosis in Colorectal Cancer Sirt7, a member of the sirutin family, is overexpressed in some cancers. In a study of the potential role of Sirt7 in colorectal cancer reported in Clinical Cancer Research, Yu and colleagues found that increased Sirt7 protein level in colorectal cancer tissue was associated with higher tumor stage (P = .029), lymph node metastasis (P = .046), and reduced survival (P < .05).

Sirt7 knockdown was associated with significant inhibition of colorectal cancer cell proliferation, colony formation, and motility, whereas ectopic Sirt7 expression promoted colony formation and a more invasive phenotype and accelerated cell growth in vitro and in vivo. Increased Sirt7 expression was associated with increased

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MAPK pathway activity and simultaneous upregulation of p-ERK and p-MEK. In cells overexpressing Sirt7, the mesenchymal markers vimentin and fibronectin were upregulated and the epithelial markers E-cadherin and beta-catenin were downregulated, with these alterations being associated with increased colorectal cancer cell invasiveness.

The investigators concluded, “Our findings suggest that Sirt7 plays an important role in the development and progression of human [colorectal cancer] and functions as a valuable marker of [colorectal cancer] prognosis.”

Yu H, et al: Clin Cancer Res 20:34343445, 2014.

OUTCOME PREDICTORS Remarkable Response to Sorafenib in Advanced Lung Adenocarcinoma and Oncogenic ARAF Mutation As reported in Journal of Clinical Investigation by Imielinski and colleagues, whole-genome and RNA sequencing of tumor and normal tissue in a patient with advanced lung adenocarcinoma who exhibited a remarkable response to sorafenib (Nexavar) revealed a somatic ARAF S214 mutation expressed at high levels in tumor. The patient had exhibited near-complete clinical and radiographic remission for 5 years.

The investigators identified additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 across 1% of an independent cohort of lung adenocarcinomas. The ARAF mutations were found to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner.

As stated by the investigators, “These results suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.”

Imielinski M, et al: J Clin Invest 124:1582-1586, 2014.

GENE PROFILING LCS6 Genotype Not Associated With KRAS Mutation Status or Outcome in Stage III Colon Cancer A let-7 microRNA-complementary site (LCS6) polymorphism in the 3’UTR of KRAS has been shown to disrupt let-7 binding and upregulate KRAS expression.

As reported in Clinical Cancer Research, Sha and colleagues found that LCS6 genotype was not associated with KRAS mutation status or disease-free survival in pa-

tients with stage III colon cancer enrolled in a phase III trial (NCCTG N0147).

The LCS6 genotype was assayed by real-time polymerase chain reaction in DNA from whole blood (n = 2,834) and compared to paired tumor tissue (n = 977). A total of 432 blood samples (15.2%) and 143 tumor samples (14.6%) were heterozygous or homozygous for the LCS6 G-allele, and 2402 blood samples (84.8%) and 834 tumor samples (85.4%) were homozygous for the LCS6 T-allele.

Genotype results were highly concordant (99.8%) in 977 cases with paired blood and tumor tissue. G-allele carriers were significantly more frequent in Caucasians vs other races (P < .0001). The LCS6 genotype was not significantly associated with KRAS mutation status, clinicopathologic features (all P > .2), or disease-free survival (hazard ratio = 0.929, P = .49). Results were unchanged in analysis combining LCS6 genotype and KRAS mutation status.

The investigators concluded, “In the largest association study investigating the LCS6 polymorphism in colon cancers, the germline LCS6 genotype was not associated with KRAS mutation status or with clinical outcome in patients with stage III tumors.”

Sha D, et al: Clin Cancer Res. April 11, 2014 (early release online).

repertoire, including mutated neoantigen-specific CD8-positive lymphocytes.

In contrast, only a fraction of the tumorreactive population expressed the costimulatory receptor 4-1BB (CD137).

Deep sequencing of T-cell receptor β chain showed oligoclonal expansion of specific T-cell receptor β chain clonotypes in CD8-positive/PD-1–positive vs CD8-positive/PD-1–negative tumorinfiltrating lymphocyte populations. The T-cell receptor β chain clonotypes in the CD8-positive and the CD8-positive/ PD-1–positive populations that exhibited the greatest expansion recognized autologous tumor and included clonotypes that targeted mutated antigens.

The investigators concluded, “[I]n addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on [CD8-positive] tumor-infiltrating lymphocytes] also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment.”

Gros A, et al: J Clin Invest 124:22462259, 2014.

TUMOR MICROENVIRONMENT

CS1 is a cell surface glycoprotein that appears to be highly expressed on myeloma cells and less expressed on normal cells; CS1 overexpression has been found to promote myeloma cell growth and survival by increasing myeloma adhesion to bone marrow stromal cells and increasing myeloma colony formation. In a study reported in Clinical Cancer Research, Chu and colleagues developed chimeric antigen receptor (CAR) T cells targeting CS1 and assessed their effects on multiple myeloma tumor cells.

In response to CS1-positive myeloma cells in vitro, CS1-CAR-transduced T cells exhibited greater interferon -γ and interleukin-2 production, greater expression of the activation marker CD69, higher degranulation capacity, and increased cytotoxicity compared with mock-transduced T cells. Ectopically forced expression of CS1 in cells with low CS1 expression resulted in improved recognition and killing by CS1-CAR T cells. Similarly enhanced activities were observed with CS1-CAR T cells in ex vivo studies using primary multiple myeloma cells. Adoptive transfer of human primary T cells expressing CS1-CAR in orthotopic xenograft mouse models resulted in inhibition

PD-1 Identifies Patient-Specific CD8-Positive Tumor-Infiltrating Lymphocytes in Melanoma Adoptive transfer of tumor-infiltrating lymphocytes can mediate regression of metastatic melanoma. However, there are no effective markers to identify and select patient-specific repertoires of tumor-reactive and mutation-specific CD8positive lymphocytes, limiting the ability to develop strategies to increase clinical efficacy and extend such therapy to other malignancies.

In a study reported in Journal of Clinical Investigation, Gros and colleagues assessed unique phenotypic traits of CD8positive tumor-infiltrating lymphocytes and T-cell receptor β chain clonotypic frequency in 6 melanoma tumors in the attempt to identify patient-specific repertoires of the tumor-reactive CD8-positive lymphocytes. In all tumors, expression of the inhibitory receptors PD-1 (CD279), lymphocyte-activation gene 3 (LAG-3, CD223), and T-cell immunoglobulin and mucin domain 3 (TIM-3) on CD8positive tumor-infiltrating lymphocytes identified the autologous tumor-reactive

TARGETED THERAPY Modification of T Cells to Target CS1 Improves Eradication of Myeloma Cells

of human MM.1S and IM9 myeloma cells and significantly prolonged survival.

The investigators concluded, “CS1 is a promising antigen that can be targeted by CAR-expressing T cells for treatment of [multiple myeloma].”

Chu J, et al: Clin Cancer Res 20:39894000, 2014.

NOVEL STRATEGIES Potential for Therapeutic Autovaccination Against Solid Tumors With Intratumoral Poly-ICLC In a study reported in Cancer Immunology Research, Salazar and colleagues found a remarkable response to a strategy of sequential intratumoral and intramuscular injections of the stabilized dsRNA viral mimic and pathogenassociated molecular pattern (PAMP) polyinosinic-polycytidylic acid-polylysine-carboxymethylcellulose (polyICLC) in a patient with advanced facial embryonal rhabdomyosarcoma with extension to the brain. After treatment, the patient showed tumor inflammation consistent with immunotherapy followed by a gradual marked tumor regression and extended survival. The strategy, in which the sequential intratumoral and intramuscular injections mimic a viral infection, may allow “personalized systemic therapeutic ‘autovaccination’” against individual patient tumor antigens.

The investigators posit that the strategy comprises a three-step immunomodulatory process consisting of (1) innate immune system local tumor killing induced by intratumoral poly-ICLC; (2) activation of dendritic cells with response weighted for Th1 cell and cytotoxic T lymphocyte priming against the tumor antigens released in response; and (3) maintenance of a systemic antitumor immune response via the intramuscular injections of poly-ICLC, including chemokine induction, facilitation of cytotoxic T-lymphocyte killing, inflammasome activation, and an increase in the T-effector/ regulatory T-cell ratio.

They concluded, “These results support the use of certain simple and inexpensive [intratumoral] PAMPs to favorably stimulate effective immunity against solid cancers. A phase II clinical trial testing the hypothesis presented has begun accrual (clinicaltrials.gov, NCT01984892).”

Salazar AM, et al: Cancer Immunol Res 2:720-724, 2014.

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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Emerging Clinical Data on Cancer Management LYMPHOMA Pro-oxidant Molecule Imexon Shows Clinical Activity in Relapsed/Refractory B-Cell NHL The pro-oxidant molecule imexon (Amplimexon/NSC-714597) produced an overall response rate of 30% in patients with relapsed/refractory Bcell non-Hodgkin lymphoma (NHL) participating in a phase II study. Noting that “lymphoma cells are subject to higher levels of oxidative stress than their normal counterparts,” the investigators hypothesized that the lymphoma cells “may be vulnerable to manipulations of the cellular redox balance.”

The results of the trial represent “the first demonstration of clinical activity with a pro-oxidant molecule in lymphoma, Paul M. Barr, MD, of the University of Rochester Wilmot Cancer Center, New York, and colleagues reported in Blood. They also found that antioxidant-related gene expression predicted for response to imexon.

The trial enrolled 22 patients with a variety of non-Hodgkin lymphomas: 9 with follicular, 5 with diffuse large B-cell, 3 with mantle cell, 2 with transformed follicular, 2 with small lymphocytic, and 1 with Burkitt lymphoma. The median number of prior therapies received was four, and all patients had received previous anti-CD20 antibody therapy. The median age was 64.

Imexon was administered at 1,000 mg/m2 intravenously for the first 5 days in 21-day cycles and continued until disease progression or unacceptable toxicity. The 30% overall response rate (P = .011) for the 20 evaluable patients included 4 patients with follicular lymphoma and 2 with diffuse large B-cell lymphoma. “All 6 responding patients achieved a partial response; an additional 35% of patients achieved stable disease,” the researchers reported.

The most common adverse event of any grade was fatigue, occurring in 91% of patients. The most common grade 3/4 adverse events were anemia, occurring in 14% of patients, and neutropenia in 9%.

Two patients died while on study, one with progressive diffuse large B-cell lymphoma and one with a septic event.

“Gene expression analyses revealed CD68 and the redox related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses,” the researchers reported. “Pre-treatment markers of oxidative stress may identify patients likely to respond to this therapeu-

tic approach,” the authors added.

This study was registered at ClinicalTrials.gov with the identifier NCT01314014.

Barr PM, et al: Blood. July 11, 2014 (early release online).

BREAST CANCER Most Women Who Choose Breast Reconstruction Are Satisfied With Decision-Making Process Most patients who choose to have breast reconstruction following mastectomy are satisfied with the decision-making process. Reasons for not choosing reconstruction vary by race and include the desire to avoid additional surgery and fear of implants. These and other conclusions of an analysis of women undergoing mastectomies following diagnoses for ductal carcinoma in situ or stage I–III invasive breast cancer were reported in JAMA Surgery by Monicia Morrow, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues.

The researchers used Surveillance, Epidemiology, and End Results (SEER) registries from Los Angeles and Detroit to identify a sample of women aged 20 to 79 years. Because the study was limited to women from two metropolitan areas, the results “may not reflect access to reconstruction nationally, particularly in rural areas where plastic surgeons may be less available,” the investigators noted.

Of 3,252 women who were sent the initial survey a median of 9 months after diagnosis, 2,290 completed it. The analysis focused on the 485 who also completed a follow-up survey sent 4 years later to determine the frequency of immediate and delayed reconstruction, patient attitudes toward the procedure, and who had remained disease-free. The median age of these patients was 55.8 years, and 64.3 had stage I or II breast cancer.

Among those 485 patients, 24.8% had immediate and 16.8% had delayed reconstruction. Most of those who delayed treatment reported that they did so to focus on cancer treatment (68.7%) or to accommodate chemotherapy (50.7%) or radiotherapy (26.3%). “Residual demand for reconstruction at 4 years was low, with only 30 of 263 who did not undergo reconstruction still considering the procedure,” the investigators found.

Most women were satisfied with the decision-making process surrounding reconstruction. Only 13.3% of women

were dissatisfied with the reconstruction decision-making process, but dissatisfaction was higher among nonwhite patients in the sample (P = .03), the researchers reported.

“The most common patient-reported reasons for not having reconstruction were the desire to avoid additional surgery (48.5%) and the belief that it was not important (33.8%), but 36.3% expressed fear of implants,” according to the study report. “Many women continue to report fear of implants as 1 reason for forgoing reconstruction, despite their proven safety. Nearly one fourth of women who did not undergo reconstruction in our sample reported concern about potential interference with cancer detection as a decision factor despite the clinical evidence not supporting this contention,” the investigators commented.

“Although the optimal rate of breast reconstruction is uncertain, our results suggest that patient demand and clinical and treatment factors largely determined who underwent the procedure,” the authors concluded.

Among patients not having reconstruction, the reasons varied by race.

“Black patients were less likely than nonblack, non-Latina patients to undergo reconstruction. In addition, patients without private insurance plans were less likely to undergo reconstruction,” the authors stated.

“Our study suggests that room exists for improved education regarding the safety of breast implants and the effect of reconstruction on follow-up surveillance, information about which could be readily addressed through decision tools,” the investigators concluded. “Finally, development of specific approaches to address patient-level and systems factors with a negative effect on the use of reconstruction among minority women is needed.”

Morrow M, et al: JAMA Surg. August 20, 2014 (early release online).

LUNG CANCER No Survival Benefits With Erlotinib and Whole-Brain Radiotherapy for NSCLC With Multiple Brain Metastases “To exploit the potential radiosensitizing properties, the direct effect on brain metastases, and systemic activity of erlotinib,” researchers from the United Kingdom tested concurrent erlotinib and whole-brain radiotherapy followed by maintenance erlotinib in patients with of

non–small cell lung cancer (NSCLC) and untreated brain metastases. No significant improvements in neurologic progressionfree survival (the primary endpoint of the study), overall survival, or quality of life were found for patients receiving wholebrain radiotherapy with erlotinib vs placebo, Siow Ming Lee, MD, PhD, of University College London (UCL) and UCL Hospitals, and colleagues reported in the Journal of the National Cancer Institute.

The 80 study patients all had Karnfosky performance status of 70 and multiple brain metastases. Inclusion criteria also included Radiation Therapy Oncology Group Recursive Partitioning Analysis (RTOG RPA) class I and II. Class I is defined as Karnofsky score ≥ 70, controlled primary tumor, and metastases to brain only, whereas class II involves uncontrolled primary tumor or primary controlled but metastases to brain and other sites, the investigators explained.

“The frequency of epidermal growth factor receptor (EGFR) mutations was low with only 1 of 35 (2.9%) patients with available samples had activating EGFR mutations,” the researchers noted. The median age was 62.2 years in the placebo group and 61.3 years in the erlotinib group.

Patients were randomly assigned in equal numbers to receive placebo or erlotinib at 100 mg/d given concurrently with whole-brain radiotherapy at 20 Gy in 5 fractions. Patients continued with placebo or erlotinib at 150 mg/d until disease progression.

At 2 months after whole-brain radiotherapy, 15 patients (37.5%) from each arm were alive and without neurologic progression. Median neurologic progression-free survival was 1.6 months in both arms (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.59–1.54, P = .84). Median overall survival was 2.9 in the placebo arm and 3.4 months in the erlotinib arm (HR = 0.95, 95% CI = 0.58 to 1.55, P = .83).

“The median neurological [progression-free survival] and [overall survival] in this group were disappointingly low; 1.6 months and 3.4 months respectively, despite selecting only patients with agemodified RTOG RPA class I and II,” the researchers wrote.

Overall 70% of patients in both groups experienced a grade 3/4 adverse event.

Rash was more frequent in the erlotinib group (20% vs 5% in the placebo group), and fatigue was more frequent in the placebo group (35% vs 17.5% for the erlotinib group). No statistically significant

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In the Literature

quality-of-life differences were observed.

“Our finding does not preclude the possibility that erlotinib is effective for EGFR mutation positive tumors as only 2.9% of assessed patients manifested EGFR mutations,” the investigators wrote.

“Future studies should focus on the role of erlotinib with or without [whole-brain radiotherapy] in NSCLC patients harboring EGFR mutations.”

Lee SM, et al: J Natl Cancer Inst 106(7):dju151, 2014.

COLORECTAL CANCER

outcome was the rate of superficial surgical site infections before and after implementation of the surgical site infection bundle in July 2011.

Of 559 patients in the study, 346 (61.9%) had surgery before and 213 (38.1%) after implementation of the bundle. The median age was older in the prebundle group (62.2 vs 58.7 years, P =

.04),” the study report noted. “In addition, a higher percentage of patients in the prebundle group received preoperative radiation therapy (19.1% vs 12.2%, P = .04). In contrast, a lower percentage of patients in the prebundle group had received recent chemotherapy (5.5% vs 14.6%, P < .001).

The proportion of laparoscopic cases was lower in the prebundle group (38.4% vs

TELL YOUR ADVANCED PRACTICE COLLEAGUES TO

58.7%, P < .001) as well.” Other factors included in the analysis did not differ significantly between the two groups.

Due to the differences that might affect the rate of surgical site infections, propensity matching for the bundling was performed. “No significant difference was observed in patient demographics, basecontinued on page 148

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Substantial Reductions in Surgical Site Infections After Colorectal Surgery With Bundling Approach Use of a preventive surgical site infection bundle that spanned the phases or perioperative care “was associated with a substantial reduction in [surgical site infections] after colorectal surgery,” according to results of a retrospective study of 559 patients who underwent major elective colorectal surgery. “The elements of the bundle included existing evidencebased measures as well as commonsense measures that were thought to pose minimal risk and hold potential for benefit,” Jeffrey E. Keenan, MD, and colleagues from Duke University Medical Center, Durham, North Carolina, reported in JAMA Surgery.

Surgical infections “represent a particularly important problem in colorectal surgery, for which [surgical site infection] rates are disproportionately high, ranging from 15% to 30%,” the authors noted. “The use of the bundle involved a systematic approach to improve the use of [surgical site infection] preventive measures across the phases of perioperative care. It was a multidisciplinary effort, calling on surgeons, anesthesiologists, clinic nurses, operating room staff, unit nurses, house staff, and hospital midlevel providers to enact the prescribed elements.” Patients were also involved and received educational materials and instructions for preventing surgical site infections, such as taking disinfecting showers before surgery.

The investigators identified a sample group of patients undergoing major colorectal surgery at Duke from January 2008 through December 2012. Procedures included low anterior resection, abdominoperineal resection, partial or total abdominal colectomy with or without proctectomy, proctectomy, pelvic exenteration, or Hartmann-type procedure, the author explained. Open and laparoscopic cases were included. The primary

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In the Literature Emerging Clinical Data continued from page 147

line characteristics, or procedure-specific factors between the matched groups.

Evaluation of outcomes indicated a significant reduction in superficial [surgical site infection] (19.3% vs 5.7%, P < .001) and postoperative sepsis (8.5% vs 2.4%, P = .009) in the postbundle period,” the researchers reported.

“No significant difference was observed in deep [surgical site infections], organ-space [surgical site infections], wound disruption, length of stay, 30-day readmission, or variable direct costs between the matched groups. However, in a subgroup analysis of the postbundle period, superficial [surgical site infection] occurrence was associated with a 35.5% increase in variable direct costs ($13,253 vs $9,779, P = .001) and a 71.7% increase in length of stay (7.9 vs 4.6 days, P < .001),” the authors added. They concluded that the “increased costs associated with [surgical site infections] support that the bundle represents an effective approach to reduce health care costs.”

Several recent studies, including the one by Keenan et al, “support that colorectal surgical site infection is a preventable harm with adherence to published evidence, best practice guidelines, and culture change,” according to an accompanying editorial. “In all of these studies, significant surgical site infection reduction stems from implementation of processes that span the continuum of care from before surgery through postoperative recovery,” noted Ira L. Leeds, MD, MBA, and Elizabeth C. Wick, MD, of the Department of Surgery at Johns Hopkins University, Baltimore.

Keenan JE, et al: JAMA Surg. August 27, 2014 (early release online).

Leeds IL, Wick EC: JAMA Surg. August 27, 2014 (early release online).

LEUKEMIA/LYMPHOMA Allogeneic Conditioning Regimen Reduces Myelosuppression, Graft-vsHost Disease in Lymphocytic Leukemia/Lymphoma The combination of bendamustine (Treanda), fludarabine, and rituximab (Rituxan), or BFR, was shown to be safe and effective conditioning for patients with relapsed chronic lymphocytic leukemia/lymphoma receiving allogeneic stem cell transplantation from related or unrelated donors. “Remarkably, this BFR regimen resulted in a low incidence of myelosuppression and severe acute graftvs-host disease,” Issa F. Khouri, MD, and

colleagues from The University of Texas MD Anderson Cancer Center in Houston stated in Blood.

The phase I/II study tested the safety and efficacy of escalating doses of bendamustine (70, 90, 110, and 130 mg/m2/d for 3 days), coupled with fixed doses of fludarabine and rituximab as a nonmyeloablative allogeneic conditioning regimen. Eligibility criteria included a diagnosis of resistant or relapsed CD20-positive chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL).

After none of the 10 patients in the phase I study experienced a dose-limiting toxicity, the other 46 patients were added for the phase II study and treated at the maximum dose of 130 mg/m2/d for 3 days. Among the total of 56 patients, 15 had CLL and 41 had lymphoma. “The CLL patients were generally considered to have high-risk disease,” the authors noted.

The median age of the patients was 59, and 63% were male. A total of 11 patients (20%) had bone marrow involvement, and 14 (25%) had more than one extranodal site of involvement with disease, the investigators reported. The median number of prior chemotherapies was three (range, 1–7).

“All patients received unmanipulated grafts from the peripheral blood (52 patients) or bone marrow (4 patients),” the researchers reported. Thirty patients (54%) received transplants from matched siblings and 26 patients (46%) from unrelated donors.

The clinical response included 50 patients (89%) with complete response and 3 (5%) with a partial response. In addition, two patients (10%) had stable disease and one patient was not evaluable because of early death. After a median follow-up of 26 months (range, 6–50 months), the 2-year overall survival rate was 90% and the progression-free survival rate was 75%.

“Recovery of neutrophils and platelets was prompt,” the researchers reported.

“Remarkably, 55% of patients did not experience severe neutropenia,” the authors wrote, and 49 patients (88%) did not require platelet transfusion. The incidence of acute grade 2 to 4 graft-vs-host disease was 11% and grade 4 acute graft-vs-host disease occurred in only one patient. The 2-year rate of extensive chronic graft-vshost disease was 26%.

Seven patients died, with two deaths related to disease progression, one to acute graft-vs-host disease, and 1 to chronic graft-vs-host disease. The other deaths were related to gastrointestinal bleeding, fungal infection, and West Nile virus infection.

“We were surprised by the low level of myelosuppression in this study,” the authors noted. “Through the course of the trial, it was noted that many patients with normal [absolute neutrophil counts (ANCs)] at study entry maintained an ANC of > 500 cells/μL throughout and did not need growth factor support. This observation prompted us to modify our administration of growth factors, which led to the full recovery of counts in 23% of patients with no growth factor support.”

The researchers concluded that the BFR regimen is safe and effective for relapsed CLL and lymphoma patients and “may be considered as a platform for outpatient allogeneic transplantation.”

This trial is registered at www.clinicaltrials.gov as NCT00880815.

Khouri IF, et al: Blood. August 21, 2014 (early release online).

Para-Aortic Lymph Node Radiation Raises Risk of Developing Diabetes Mellitus in Hodgkin Lymphoma Survivors Radiation to the para-aortic lymph nodes, “leading to radiation exposure of the pancreas, is associated with a dose-dependent increased risk” of developing diabetes mellitus among long-term survivors of Hodgkin lymphoma (HL), according to a study by Frederika A. van Nimwegen, MSc, of the Netherlands Cancer Institute, Amsterdam, and colleagues.

“We found that the risk of [diabetes mellitus] is especially increased in patients who received a prescribed radiation dose of ≥ 36 Gy to the [para-aortic] fields or a mean radiation dose of ≥ 36 Gy to the pancreatic tail or whole pancreas,” the investigators reported in the Journal of Clinical Oncology. “Screening for [diabetes mellitus] should be considered in follow-up guidelines for HL survivors, and treating physicians should be alert to this increased risk,” the researchers advised.

The study cohort comprised 2,264 patients who were diagnosed with HL before age 51 and survived at least 5 years after diagnosis. Patients were treated between 1965 and 1995 in five Dutch hospitals and cancer centers.

“Primary treatment was usually given according to treatment protocols of the European Organisation for Research and Treatment of Cancer,” the authors noted.

In the 1960s and 1970s, patients usually received 40 Gy in fractions of 2.0 Gy when they were treated with radiotherapy only, and 30 to 36 Gy in fractions of 1.5 to 2.0 Gy when they also received chemotherapy. Infradiaphragmatic radiotherapy usually involving the para-aortic lymph

nodes, “with or without the spleen/splenic hilum, but frequently also including the iliac and inguinal nodes, was given until the late 1980s as part of (sub)total nodal irradiation,” the investigators stated.

“After a median follow-up of 21.5 years, 157 patients developed [diabetes mellitus],” the researchers reported. The median age of those patients was 32.4 years during HL treatment and 53.9 years at diagnosis of diabetes mellitus. While the overall cumulative incidence of diabetes mellitus after 30 years was 8.3%, the incidence among patients who had received para-aortic radiation at ≥ 36 Gy was 14.2%.

“Irradiation with ≥ 36 Gy to the paraaortic lymph nodes and spleen was associated with a 2.30-fold increased risk of [diabetes mellitus] [95% confidence interval (CI) = 1.54- to 3.44-fold] whereas para-aortic radiation alone with ≥ 36 Gy was associated with a 1.82-fold increased risk [95% CI = 1.02- to 3.25-fold],” according to the study report. Lower doses (10–35 Gy) did not significantly increase the risk of diabetes mellitus, but that risk significantly increased with higher mean radiation doses to the pancreatic tail (P < .001).

“The radiation-associated increased risk of [diabetes mellitus] was independent of the presence of obesity, which supports the results of previous studies,” the authors noted. “Only 8% of patients with [diabetes mellitus] were obese. A limitation of this study, however, is that the information on obesity status was obtained at end of follow-up and not at the time of [diabetes mellitus] diagnosis. Because patients may have lost weight after [diabetes mellitus] diagnosis, some misclassification may have occurred.”

While “radiotherapy to the spleen is rarely administered nowadays,” physicians should be aware of the increased risk of diabetes mellitus among long-term HL survivors who have received splenic or para-aortic irradiation as part of HL treatment in the past. “In addition, current patients with HL with (residual) upper abdominal disease as well as patients with testicular cancer or stomach cancer may still be exposed to radiation to the pancreas,” the authors noted.

“Early detection of [diabetes mellitus] may contribute to a substantial reduction of morbidity in long-term survivors of HL and may even reduce mortality by decreasing cardiovascular disease risk,” the researchers concluded. van Nimwegen FA, et al: J Clin Oncol.

August 25, 2014 (early release online).

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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Announcements

Residents Association Recognizes 57 Mentors and Teachers With 2014 Educator of the Year Award

T

he Association of Residents in Radiation Oncology (ARRO) has honored 57 educators with the 2014 Educator of the Year Award. The award, presented annually, recognizes outstanding teachers and mentors of radiation oncology residents. Each radiation oncology residency program may nominate one faculty member for the award.

“Mentoring radiation oncology residents is an essential element of their training and education, and has a significant impact on the advancement of the specialty,” said Jordan Kharofa, MD, Immediate Past Chair of ARRO’s Executive Committee. “We are proud to recognize these outstanding educators for their dedication to providing guidance, support and mentorship to radiation oncology residents at their institutions.”

2014 Educator of the Year Award Recipients • Sudha Amarnath, MD, Cleveland Clinic, Cleveland • Jonathan J. Beitler, MD, MBA, FASTRO, Emory University, Atlanta • Ranjit S. Bindra MD, PhD, Yale University School of Medicine, New Haven, Connecticut • Tithi Biswas, MD, Case Western Reserve University, Cleveland • Michael Buckstein, MD, PhD, Icahn School of Medicine at Mount Sinai, New York • Michael Chan, MD, Wake Forest University School of Medicine, Winston-Salem • Lynn Chang, MD, Fox Chase Cancer Center, Philadelphia • Yi-Jen Chen, MD, PhD, City of Hope National Medical Center, Philadelphia • Yuhchyau Chen, MD, PhD, University of Rochester Medical Center, Rochester, New York

• Kevin Choe, MD, PhD, University of Texas Southwestern Medical Center, Dallas • Charles W. Coffey II, PhD, Vanderbilt University Medical Center, Nashville, Tennessee

• Paul Graves, PhD, New York Methodist Hospital, Brooklyn, New York • Gregory S. Gustafson, MD, Oakland University William Beaumont School of Medicine, Rochester, Michigan • Sandra Hatch, MD, University of

Mentoring radiation oncology residents is an essential element of their training and education, and has a significant impact on the advancement of the specialty.

• • • • • •

—Jordan Kharofa, MD

• • Candace R. Correa, MD, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida • Rupak K. Das, PhD, University of Wisconsin, Madison, Wisconsin • Eric D. Donnelly, MD, Northwestern Memorial Hospital, Chicago • Kevin Du, MD, PhD, New York University School of Medicine, New York • Steven J. Feigenberg, MD, University of Maryland Medical Center, Baltimore • Christine Fisher, MD, MPH, University of Colorado, Denver • John B. Fiveash, MD, University of Alabama at Birmingham Medical Center, Birmingham, Alabama • John Ford, MD, Texas A&M University, College Station, Texas • Barbara L. Fowble, MD, FASTRO, University of California, San Francisco • Gary Freedman, MD, University of Pennsylvania, Philadelphia • David K. Gaffney, MD, PhD, Huntsman Cancer Institute and University of Utah, Salt Lake City • Sharad Goyal, MD, MS, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey

• • • • • • • • • • • •

Texas Medical Branch Hospitals, Galveston, Texas John Holland, MD, Oregon Health and Science University, Portland, Oregon Richard Jennelle, MD, Los Angeles County Medical Center/University of Southern California, Los Angeles Hayeon Kim, MS, DABR, University of Pittsburgh Cancer Institute, Pittsburgh Stephen J. Ko, MD, Mayo Clinic, Jacksonville, Florida Nataliya Kovalchuk, PhD, Massachusetts General Hospital, Boston Quynh-Thu Le, MD, Stanford Cancer Institute, Stanford Francisco Lopez, MS, Medical College of Wisconsin, Milwaukee Omar Mahmoud, MD, University of Miami, Miami Weiyuan Mai, MD, Baylor College of Medicine, Houston Raymond H. Mak, MD, Brigham and Women’s Hospital, Boston Anne R. McCall, MD, University of Chicago, Chicago Edward Melian, MD, Loyola University Medical Center, Maywood,

• • • • • • • • • • • •

Illinois John Mignano, MD, PhD, Tufts Medical Center, Boston Melissa P. Mitchell, MD, PhD, University of Kansas Medical Center, Kansas City, Kansas Sabin Motwani, MD, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey Thomas R. Niedermayr, PhD, Brigham and Women’s Hospital, Boston Bhupesh Parashar, MD, New York Presbyterian Hospital, New York Javad Rahimian, PhD, Kaiser Permanente Southern California, Los Angeles Eric Schreiber, PhD, University of North Carolina Hospitals, Chapel Hill, North Carolina Varun Sehgal, PhD, University of California, Irvine, California Ronald H. Shapiro, MD, Indiana University School of Medicine, Indianapolis David J. Sher, MD, MPH, Rush University Medical Center, Chicago M. Salim U. Siddiqui, MD, PhD, Henry Ford Health System, Detroit Matthew Stenmark, MD, University of Michigan, Ann Arbor Keqin Tang MD, PhD, Wayne State University, Detroit Stephanie Terezakis, MD, Johns Hopkins University, Baltimore Keith R. Unger, MD, Medstar Georgetown University Hospital, Washington, D.C. Xin Wang, MD, PhD, University of Minnesota, Minneapolis Julia White, MD, The Ohio State University, Columbus, Ohio Suzanne Wolden, MD, Memorial Sloan Kettering Cancer Center, New York Li-Xi Yang, MD, PhD, California Pacific Medical Center, San Francisco n

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Psycho-oncology

Memorial Sloan Kettering Cancer Center Launches Meaning-Centered Psychotherapy Programs for Terminally Ill Patients, Cancer Survivors, and Caregivers

By Jo Cavallo

A

lthough most major cancer centers in the United States offer support groups and individual counseling sessions to help patients with cancer cope with their disease

seling interventions for patients with advanced cancer, as well as for bereaved parents who have lost a child to cancer, cancer survivors, caregivers, and bereaved family members.

The whole psycho-oncology world is struggling with developing some type of effective psychotherapy interventions for fear of recurrence among breast cancer survivors. I think our research is perhaps the most promising.

—William S. Breitbart, MD

and treatment, over the past decade Memorial Sloan Kettering Cancer Center in New York has broadened its psycho-oncology programs to include interventions for patients, cancer survivors, and caregivers. Recently, the cancer center established the Program for Family Care in Cancer, which integrates novel types of coun-

Inspired by Holocaust Survivor One approach used by clinical researchers in the program is meaning-centered psychotherapy, which provides people touched by cancer with a way to find a sense of meaning, hope, peace, and purpose in their lives. This approach was developed by William S.­

Breitbart, MD, Acting Chair, Department of Psychiatry and Behavioral Sciences and Chief of the Psychiatry Service at Memorial Sloan Kettering, and is based on the writings of Viktor Frankl, MD, PhD, who was an Austrian neurologist and psychiatrist and Holocaust survivor.

Dr. Frankl’s book, Man’s Search for Meaning (Beacon Press, 1959), chronicles his experiences as a concentration camp inmate and describes his conviction that people can find meaning and a reason to continue living even in the most difficult circumstances.

Meaning-centered psychotherapy is a manualized treatment that includes contemplation exercises and discussion. It has been evaluated in randomized controlled clinical studies conducted by Memorial Sloan Kettering investigators, and delivered in individual and group counseling sessions or via the Internet. Two years ago, Dr. Breitbart published the results of his study on individual

meaning-centered psychotherapy for patients with advanced cancer.1 The study investigated brief interventions targeting spiritual wellbeing and meaning for patients with stage III or IV cancer. The researchers enrolled 120 patients in treatment at Memorial Sloan Kettering who had a life expectancy of 6 months or less.

The patients were randomly assigned to seven sessions of either individual meaning-centered psychotherapy or therapeutic massage. Those assigned to the meaning-centered psychotherapy met for 1 hour with a therapist to explore personal sources of meaning in their lives, such as love, relationships, and work, and to discuss existential themes, such as hope, legacy, and the impermanence of life.

Combatting Fear of Recurrence The results show that patients receiving individual meaning-centered psychotherapy had improvement in their quality of life and spiritual well-being and fewer physical symp-

Clinical Studies in Psychotherapy Currently Recruiting Participants

T

hese studies are investigating psychosocial and individual meaning-centered psychotherapy interventions for patients with cancer and bereaved parents. They are sponsored by Memorial Sloan Kettering Cancer Center and are currently recruiting participants. The studies are listed on the ClinicalTrials.gov website.

Study Type: Observational Study Title: Attention and Interpretation Modification (AIM) for Fear of Breast Cancer Recurrence: An Intervention Development Study Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center; Brown University, Weill Medical College of Cornell University, Wake Forest School of Medicine, and McLean Hospital Purpose: To customize and personalize an existing computer-based intervention program to help breast cancer survivors cope with fears of cancer recurrence

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Female Accepts Health Volunteers: No Primary Outcome Measures: Develop and refine materials (time frame: 1 year) Principal Investigator: Wendy Lichtenthal, PhD, Memorial Sloan Kettering Cancer Center. Contact: Elizabeth Slivak, 646-888-0134 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01517945 Study Type: Observational Study Title: Adaptation of Individual Meaning-Centered Psychotherapy for Chinese Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center; Queens Cancer Center of Queens Hospital, Charles B. Wang Community Health Center, ACS Asian Initiatives, New York Coalition for Asian American Mental Health,

and New York Hospital Queens Purpose: To modify individual meaning-centered psychotherapy to meet the needs of Chinese patients with cancer. Meaning-centered counseling aims to teach patients with cancer how to maintain or increase a sense of meaning and purpose in their lives despite their cancer diagnosis.

Ages Eligible for Study: 21 to 80 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Adapt the individual meaning-centered psychotherapy intervention (time frame: 2 years) Principal Investigator: Jennifer Leng, MD, MPH, Memorial Sloan Kettering Cancer Center; 646-888-4243 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02112188 Study Type: Interventional/randomized Study Title: Development of Psy-

chotherapeutic for a Parent Who Lost a Child to Cancer Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center, University of Memphis, University of Hawaii, Adelphi University, Weill Medical College of Cornell University Purpose: To study a new counseling program for parents who have lost a child to cancer Ages Eligible for Study: N/A Genders Eligible for Study: Both Accepts Health Volunteers: Yes Primary Outcome Measures: Feasibility (time frame: 4 years) Principal Investigator: Wendy Lichtenthal, PhD, Memorial Sloan Kettering Cancer Center. Contacts: Corinne Sweeney, MA, 646-8880134; Polly Korbel, BA, 646-8880129; Wendy Lichtenthal, PhD, 646888-4812 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02153619 n

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Psycho-oncology

toms such as pain. In contrast, the patients receiving massage therapy alone reported no significant benefit. Dr. Breitbart and his colleagues in Memorial Sloan Kettering’s Program for Family Care in Cancer have recently adapted meaning-centered psychotherapy programs for breast

not been very impressive. Our hope is to expand this study to include survivors of ovarian cancer with a fear of recurrence. Fear of recurrence is a common issue for many cancer ­survivors.”

The clinician/researchers involved in the Program for Family Care include Allison J. Applebaum, PhD, Direc-

tor of the Caregivers Clinic; Wendy G. Lichtenthal, PhD, Director of the Bereavement Clinic; Christina G. ­Salley, PhD, Pediatric Psychologist; and Talia I. Zaider, PhD, Clinical Psychologist in the Family Therapeutic Clinic and Associate Co-Director of Memorial Sloan Kettering’s Psychotherapy Laboratory. n

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

Reference 1. Breitbart W, Poppito S, Rosenfield B, et al: Pilot randomized controlled trial of individual meaning-centered psychotherapy for patients with advanced cancer. J Clin Oncol 30:1304-1309, 2012.

Allison J. Applebaum, PhD

Patient Advocacy Summit:

Patient Concerns in 2014 – Big Data, Access, and Palliative Care NCCN will be hosting its 5th annual Patient Advocacy Summit: Patient Concerns in 2014 – Big Data, Access,

Wendy G. Lichtenthal, PhD

and Palliative Care, on November 3, 2014 at the National Press Club in Washington, DC. Patients today are facing a variety of concerns and considerations when confronting cancer. From the plethora of data they encounter when making treatment decisions to accessing and paying for drugs and biologics to palliative care, patients need resources to help them make appropriate care and financial decisions. Register to learn more!

Talia I. Zaider, PhD

Photos courtesy of MSKCC

Christina G. Salley, PhD

cancer survivors, bereaved parents, caregivers, and Chinese patients with cancer. (See “Clinical Studies in Psychotherapy Currently Recruiting Participants,” on page 150.) There is also an intervention study targeting fear of disease recurrence in breast cancer survivors.

“The whole psycho-oncology world is struggling with developing some type of effective psychotherapy interventions for fear of recurrence among breast cancer survivors,” said Dr. Breitbart. “I think our research is perhaps the most promising, because most of the research I’ve seen based on cognitive behavioral therapy has

Monday, November 3, 2014 9:30 AM – 3:30 PM ET (Breakfast & registration begin at 8:45 AM) National Press Club Washington, DC

Agenda Highlights*: • Big Data and the Patient • Addressing Patient Access Issues • Palliative Care and the Patient *Subject to change.

Visit NCCN.org/policy for upcoming events, summaries, and white papers.

This activity is supported by a contribution from Exelixis Inc. Supported by grants from Abbott Molecular and ImmunoGen, Inc. Supported by Apotex Corp.; Astellas Pharma US, Inc.; Biodesix; Gilead Sciences, Inc; ImpediMed; Incyte Corporation; Janssen; Medivation Inc.; Millennium: The Takeda Oncology Company; Onyx Pharmaceuticals, Inc., an Amgen subsidiary; Pharmacyclics, Inc., and TEVA Oncology. This activity is supported by an unrestricted grant from Eisai Inc. This activity is sponsored by Boehringer Ingelheim Pharmaceuticals, Inc.; HELSINN; and Xcenda, an AmerisourceBergen Consulting Services company. This activity is supported by a contribution from Lilly.

Updated as of August 20, 2014.

JNCCN-N-0197-0914

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PAGE 152

Future of Oncology How Evolutionary Game Theory Is Offering Clues to Disrupt Cancer Cell Metabolism A Conversation With Kenneth J. Pienta, MD

By Jo Cavallo American Cancer Society’s Clinical Research Professor Award.

The ASCO Post talked with Dr. Pienta about his research in the ecology of cancer and how game theory can be used to target the tumor microenvironment and lead to more effective cancer therapies.

Computational Model Kenneth J. Pienta, MD

K

enneth J. Pienta, MD, and his colleagues at Johns Hopkins Medicine in Baltimore are using the principles of evolutionary game theory to learn how cancer cells cooperate within a tumor to gather energy and metastasize. Game theory, the mathematic study of strategic decision-making that is commonly used to predict conflict and cooperation between individuals, is increasingly being applied in science to predict cell-to-cell interactions in biology with an ecologic perspective.

In a recent study,1 Dr. Pienta used a game theory model based on biologic interactions between two types of cancer cells—hypoxic (or energy deficient) and oxygenated—to study the metabolic symbiosis in which lactate from stromal cells fuels energy generation in the oxygenated microenvironment of the tumor, while hypoxic cells use sugar glucose to produce energy and promote tumor progression.

Dr. Pienta’s research found that within certain ranges of cell mutation rates, transitions take place in which a tumor switches between different types of energy metabolic strategies. During this process might be the ideal time to disrupt cancer cell cooperation and make metastatic cells more vulnerable to cancer therapeutics, he speculated.

Dr. Pienta is the Donald S. Coffey Professor of Urology at the Johns Hopkins Brady Urological Institute, Director of the Prostate Cancer Program at the Johns Hopkins Kimmel Cancer Center; and Professor of Oncology and Professor of Pharmacology and Molecular Sciences at Johns Hopkins Medicine. In 2007, Dr. Pienta was the recipient of the American Association of Cancer Research Team Science Award and is a two-time recipient of the

Please describe how you are using evolutionary game theory to learn how cancer cells cooperate to gather energy and multiply.

Game theory allows us to look at how cancer cells interact with each other, as well as how they interact with various other cells of the host within the tumor microenvironment. We have been using various ecologic frameworks, including cooperation theory, game theory, and population biology, to try to come up with and think about new ways to gain insights into how cancer metastasizes in

grow, many cancer cells appear to rely on aerobic glycolysis—a phenomenon called the “Warburg effect.” We have long known about the Warburg effect.

The question is, why would a cancer cell that uses regular oxidative phosphorylation to create ATP and energy, use the glycolytic pathway, which uses lactate to produce ATP? What we have suggested, and first tried to model here, is that cancer cells that are stressed can actually use both oxidative phosphorylation as well as aerobic glycolysis when there is still enough oxygen around. The modeling we have done shows that a cancer cell, in an environment that is producing lactate, can actually use both oxidative phosphorylation and aerobic glycolysis to produce energy for different cellular functions—even when there is enough oxygen around. Now we are testing this tumor metabolism coupling in our in vitro systems.

What is fascinating about the ecology argument is that it takes into account not only cell evolution, but the environment the tumor is living in as well. By looking at both together we can potentially develop better therapies.

—Kenneth J. Pienta, MD

people and eventually kills them.

We start with a computational model, which in our most recent paper looked at cell metabolism. We have also used population biology computational models to look at cell metastasis and cooperation theory models to look at how cancer cells share resources like cytokines, hormones, and growth factors to basically ask, how can cancer cells help or hurt each other in the microenvironment of the tumor? And as the cells grow and become hypoxic, how can they create a resource-sharing environment?

Underlying Mechanisms Your research has found that an intercellular signal can induce a critical transition between high and low levels of tumor glucose consumption. How does that process affect cancer growth?

In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cells to

Targeting Metabolic Coupling How can the process of metabolic coupling in tumors be broken?

We are studying that now. The question is, is there a drug that can break the shuttle somehow between oxidative phosphorylation and aerobic glycolysis? Researchers have been trying to target the Warburg effect in cancer cells as a therapy for a long time, and we don’t yet have a magic bullet to do that. But what our study results provide is some new insights into how one cancer cell can help another cancer cell survive that hypoxic environment—that insult—potentially to its own detriment.

At the risk of anthropomorphizing a disease, we view cancer as a community of cells that are interacting together—it is not every cancer cell for itself—and these cancer cells interact in a mindless manner to help each other.

Cooperation theory and game theory allows us to set up modeling of mutualism relationships, in which both parties benefit, as well as parasitism, where

only one of the cells benefits and the other is hurt. For reasons we don’t yet understand, one cancer cell will parasitize another.

Are there some cancer types that are more vulnerable to metabolic uncoupling than others?

We don’t know the answer to that yet. We think that solid tumors in which hypoxic environments are created are more likely to benefit from this process, but we don’t have any proof yet.

Interventional Strategies How do you envision game theory models being used in the clinic to disrupt cancer cell cooperation?

Unfortunately, I cannot make that jump from the laboratory to the clinic yet. That said, one example of how we’ve used cooperation theory to help our own framework is we established a cooperation game theory relationship between tumor-promoting macrophages in cancer cells and showed through game theory models how they can help each other exhibiting mutualism. We found that the cancer cells release factors that help the tumor attract the tumor-associated macrophages and help them grow. Then we found how the tumor-associated macrophages secrete matrix metalloproteinases and break down the environment, so the cancer cells can escape, as well as secreting a lot of other factors like interleukin 6 that help the cancer cells grow and become resistant to therapy.

So we took those findings, proved them in vitro and in vivo, and launched a clinical trial to treat metastatic prostate cancer using a monoclonal antibody to block one of the main factors that attract macrophages, CCL2, to the tumor microenvironment. Unfortunately, the trial failed, not because the theory was wrong, but because the antibody was not strong enough.

Now we are developing therapies based on knocking out the macrophages themselves. We just have not had time to develop the interventional strategies from a metabolism standpoint.

Looking Ahead Will it be possible to detect and intercontinued on page 153

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In Memoriam

John H. Saiki, MD, SWOG Investigator, Dies at 77

J

ohn “Jack” Harris Saiki, MD, Professor Emeritus at the University of New Mexico Department of Medicine, Hematology/Oncology Division, lived the history of modern day oncology

John “Jack” Harris Saiki, MD

with a career spanning 44 years. In the early days of his career, with the support of a grant from the federally funded New Mexico Regional Medical Program, Dr. Saiki developed a leukemialymphoma treatment program at a time when no formal medical oncology program existed in New Mexico. Dr. Saiki died peacefully on August 8, 2014, at his home in New Mexico surrounded by his loving family.

Education and Early Career Born on December 31, 1936 in Grand Forks, North Dakota to Lydia Elizabeth Kuoppala and Arthur Kazu Saiki, MD, Dr. Saiki spent most of his childhood in Grand Forks and 3 formative years in Kauai, Hawaii. Dr. Saiki received his medical degree from McGill University in Montreal, Canada in 1961. It was there that he met his future wife, Julie Singleton. Dr. Saiki served 2 years with the United States Public Health Service in Fort Defiance, Arizona. He completed his residency and fellowship training in medicine and hematology at the University of New Mexico School of Medicine and his oncology training at the University of Texas, MD Anderson Cancer Center. Dr. Saiki joined the faculty at the University of New Mexico School of Medicine in 1970.

Dr. Saiki was subsequently awarded funding from the National Institutes of Health in support of his membership in SWOG, which ushered in cancer clinical trials and new cancer treatments

for New Mexicans. In 1973, Dr. Saiki received Board certification in medical oncology, the year the subspecialty of medical oncology was first created.

Dr. Saiki served in various capacities while on the faculty, including Clinical Director of the University of New Mexico Cancer Center and Principal Investigator for the Southwest Oncology Group. In addition, Dr. Saiki served on the Board of Trustees for Blood Systems for 29 years and was Medical Director of the Presbyterian Hospice Program.

Brilliant, Humble, and Kind Dr. Saiki was the recipient of numerous awards for teaching and service, including the Laureate Award by the New Mexico Chapter of the American College of Physicians and nine Khatali Awards, an honor bestowed by each graduating class of the University of New Mexico School of Medicine in recognition of teaching excellence.

Throughout his career, Dr. Saiki loved teaching but patient care was foremost

in his heart. Dr. Saiki was beloved for his humility, compassion, integrity, and dedication.

Dr. Saiki and his wife of 52 years, Julie, shared a mutual love of the Southwest, hiking, birding, identifying wildflowers, and enjoying the tranquility of the Taos mountains. He was deeply loved and admired by his three children. He encouraged them to carve out their own unique paths and, importantly, to appreciate the journey.

He was a beloved granddad. With his playful spirit and love of teaching, he spent endless hours with his grandchildren on projects fostering their love of science and nature. Dr. Saiki’s curiosity and appreciation of life included photography, tennis, geology, woodworking, taking up the banjo at age 40, and driving his ’66 Volvo. His gift for storytelling, endearing sense of humor, and gentle nature remained ever-present to the end.

A celebration of Dr. Saiki’s life was held earlier this month at the University of New Mexico Cancer Center. n

 In Memoriam

John H. Saiki, MD December 31, 1936 – August 8, 2014  Kenneth J. Pienta, MD continued from page 152

rupt cell metabolic coupling and stop cancer metastasis over the next decade?

Absolutely. Over the past couple of years, there has been a true resurgence in interest in cancer metabolism, in learning about what is going on metabolically in a tumor, and in how that process can be targeted.

I wish I could report to you that I have a new therapy based on our findings. But we are looking very hard not

only at the tumor-associated macrophage interruption and targeting story, as well as the metabolism story. I am very keen on thinking about cancer as an ecosystem, and I believe that in the next 10 years there is going to be a huge step forward in this area.

A few years ago, oncologists were enthusiastic about sequencing every patient’s tumor, and that is still true today. But except in a few instances, the number of actionable targets for which a drug has been found is probably less

than 20%. And while those targeted therapies are good, they are not curative. We are now recognizing that such a low percentage is just not good enough.

What is fascinating about the ecology argument is that it takes into account not only cell evolution, but the environment the tumor is living in as well. By looking at both together we can potentially develop better therapies, and we are doing this all the time.

Bevacizumab (Avastin), for example, is a microenvironment-targeted drug.

We think that the answer to how cancer is going to be treated in the future is with combination therapy that targets both the malignant cells and the cancer ecosystem. n

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

Reference 1. Kianercy A, Beltri R, Pienta KJ: Critical transitions in a game theoretic model of tumour metabolism. Interface Focus 4:20140014, 2014.

T:10.25" S:9.5"

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AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

Announcements

St. Jude Children’s Research Hospital Mourns Loss of Friend, Supporter, Robin Williams

S

t. Jude Children’s Research Hospital acknowledged the death of Robin Williams with the following statement: “On August 11, 2014, the world lost an iconic man and entertainer, and St. Jude Children’s Research Hospital lost an incredible friend and sup-

porter. Robin Williams generously gave his time to raise awareness and funds for St. Jude and for patients battling childhood cancer. His humor brought bright smiles and laughter to our patients and families and his generosity deeply touched the hearts of all who knew him.” n

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy.

Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).]

1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Robin Williams with St. Jude patients throughout the years. (Courtesy of St. Jude Children’s Research Hospital).

Coming Next Month in The ASCO Post ■■ Hagop Kantarjian, MD, on the Hippocratic Oath in the 21st Century

Plus: October Is Breast Cancer Awareness Month ■■ Journal Spotlight: ASCO Clinical Practice Guideline: Chemotherapy and Targeted Therapy in Advanced HER2Negative or Unknown HER2 Status Breast Cancer ■■ Important Reports from the 2014 Breast Cancer Symposium ■■ Oncology Worldwide: Breaking the Silence of Breast Cancer in the Arab World

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4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

AVASTIN® (bevacizumab) 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies.

The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).]

Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

• Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

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

The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin.

[See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of

T:10.25" S:9.5"

AVASTIN® (bevacizumab) 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.

In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs.

19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.

In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of

a

Arm 2 IFL+ + Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

AVASTIN® (bevacizumab) In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3.

Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

a

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs.

5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs.

1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs.

13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs.

3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs.

2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan.

Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

AVASTIN® (bevacizumab) 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations.

Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility.

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

17 PATIENT COUNSELING INFORMATION Advise patients: • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated.

• To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting.

• Of increased risk of wound healing complications during and following Avastin.

• Of increased risk of an arterial thromboembolic event.

• Of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following last dose of Avastin.

• Of the increased risk for ovarian failure following Avastin treatment.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

03/14 AVA0000765907 Initial U.S. Approval: February 2004 Code Revision Date: March 2014 Avastin® is a registered trademark of Genentech, Inc. © 2014 Genentech, Inc.

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Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone.

The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%).

Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

Arm 1 IFL+ + Placebo (n = 396) 74%

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Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8.

The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8).

In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.8).]

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

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Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%).

Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

AVASTIN® (bevacizumab) 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

To confront a threat in first-line metastatic non-squamous NSCLC…

Think Avastin

Because survival matters most

Percentage Surviving

Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991 100

1-year survival: 51% vs 44%2

80

2-year survival: 23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

10

20

30

40

50

OS (Months) Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68– 0.94], P=0.013).1 Clinically meaningful 1- and 2-year survival rates were demonstrated with Avastin plus PC (51% and 23%, respectively, vs 44% and 15% with PC alone).2

Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; OS=overall survival; HR=hazard ratio; CI=confidence interval.

Indication

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Most common adverse events

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)

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All rights reserved.

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Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/ pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

References: 1. Avastin Prescribing Information. Genentech, Inc. March 2013.

2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

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