TAP Vol 5 Issue 10

Fertility Preservation in Breast Cancer 22, 98 | Cancer Care Under Affordable Care Act

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| Tumor Genomic Testing

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

ASCO Annual Meeting Plenary Session

Exemestane/Ovarian Suppression Reduces Recurrence vs Tamoxifen/Ovarian Suppression in Premenopausal Breast Cancer

Time to Move Forward With Lung Screening

By James L. Mulshine, MD

By Alice Goodman

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joint analysis of two important phase III clinical New Adjuvant Option “Exemestane was previtrials—TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Tri- ously recommended only al)—showed that exemestane plus ovarian function for postmenopausal women. suppression was superior to tamoxifen plus ovarian This analysis demonstrates suppression in preventing recurrence in premeno- that an aromatase inhibitor is effective adjupausal women with hormone-sensitive vant therapy for breast cancers. premenopausal “This joint analysis provides new and Olivia Pagani, MD women when long-awaited information on how to treat precombined with ovarian suppression. Exemesmenopausal patients with hormone-sensitive tane [plus ovarian suppression] is a valid alterbreast cancer who have the potential to be native to tamoxifen [plus ovarian suppression] cured,” said ASCO Immediate Past President See page 6 in young women with hormone-sensitive early Clifford A. Hudis, MD, FACP, at a press conference during the 2014 ASCO Annual Meeting, where breast cancer. It is a new adjuvant treatment option that these data were presented at a Plenary Session.1 Study reduces recurrence in this setting,” said lead author ­Olivia results were published simultaneously online in The New Pagani, MD, Clinical Director of the Breast Unit at the continued on page 8 England Journal of Medicine.2 Director’s Corner

Advancing Immune Checkpoint Targeting in Cancer Treatment

continued on page 97

Dr Mulshine is Professor, Associate Provost for Research and Vice President, Rush Medical College, Rush University, Chicago, Illinois.

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

MORE IN THIS ISSUE

A Conversation With James P. Allison, PhD

By Jo Cavallo

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tart with the most lethal cancer globally—lung cancer—for which standard approaches result in a modest 5-year survival.

Then consider the results from the National Lung Screening Trial (NLST), suggesting in a well done randomized study that significant mortality reduction does occur with low-dose computed tomography (CT) in individuals at high risk for lung cancer. Add to that the fact that the U.S. Preventive Services Task Force (USPSTF) looked comprehensively at over 8,000 papers reported on the topic over the past 10 years and concluded that the service is recommended with a B rating.

ames P. Allison, PhD, Professor and Chair of the Department of Immunology, Executive Director of the Moon Shots Immunotherapy Platform, and Deputy Directory of the David H. Koch Center for Applied Research of Genitourinary Cancers at The University of Texas MD Anderson Cancer Center, Houston, is renowned for his groundbreaking research in cancer immunotherapy.

As a young investigator at The University of Texas in the early 1980s, Dr. Allison identified the antigen receptor CTLA-4 on the surface of T cells that functions as an ignition switch, turning on an immune response when it comes in contact with a foreign antigen. In 1992, while a professor at the University of California, Berkeley, Dr. Allison identified a second molecule on the surface of T cells, called CD28, which acts as the T I think we have to focus on how to cell’s gas pedal, accelerating immune response. increase the durable effect of cancer He and another investherapies, and it’s going to require tigator, Jeffrey Bluestone, PhD, Executive Vice some thinking about how to combine Chancellor and Provost immunotherapies with other agents to at the University of California, San Francisco, improve durable antitumor responses. performed independent —James P. Allison, PhD

Oncology Meetings Coverage ASCO 50th Annual Meeting �������������� 1–28 AACR Conference on Pancreatic Cancer �������������������������������������30 American Roentgen Ray Society Annual Meeting ����������������������������������������35 Digestive Disease Week ������������������� 40–42 Inside the Black Box ���������������������������������52 Direct From ASCO �������������������������� 56–59 ASCO Guideline: HER2-Positive Breast Cancer ���������������������������������������������63 In Memoriam: Eddie Reed, MD ���������� 104 Chandrakanth Are, MD, on Quality Measures and Metrics ���������������� 105

continued on page 50

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The ASCO Post | JUNE 25, 2014

PAGE 2

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PAGE 3

ASCO Annual Meeting Gastrointestinal Oncology

Combined With Chemotherapy, Cetuximab and Bevacizumab Found Comparable for First-Line Metastatic Colorectal Cancer Treatment

By Caroline Helwick

C

all it a draw: Cetuximab (Erbitux), an EGFR inhibitor, and bevacizumab (Avastin), a VEGF inhibitor, confer comparable benefits as first-line treatment with chemotherapy for metastatic colorectal cancer, according to the phase III Can-

These two distinctly different biological treatments did not impart differences in outcomes. Either is appropriate in the first-line metastatic setting.

—Alan P. Venook, MD

See page 6

cer and Leukemia Group B (CALGB)/ Southwest Oncology Group (SWOG) 80405 trial presented at the 2014 ASCO Annual Meeting Plenary Session.1 “We did not show a meaningful difference between the arms. These two distinctly different biological treat-

ments did not impart differences in outcomes. Either is appropriate in the firstline metastatic setting,” said Alan P. Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco.

The high median overall survival— 29-plus months—along with the finding that 10% of patients were alive past 5

years, confirms the progress that has been made in metastatic colorectal cancer over the years, Dr. Venook emphasized. Approximately 25 years ago, the median overall survival for these patients was about 8 months, he noted.

Clifford A. Hudis, MD, FACP, Immediate Past President of ASCO, who moderated the press briefing, commented, “This study sets a new standard

EXPERT POINT OF VIEW

J

osep Tabernero, MD, PhD, Head of Medical Oncology and the Institute of Oncology at Vall d’Hebron University Hospital in Barcelona, Spain, discussed the results of CALGB/SWOG 80405 at the ASCO Plenary Session.

“CALGB/SWOG 80405 did not meet the primary endpoint of superiority [for cetuximab] in a population of patients with KRAS exon 2 wild-type

curve. FOLFIRI/cetuximab and FOLFIRI/bevacizumab seem comparable, but the FOLFIRI results may be less robust, as they account for only onefourth of the population,” he observed.

More Data Essential He said the future presentation of overall response rates, depth of response, degree of tumor shrinkage, and

I am reluctant to describe this as a negative study, because it is very informative and, with additional analyses, the interpretation may change.

—Josep Tabernero, MD, PhD

tumors. Nevertheless, I am reluctant to describe this as a negative study, because it is very informative and, with additional analyses, the interpretation may change,” Dr. Tabernero said.

“FOLFOX/cetuximab and FOLFOX/bevacizumab seem comparable in this setting, although a slight trend favoring cetuximab arm may be seen in the second part of the [survival]

other factors “will be important in order to obtain essential knowledge regarding the initial effects of the treatment on tumor burden.”

Similarly, he urged the FIRE-3 investigators to “present as soon as possible” that study’s other efficacy data.

“It is very difficult indeed to understand differences in overall survival without any difference in response rate or

progression-free survival.” He would like to see the independent review of response, evidence of tumor shrinkage, and depth of response “to help us understand the different effect in overall survival,” he said.

In CALGB/SWOG 80405, expanded RAS testing—looking for KRAS mutations in exons 3 and 4, and NRAS mutations—will be highly informative and could change the results, he predicted, figuring that expanded RAS analysis could narrow the population from 1,137 to 900 or 975 RAS wild-type patients, and alter the overall survival hazard ratio from 0.92 to 0.87–0.85.

“For the time being,” he said, “We cannot conclude that there is specific evidence for a regimen sequence for the KRAS wild-type exon 2 population, though there are emerging data that can be utilized on an individual basis.”

“The results of CALGB/SWOG 80405 mark an important milestone in the roadmap of metastatic colorectal cancer treatment,” he said. Future analyses, he added, “will shed light on the important questions that remain unanswered.” n Disclosure: Dr. Tabernero is a consultant and/or advisor for Amgen, ImClone, Lilly, Merck KGaA, Millennium, Novartis, Roche, Sanofi, Celgene, Chugai, and Taiho.

and a new high bar for clinical trials in advanced colorectal cancer.”

Rationale for the Federally Funded Trial CALGB/SWOG 80405, designed in 2004, was a Herculean effort, involving 14 amendments and 11 interim analyses as the field of colorectal cancer treatment evolved over 10 years. At the time it was designed, bevacizumab and cetuximab had been only recently approved.

“The drugs were new at the time, and they had very different toxicity profiles.

The question was, which was the optimal first-line treatment?” Dr. Venook said at a press briefing. “The assumption at the start was that maybe one was better.”

The results of the trial were highly anticipated, since the previous FIRE-3 trial, reported at the 2013 ASCO Annual Meeting, found that cetuximab improved overall survival but not progression-free survival.2 The findings puzzled many experts, who looked forward to the results of this nonindustry, federally funded trial that compared the two monoclonal antibodies.

“Some of our results appear contrary to findings in other studies. We await complete data to place these in perspective,” Dr. Venook said.

Survival High in Both Arms The study involved 1,137 previously untreated KRAS wild-type (codons 12, 13) metastatic colorectal cancer patients.

The study had a superiority design for the cetuximab combination, with overall survival the primary endpoint.

Patients were randomly assigned to chemotherapy plus either bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 initial dose, then 250 mg/m2 weekly). The selection of chemotherapy was based on physician preference: 73.4% received FOLFOX (fluorouracil [5-FU], leucovorin, oxaliplatin) and 26.6% received FOLFIRI (5-FU, leucovorin, irinotecan).

Four-week treatment holidays were permitted.

At a median follow-up of 24 months, no significant differences were observed in either overall survival or progressionfree survival between the treatment groups, which was 29 months and 10.8 continued on page 4

The ASCO Post | JUNE 25, 2014

PAGE 4

ASCO Annual Meeting Genitourinary Oncology

Updated Information on Prostate Cancer Drugs: Enzalutamide, Orteronel, and Cixutumumab

By Alice Goodman

T

hree separate studies of treatments for prostate cancer reported at the 2014 ASCO Annual Meeting in Chicago showed excellent, intermediate, and disappointing results. An update of the previously reported PREVAIL trial (see March 1 issue of The ASCO Post, page 1) was overwhelmingly positive for the androgen receptor antagonist enzalutamide (Xtandi). A second study showed that the androgen-synthesis inhibitor orteronel improved radiographic progression-free survival but failed to improve overall survival, while a third study of the monoclonal antibody cixutumumab was negative.

Enzalutamide a ‘Home Run’ “In the PREVAIL trial, treatment with enzalutamide significantly delayed radiographic progression-free survival, significantly reduced the risk of death by nearly 30%, delayed the time to initiation of cytotoxic chemotherapy, and

Metastatic Colorectal Cancer continued from page 3

months, respectively, with bevacizumab/ chemotherapy and 29.9 months and 10.4 months, respectively, with cetuximab/ chemotherapy. In the FOLFOX arm, median overall survival was 30.1 months with cetuximab and 26.9 months with bevacizumab (P = .09).

Since three-quarters of the physicians chose FOLFOX as the chemotherapy backbone, the small subset receiving FOLFIRI limits any comparison of the chemotherapy backbone. The results suggest that either is “a perfectly reasonable first-line option,” Dr. Venook said.

No Surprises in Toxicity No new toxicities emerged in this study. With bevacizumab, common side effects were hypertension, headache, mucositis, nosebleed, diarrhea, rectal bleeding, loss of appetite, fatigue, and weakness, while cetuximab patients were more likely to have acneiform rash, pruritus, changes in fingernails and toenails, infections, fatigue, and low serum electrolyte levels. FOLFOX was associated with more neuropathy, whereas FOLFIRI caused more alopecia and diarrhea.

The overall quality of life for patients on either drug was similar, though, as expected, cetuximab-treated patients reported less “skin satisfaction” with that drug.

improved quality of life on the FACTP. Enzalutamide added to androgendeprivation therapy provides clinically meaningful benefits to men with metastatic castration-resistant prostate cancer,” said Andrew J. Armstrong, MD, ScM, FACP, Associate Professor of Medicine at Duke Cancer Institute, Duke University, Durham, North Carolina.1 Results of PREVAIL were published online in The New England Journal of Medicine to coincide with Dr. Armstrong’s presentation.2 Enzalutamide is already approved by the U.S. Food and Drug Administration (FDA) for postdocetaxel treatment of metastatic castration-resistant prostate cancer. These favorable data show that the drug is effective in the predocetaxel setting, and may pave the way for approval of that indication. Abiraterone (Zytiga), another drug that targets the androgen receptor, is now FDA-approved for treatment before and after

CALGB/SWOG 80405 and FIRE-3 In an interview with The ASCO Post, Dr. Venook discussed his findings vis-àvis those of FIRE-3. He attributed differences in the findings as a reflection of the “different patterns of care” in Germany vs North America, especially the nearuniversal use of FOLFIRI in the former, the greater and “less biased” use of effective second- and third-line treatments in

Enzalutamide added to androgendeprivation therapy provides clinically meaningful benefits to men with metastatic castration-resistant prostate cancer.

—Andrew J. Armstrong, MD, ScM, FACP

chemotherapy in metastatic castrationresistant prostate cancer.

The double-blind, phase III PREVAIL study randomly assigned 1,717 men with metastatic castration-resistant prostate cancer not previously treated with chemotherapy to receive enzalutamide at 160 mg/d or placebo.

Enzalutamide was significantly superior to placebo for the co–primary endpoints of radiographic progression-free survival and overall survival and for all

secondary endpoints as well.

The median duration of enzalutamide treatment was 16.6 months vs 4.6 months for those receiving placebo.

At data cutoff, 42% of men were still on enzalutamide. Compared with placebo, enzalutamide reduced the risk of death or radiographic progression-free survival by 81% (hazard ratio [HR] = 0.19; P < .0001).

The 12-month rate of radiographic

what cooperative groups do: treat patients in studies for which companies are not paying the bill.”

mens for what is called “expanded” RAS. The exclusion of patients with RAS mutations other than codons 12 and 13, and including mutations in NRAS, has been shown to enrich populations likelier to benefit from the EGFR antibodies. This might result in a subset of patients being identified who would best be treated by the EGFR antibodies. n

Future Analyses “The clinical information and biospecimens from the patients in this study represent a rich resource and unique opportunity to gain a deeper understanding of colorectal cancer,” Dr. Venook said.

Yet to come are the clinical subset

Cetuximab vs Bevacizumab in Metastatic Colorectal Cancer ■■ In the first-line metastatic colorectal cancer setting, cetuximab and bevacizumab, plus chemotherapy, yielded comparable overall and progression-free survival benefits.

■■ The toxicity of the regimens differed.

■■ CALGB/SWOG 80405 was a federally funded study of 1,137 patients.

CALGB/SWOG 80405 (88% vs 67%), and the 15% rate of liver metastasis resection in the current study.

He acknowledged that the CALGB/ SWOG data “still need to be vetted and validated,” but he emphasized, “our patients’ 29-plus months of median overall survival is unprecedented, and is longer than the 27 months shown in FIRE-3.”

He added, “These patients are doing a little better, and I believe this represents a less biased approach. This is

analyses and molecular studies. The investigators will evaluate outcomes by site of primary tumor and patient gender; outcomes in patients with intact primary tumors; pharmacoeconomics and disparities; effect of vitamin D, lifestyle, and diet; and outcomes in the preamendment cohorts, which included patients with KRAS-mutant disease and those receiving two biologics.

The focus for the next few months will be on analyzing the tumor speci-

continued on page 5

Disclosure: Dr. Venook is a consultant or advisor for Bristol-Myers Squibb, Chugai Pharma, Mirna, Pharmacyclics, Roche/ Genentech, and Sanofi, and has received research funding from Bayer, Genomic Health, GlaxoSmithKline, Onyx, and Roche/ Genentech. For full disclosures of the study authors visit abstracts.asco.org.

References 1. Venook AP, Niedzwiecki D, Lenz H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum. ASCO Annual Meeting. LBA3. Presented June 1, 2014.

2. Heinemann V, von Weikersthal LF, Decker T, et al: Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE3). ASCO Annual Meeting. Abstract LBA3506. Presented June 1, 2013.

ASCOPost.com | JUNE 25, 2014

PAGE 5

ASCO Annual Meeting Prostate Cancer Drugs continued from page 4

progression-free survival was 65% for enzalutamide vs 14% for placebo (P < .001). At data cutoff, enzalutamide reduced the risk of death by 29% (hazard ratio [HR] = 0.71; P < .0001); 626 patients (72%) treated with enzalutamide were alive vs 532 patients (63%) in the placebo group.

Dr. Armstrong presented updated overall survival data, factoring in 116 additional deaths and an additional 4 months of follow-up. At 26 months of follow-up, median survival has not yet been reached for enzalutamide vs 31 months for placebo.

Enzalutamide significantly delayed

the time to initiation of chemotherapy, achieved significantly superior prostate-specific antigen (PSA) response, time to PSA progression, objective soft-tissue response, and time to first skeletal-related event (P < .001 for all comparisons with placebo).

Dr. Armstrong presented the quality-of-life results for the first time at the Annual Meeting. “These men had compromised quality of life at baseline,” he noted. “Many had poor prognostic features.” Nearly 40% of the enzalutamide group showed [qualityof-life] response vs 22.9% of placebo patients. All quality-of-life domains on the FACT-P showed greater improvement for enzalutamide vs placebo.

Treatment with enzalutamide was associated with fatigue and hot flushes, as well as a slightly increased risk of falls.

Grade 3 or greater hypertension was reported in 6% of the enzalutamide group vs 2.3% of the placebo patients. The risk of cardiovascular events was similar in both groups of patients. One seizure occurred in each of the two arms.

Orteronel Improves Progression-Free Survival Orteronel plus prednisone significantly improved radiographic progression-free survival in men with chemotherapy-naive castration-resistant prostate cancer in the large, international, phase III ELM-PC 4 study.3 Howev-

Ronald de Wit, MD, PhD

er, orteronel failed to improve the primary endpoint of overall survival.

Lead author Ronald de Wit, MD, PhD, is Professor in the Department of Medical Oncology at Erasmus University Medical Center, Rotterdam, the Netherlands, said that the ELM-PC 5 trial of continued on page 6

EXPERT POINT OF VIEW

D

espite the availability of hormonal therapy for the treatment of metastatic prostate cancer and the high response rates for these agents, most patients eventually experience progression to castration-resistant disease.

“Multidisciplinary team approaches have contributed to the enormous progress that has been made. They have led to well-designed clinical trials. We now have new agents that substantially improve both quality of life and survival in patients with metastatic castration-resistant prostate cancer,” explained Cora N. Sternberg, MD, FACP, Chief of Medical Oncology at San Camillo Forlanini Hospital in Rome, during an Educational Session at the 2014 ASCO Annual Meeting.

Dr. Sternberg noted that patients are often treated with hormonal agents when they have biochemical failure (ie, a rise in prostate-specific antigen) with no clinical evidence of metastasis, and that these patients may also develop castration-resistant disease with metastases. Her lecture focused, however, on patients with metastatic castration-resistant prostate cancer and the new hormonal agents that have been studied before and after docetaxel—specifically, abiraterone (Zytiga), enzalutamide (Xtandi), and the investigational agent, orteronel.

“Castration-resistant prostate cancer remains driven by androgen receptor signaling from the beginning of its course until the end,” she noted. Both abiraterone and enzalutamide ultimately target the androgen receptor.

Abiraterone decreases testosterone production from the adrenal glands, the testis, and the tumor cells them-

selves. Enzalutamide interferes with androgen receptor signaling and has three different mechanism of action; enzalutamide is eight times more potent than bicalutamide in blocking the androgen receptor, she said. Both drugs are now U.S. Food and Drug Administration (FDA)-approved for metastatic castration-resistant prostate cancer that has progressed after docetaxel therapy.

Key Trials The COU-AA-301 trial showed that abiraterone administered with prednisone twice daily improved median overall survival by 4.6 months,

37% reduction in risk of death. This drug has extremely good tolerability with few side effects. However, enzalutamide is associated with a ≤ 1% risk of seizures, and oncologists should not prescribe this drug in patients with a history of seizures. This is an area for further research, Dr. Sternberg said.

Both abiraterone and enzalutamide were also studied in the predocetaxel setting in men with metastatic castration-resistant prostate cancer in the COU-AA-302 and PREVAIL trials. “Results of both trials are quite remarkable,” Dr. Sternberg commented.

In COU-AA-302, abiraterone achieved a 57% reduction in the risk

Multidisciplinary team approaches have contributed to the enormous progress that has been made. They have led to well-designed clinical trials. We now have new agents that substantially improve both quality of life and survival in patients with metastatic castration-resistant prostate cancer.

—Cora N. Sternberg, MD, FACP

representing a 26% reduction in the risk of death. Minimal toxicity was observed. This was the first study to show such impressive results in patients after having had docetaxel chemotherapy.

The AFFIRM trial showed that enzalutamide achieved a median survival benefit of 4.8 months, with a

of progression and a 21% reduction in the risk of death, according to an interim analysis. Abiraterone gained FDA approval for treatment given before docetaxel based on the results of this trial.

The PREVAIL trial, also conducted in the predocetaxel setting, found that enzalutamide reduced the risk

of radiographic progression by 81% and reduced the risk of death by 29%.

The study was halted early by an independent data monitoring committee based on these results, and FDA approval is expected soon.

Orteronel, an androgen-lowering agent, has also been studied pre- and postdocetaxel. Although the ELMPC 4 and ELM-PC 5 studies revealed an improvement in radiographic progression-free survival, the studies showed no improvement in overall survival. “The reason for this has to do with the fact that many drugs such as abiraterone and enzalutamide as well as docetaxel and cabazitaxel [ Jevtana Kit] became available and were given to patients,” Dr. Sternberg noted.

Remaining Questions Several questions remain on how best to use these new agents in metastatic castration-resistant prostate cancer, including optimal sequencing and combinations. Ongoing studies will look at these questions, including a study at The University of Texas MD Anderson Cancer Center that has combined abiraterone and enzalutamide; the phase III ALLIANCE trial, which randomly assigns patients 2:1 to enzalutamide vs enzalutamide plus abiraterone and prednisone; and the PLATO trial, in which all patients are treated with enzalutamide and, at progression, are randomly assigned to add-on abiraterone and prednisone vs abiraterone and prednisone plus placebo enzalutamide. n Disclosure: Dr. Sternberg has received research funding or honoraria from Astellas, Medivation, Janssen, and Millennium.

The ASCO Post | JUNE 25, 2014

PAGE 6

ASCO Annual Meeting Prostate Cancer Drugs continued from page 5

orteronel also showed improved radiographic progression-free survival but no improvement in overall survival; in a subset analysis of that subsequent trial, it appeared that survival was improved in the non-Europe/North America population, whereas no regional differences in overall survival were seen in the results he reported for ELM-PC 4.

Orteronel is an investigational, nonsteroidal, reversible, selective inhibitor of 17, 20-lyase, whose activity is upregulated in castration-resistant prostate cancer, Dr. de Wit explained.

The ELM-PC 4 trial enrolled 1,560 men from 43 different countries who

diographic progression-free survival or death by 30% compared to placebo and prednisone (P < .001). The final overall survival analysis, presented by Dr. de Wit, showed radiographic progressionfree survival of 13.8 months for orteronel plus prednisone vs 8.7 months for prednisone alone, for an absolute difference of 5 months, which was statistically significant (P < .0001). Overall survival was 31.4 months for the orteronel group vs 29.5 months for placebo recipients.

Cixutumumab Disappointing The addition of cixutumumab—an investigational monoclonal antibody directed at insulin-like growth factor type 1 receptor (IGF-1R)—to andro-

Treating Metastatic Castration-Resistant Prostate Cancer ■■ Enzalutamide significantly delayed radiographic progression-free survival, reduced risk of death from prostate cancer, delayed time to initiation of cytotoxic chemotherapy, and improved quality of life on FACT-P in the predocetaxel setting in the large phase III PREVAIL trial.

■■ Orteronel improved radiographic progression-free survival but not overall survival in the ELM-PC 4 trial.

■■ Cixutumumab did not meet the primary endpoint for PSA response in a phase II trial in newly diagnosed metastatic, hormone-sensitive disease.

had chemotherapy-naive metastatic castration-resistant prostate cancer that was asymptomatic without opioid use and randomly assigned them 1:1 to orteronel at 400 mg twice daily plus prednisone at 5 mg twice daily or to placebo plus prednisone. The co–primary endpoint was radiographic progression-free survival and overall survival. Key secondary endpoints were PSA response, change in circulating tumor cell levels, and time to disease progression.

Baseline characteristics were well balanced between the two arms. This was not a well population, he noted. One out of five patients discontinued treatment with orteronel by 12 weeks, and adverse events were higher with orteronel. Thirty percent of treatment discontinuations were due to adverse events, with fatigue as the most common reason. Other side effects reported more frequently with orteronel were gastrointestinal (nausea, vomiting, and diarrhea), fatigue, asthenia, cardiac disorders, and increased lipase and amylase levels.

At an interim analysis, orteronel plus prednisone reduced the risk of ra-

gen-deprivation therapy with biculatamide and luteinizing hormone–releasing hormone agonist failed to meet the primary endpoint of undetectable PSA response (ie, ≤ 0.2 ng/nL) compared with androgen-deprivation therapy alone in the randomized Southwest Oncology Group (SWOG) S0925 study of 211 men with metastatic hormone-sensitive prostate cancer.4 At 28 weeks, 40% of those in the cixutumumab group and 32.4% of those in the androgen-deprivation therapy group achieved undetectable PSA. The main adverse effect seen with cixutumumab was hyperglycemia. The rates of grades 1, 2, and 3 hyperglycemia in the cixutumumab arm were 27.7%, 14.9%, and 7.9%, respectively; in the androgen-deprivation arm, those rates were 7.7%, 0%, and 0%.

Circulating tumor cell counts declined in almost all patients, and those counts correlated with stratified PSA response, but no correlation was observed between IGF-1R biomarkers and undetectable PSA rate.

Patients will be followed for survival, said lead author of the phase II trial, Evan

EXPERT POINT OF VIEW

F

ormal discussant Scott T. Tagawa, MD, Associate Professor of Clinical Medicine and Urology at Weill Cornell Medical College, New York, had the task of putting the three prostate cancer trials—PREVAIL, ELM-PC 4, and SWOG S0925—into context.

“Since the approval of docetaxel, we have learned much about the biology of prostate cancer. Multiple new drugs have demonstrated efficacy leading to [U.S. Food and Drug Administration] approval,” he noted.

Scott T. Tagawa, MD The PREVAIL trial looked at earlier use of an approved drug, enzalutamide (Xtandi), in the course of disease, while SWOG S0925 evaluated combinations of approved drugs and new targets. The ELM-PC 4 trial looked at a new version of similar drugs.

“PREVAIL was a very positive trial, and enzalutamide is an excellent drug with a high level of efficacy,” Dr. Tagawa said. That said, he urged clinicians to be attentive to the potential grade 3 and 4 adverse events with enzalutamide, including seizures, as well as drug-drug interactions.

The orteronel trial was positive in terms of radiographic progression-free survival benefit in the absence of overall survival benefit for men with minimally symptomatic metastatic castration-resistant prostate cancer. He referenced the ELM-PC 5 trial, which was recently presented at the 2014 Genitourinary Cancers Symposium and was also negative for overall survival.

“Looking at these two large randomized trials of investigational agents in [metastatic castration-resistant prostate cancer], we can confirm antitumor activity of these drugs, but the endpoint of overall survival was negative,” Dr. Tagawa said.

Though there may have been explanations for the negative results based on the availability of other life-prolonging drugs during the conduct of these studies, he questioned the necessity of justifying results of these disappointing clinical trials.

“We now have multiple phase III studies [of agents for metastatic castration-resistant prostate cancer]. We need to know how to use them in an optimal setting such as earlier-stage disease, we need to explore combinations and sequencing of these drugs, and we need to study how to overcome resistance. I urge continued research, collection of specimens, and collaborations with colleagues,” Dr. Tagawa stated. n Disclosure: Dr. Tagawa reported no potential conflicts of interest.

Ya-Wen Yu, MD, a medical oncologist at the Seattle Cancer Care Alliance. n Disclosure: Dr. Armstrong has served as a consultant or advisory for Amgen, Astellas/ Medivation, Bristol-Myers Squibb, Dendreon, Janssen, and Sanofi, has received honoraria from Dendreon, Pfizer, and Sanofi, and has received research funding from Active Biotech, Dendreon, Janssen, Medivation, Novartis, Pfizer, and Sanofi.

Dr. de Wit has served as a consultant or advisor for and has received honoraria from Millennium. Dr. Yu has received research funding from ImClone Systems and Veridex. For full disclosures of all study authors, visit abstracts.asco.org.

References 1. Armstrong AJ, Tombal B, Sternberg CN, et al: Primary, secondary, and quality of life endpoint results from PREVAIL.

ASCO Annual Meeting. Abstract 5007.

Presented June 1, 2014.

2. Beer TM, Armstrong AJ, Rathkopf DE, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. June 1, 2014 (early release online).

3. de Wit R, Fizazi K, Jinga V, et al: Phase 3, randomized, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (ELM-PC 4 trial). ASCO Annual Meeting. Abstract 5008.

Presented June 1, 2014.

4. Yu EY, Tangen CM, Higano CS, et al: SWOG S0925: A randomized phase 2 study of androgen deprivation combined with cixutumumab versus androgen deprivation alone in patients with new metastatic hormone-sensitive prostate cancer. ASCO Annual Meeting.

Abstract 5006. Presented June 1, 2014.

The Value of Federally Funded Cancer Research ASCO has created a badge to raise awareness of the importance of federally funded biomedical research that improves the lives of people worldwide.

The plenary presentations at ASCO’s Annual Meeting all were the result of federally funded research. To call attention to the value of federal funds, The ASCO Post has printed this badge alongside reports on data resulting from federally funded research (see pages 1, 3, 20, and 22 in this issue).

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The ASCO Post | JUNE 25, 2014

PAGE 8

ASCO Annual Meeting Breast Cancer

Premenopausal Breast Cancer continued from page 1

Oncology Institute of Southern Switzerland in Bellinzona. Optimal endocrine therapy for premenopausal women is still uncertain, she said.

Ovarian suppression is used more frequently in Europe than in the United States to achieve low estrogen levels in patients with hormone-sensitive breast cancer. Tamoxifen is considered the standard of care in this setting, and adjuvant chemotherapy is sometimes used depending on the judgment of the patient’s risk by the oncologist and patient preference.

SOFT and TEXT Trials Both SOFT and TEXT were designed to compared tamoxifen for 5

years plus ovarian suppression vs exemestane for 5 years plus ovarian suppression; SOFT was a three-arm trial comparing both of those treatment approaches vs tamoxifen alone (results of the tamoxifen arm are not yet available). TEXT was a two-arm trial comparing exemestane plus ovarian suppression vs tamoxifen plus ovarian suppression. The joint analysis presented at the ASCO Annual Meeting was based on a total of 4,690 patients from both trials enrolled in the ovarian suppression–containing arms.

Overall, two-thirds of patients were aged 40 to 49; and 42% node-positive; 62.3% had tumors of 2 cm or less; and 12% were HER2-positive. Chemotherapy was given at the discretion of the

treating physician, and 42.6% did not receive chemotherapy. In a separate interview, Dr. Pagani explained that 21%

least in some patients. Our study suggests that for some hormone-sensitive tumors, exemestane and [ovarian sup-

Our study suggests that for some premenopausal women with hormone-sensitive tumors, exemestane and [ovarian suppression] can replace chemotherapy.

—Olivia Pagani, MD

of TEXT patients and 8% of SOFT patients who did not receive chemotherapy had tumors larger than 2 cm and some positive nodes, usually considered adverse prognostic features that can lead to the prescription of chemotherapy.

“Exemestane plus [ovarian suppression] could replace chemotherapy at

pression] can replace chemotherapy,” Dr. Pagani stated.

Key Findings At a median follow-up of 68 months, 5-year disease-free survival was 91.1% with exemestane plus ovarian suppression and 87.3% in the tamoxifen plus ovarian

EXPERT POINT OF VIEW

“T

his study provides key insights into the longstanding and vexing debate about optimal systemic therapy for these young women. We wonder about the role of tamoxifen, aromatase inhibitors, chemotherapy, and ancillary therapies like bisphosphonates,” said Nancy E. Davidson, MD, Director of the University of Pittsburgh Cancer Institute, who was formal discussant of the TEXT and SOFT trials during the Plenary Session at the ASCO Annual Meeting.

The joint analysis showed a highly statistically significant improvement in the primary endpoint of disease-free survival with exemestane plus ovarian function suppression. All subgroups benefited. And there was a significant improvement in secondary endpoints, she said. “But these positive findings have not translated into improved survival,” she added, noting that it is premature to evaluate survival.

Dr. Davidson cited several strengths of this trial. It was international, used a rigorous definition of premenopausal and hormone responsiveness, and had well-balanced arms and a pragmatic follow-up algorithm. Limitations included a revised analysis plan due to betterthan-expected outcomes to compensate for a lower-than-expected event rate, short follow-up, heterogeneous patients, and a long period of accrual.

Further Considerations Several factors to consider when evaluating the results of SOFT and TEXT compared to discrepant results of the older ABCSG-12 trial include the choice of aromastase inhibitor, the

choice of luteinizing hormone–releasing hormone (LHRH) agonist, duration of endocrine therapy, different patient characteristics, the use and timing of chemotherapy, and the size and statistical power of the trial.

avoid chemotherapy, which is an important point. The decision to use chemotherapy should be individualized and based on discussions between the oncologist and the patient. “Not every premenopausal patient needs chemo-

More long-term follow-up of this analysis, as well as results of the tamoxifen arm in the SOFT trial are needed to finalize my approach.

Additionally, we need to determine the role of obesity, and develop better predictive biomarkers in this setting.

—Nancy E. Davidson, MD

From a quality-of-life perspective, it is important for premenopausal women to retain ovarian function.

It behooves us to think about who needs [ovarian suppression] and to wait to see results of the tamoxifenalone arm.

—Claudine Isaacs, MD

“Several of these factors may account for the differences. Longer follow-up may help us sort this out,” Dr. Davidson said.

The joint analysis of TEXT and SOFT suggests that some premenopausal women with early hormonesensitive breast cancer will do very well on hormone therapy alone and can

therapy,” Dr. Davidson noted.

“More long-term follow-up of this analysis, as well as results of the tamoxifen arm in the SOFT trial are needed to finalize my approach. Additionally, we need to determine the role of obesity, and develop better predictive biomarkers in this setting. What we can say today is that exemestane plus [ovarian sup-

pression] is another important option for premenopausal hormone-sensitive early breast cancer,” Dr. Davidson stated.

Another View “Ovarian suppression is controversial in the United States. We are not sure what ovarian suppression adds beyond tamoxifen in this setting. And we don’t know that yet because the results of the tamoxifen-alone arm of SOFT are not yet available,” said Claudine Isaacs, MD, Professor of Medicine and Oncology at Georgetown University School of Medicine, Washington, DC. “The question is: should I change my standard of care from tamoxifen to [ovarian suppression] based on this trial? I think we need to individualize therapy and consider risk of [ovarian suppression], age, and prior chemotherapy. The outcome is excellent with adjuvant tamoxifen alone in the majority of premenopausal women with hormonesensitive breast cancer. From a qualityof-life perspective, it is important for premenopausal women to retain ovarian function. It behooves us to think about who needs [ovarian suppression] and to wait to see results of the tamoxifen-alone arm,” Dr. Isaacs said.

Also, she said it is difficult to know whether some patients would prefer exemestane and ovarian suppression for 5 years vs chemotherapy. “Some women may prefer the transient side effects of chemotherapy. This is a complicated question, and these results cause us to reevaluate our thinking,” she said. n

Disclosure: Drs. Davidson and Isaacs reported no potential conflicts of interest.

ASCOPost.com | JUNE 25, 2014

PAGE 9

ASCO Annual Meeting suppression group (P < .001). The 5-year rate of freedom from breast cancer was 92.8% in the exemestane-treated patients compared with 88% in those who received tamoxifen (P < .001).

Among patients who did not receive chemotherapy and were treated with exemestane and ovarian suppression, 97.6% of the TEXT population and 97.5% of the SOFT population were free of breast cancer at 5 years.

Distant recurrence comprised about 60% of the events. The 5-year rate of freedom from recurrence at a distant site was 93.8% in the patients assigned to receive exemestane plus ovarian suppression compared with 92% of those treated with tamoxifen plus ovarian suppression.

The overall survival rates were high in the two groups and not significantly different. At 5 years, overall survival was 95.9% in the exemestane group and 96.9% in the tamoxifen group. However, it is premature to determine survival, Dr. Pagani said.

Side effects of both drugs were similar to what is reported in postmenopausal women. Adverse events that were more frequent with exemestane included fractures, musculoskeletal symptoms, vaginal dryness, decreased libido, and dyspareunia. Those more frequently reported with tamoxifen included thromboembolic events, hot flushes, night sweats, and urinary incontinence.

Adherence was very good in both arms, with only 14% of patients interrupting both treatments before 5 years.

Gynecologic cancers were reported in seven exemestane-treated patients and in nine tamoxifen recipients. Endometrial cancers occurred in two and five patients, respectively. About 30% of pa-

Roles of Exemestane and Ovarian Suppression in Breast Cancer Therapy ■■ Exemestane more effectively prevented breast cancer recurrences than tamoxifen, when either was given with ovarian function suppression to premenopausal women with hormone-sensitive cancers.

■■ Exemestane improved diseasefree survival by 28% and the breast cancer–free interval by 34% compared with tamoxifen plus ovarian suppression.

tients in both arms experienced grade 3 or 4 adverse events.

Convincing Evidence?

At the press briefing, Dr. Hudis said, “This is a long-awaited study that addresses a question rooted in the very beginning of modern breast cancer therapy a century ago. While this result supports the use of

[ovarian suppression] and [aromatase inhibitors] in premenopausal women with hormone-sensitive early breast cancer, we still need to see the results of the tamoxifenalone arm to complete the picture.” n Disclosure: Dr. Hudis reported no potential conflicts of interest. Dr. Pagani has received research funding from Ipsen and Pfizer. For full disclosures of the study authors, visit abstracts.asco.org.

References 1. Pagani O, Regan MM, Walley B, et al: Joint analysis of IBCSG TEXT and SOFT trials. ASCO Annual Meeting. Abstract LBA1. Presented Sunday, June 1 2014.

2. Pagani O, Regan MM, Walley B, et al: Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. June 1, 2014 (early release online).

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The ASCO Post | JUNE 25, 2014

PAGE 10

ASCO Annual Meeting Gynecologic Oncology

Early Study Explores New Approach to Treating Advanced Cervical Cancer

By Alice Goodman

A

small, federally funded study of diate regression of an epithelial cannine patients treated with hu- cer,” stated lead author Christian man papillomavirus (HPV)-targeted S. Hinrichs, MD, Assistant Cliniadoptive T-cell therapy gives reason cal Investigator at the National Canto hope that this type of therapy may cer Institute (NCI) in Bethesda, be a new effective approach for pa- ­Maryland. tients with metastatic cervical cancer Metastatic cervical cancer kills and possibly other solid tumors.1 In about 6,000 women in the United the study, two of the nine States each year. These papatients achieved dramattients are typically treated ic and durable complete with chemotherapy, but resolution of their cancer. that option is not curative Although this is very preand rarely provides durable liminary research, the study palliation. Cervical cancers provides proof of prinharbor attractive targets for See page 6 ciple and was greeted with immunotherapy: HPV on­excitement. coproteins (or antigens) E6 and E7.

“We are in the early days of this proof-of-principle study that shows it Therapeutic Mechanism “Up to now responses to immuis possible to achieve a complete tumor response in metastatic cervical notherapy have been disappointing cancer following a single infusion of in cervical cancer. Adoptive T-cell HPV-targeted tumor-infiltrating lym- therapy is an emerging treatment phocytes. This study demonstrates that has shown promise in melanoma that adoptive T-cell therapy can me- and certain B-cell malignancies,” Dr.

What better type of cancer could there be for this therapy than one caused by a virus? The immune system can recognize viral antigens as foreign and attack them.

—Christian S. Hinrichs, MD

­ inrichs said. “What better type of H cancer could there be for this therapy than one caused by a virus? The immune system can recognize viral antigens as foreign and will attack them,” he continued.

The therapy is called HPV-targeted tumor-infiltrating lymphocyte therapy. T cells are harvested from tumor tissue and cultured. The cultures are then tested for HPV E6 and E7 reactivity. The most reactive cultures are selected for infusion and

then expanded. Billions of these expanded T cells are put in an infusion bag, and the patient is given a single injection. Response is assessed by imaging 6 weeks later, then at monthly and bimonthly intervals.

The first cohort of patients in the NCI study included nine young women with metastatic cervical cancer, all with squamous or glandular carci-

EXPERT POINT OF VIEW

S

teven J. O’Day, MD, Director, Clinical Research, Beverly Hills Cancer Center and Director, Los Angeles Skin Cancer Institute, Beverly

vivo, we can attack a tumor that has not been immunologically targeted before.

This is a whole new era in oncology.”

“The best we can do now for women

By [using HPV virus to provoke a T-cell response and then expanding those T cells], we can attack a tumor that has not been immunologically targeted before. This is a whole new era in oncology.

—Steven J. O’Day, MD

Hills, California, commented on cervical cancer study by Hinrichs et al from the National Cancer Institute (NCI) during a press briefing at the ASCO Annual Meeting.

“Today, young women for whom multiple antitumor therapies have failed have achieved complete remission by attacking T cells. We are moving this therapy to a disease that is generally not recognized as well by the immune system (cervical cancer). By identifying T cells targeting cervical cancer HPV oncoproteins, and enriching for and expanding these T cells ex

with metastatic cervical cancer is to offer them chemotherapy, perhaps with targeted treatment. However, median survival is still less than 2 years. It is my hope that immunotherapy for cervical

Don S. Dizon, MD

cancer will prove effective,” said Don S. Dizon, MD, a medical oncologist and Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, Boston. He noted that it is difficult to do these studies and urged oncologists to encourage their patients with advanced cervical cancer to participate in this NCI trial.

“If we could standardize this approach at academic centers and identify which patients should benefit, we could reduce the number of deaths from this disease,” Dr. Dizon said.

Dr. Hinrichs said that it is feasible for other centers to use this technique but that HPV-targeted tumorinfiltrating lymphocyte therapy is offered only at NCI right now.

‘Spectacular’ Response

Michael Birrer, MD, PhD, Director of Gynecologic Medical Oncology, Massachusetts General Hospital, Boston, is enthusiastic about the promise of HPV-targeted tumor-infiltrating lymphocyte therapy. “We are very excited, primary because these patients have a dismal Michael Birrer, MD, PhD prognosis. Formerly, median

survival was about 3.7 months, and with bevacizumab (Avastin) we have extended it to about 6 months.”

Dr. Birrer recently referred a patient with advanced cervical cancer to the NCI phase I trial. Even though this was a very small study, about 30% of patients responded. “The duration of response in the complete responders is spectacular.

We would never see this with any combination chemotherapy,” he continued.

“I believe in the strength of the science that exploits a mechanism that underpins a viral-derived tumor targeting E6 and E7. This is not just anecdotal,” he said.

Dr. Birrer thinks it is important to figure out why the other six patients failed to respond. “It is just conjecture, but they may have had other mutations that allowed them to resist this therapy.”

HPV-targeted tumor-infiltrating lymphocyte therapy is labor intensive and technically sophisticated, requiring patients to give tissue, have cells expanded, and then come back for treatment. “This will not be available at community hospitals,” Dr. Birrer said. n Disclosure: Drs. O’Day, Dizon, and Birrer reported no potential conflicts of interest.

ASCOPost.com | JUNE 25, 2014

PAGE 11

ASCO Annual Meeting nomas. Of these, three responded to therapy (one partial response and two complete responses). Dr. Hinrichs showed images of the two patients with dramatic complete responses.

Both were 36 years old.

The first patient had a complete response that was ongoing 22 months after treatment. The second patient had a complete response that was ongoing 15 months after treatment. Dr. Hinrichs said that the second patient had very aggressive cancer that had spread to the pelvis and distant sites and she needed a ureteral stent; after treatment, she had a complete tumor response, and the stent was removed.

She is now disease-free at 15 months.

Adoptive T-Cell Therapy in Cervical Cancer

Study Expansion Dr. Hinrichs and co-investigators expect to expand the advanced cervical cancer cohort to 35 patients. They also have open on the same study a cohort for treatment of patients with other HPV-positive cancers including oropharyngeal, anal, vulvar, vaginal, and penile cancers. He encourages oncolo-

gists to refer such patients to the study.

Dr. Hinrichs expects that the next extension of this work will be to T-cellreceptor gene therapy targeting the HPV oncoproteins, an approach analogous to the CD19 chimeric antigen receptor (CAR) gene therapies, which have demonstrated promising results in early clinical trials for B-cell malignancies. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Hinrichs CS, Stevanovic S, Draper L, et al: HPV-targeted tumor-infiltrating lymphocytes for cervical cancer. ASCO Annual Meeting. Abstract LBA3008. Presented June 2, 2014.

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■■ For the first time, a preliminary study suggests that the immune system can be deployed against advanced cervical cancer.

■■ Adoptive T-cell therapy achieved about a 30% response rate in patients with a very short life expectancy. Two of nine patients achieved complete remissions with no evidence of cancer at 15 and 22 months after a single infusion of T cells.

■■ This federally funded study is continuing to accrue patients, and the investigators plan to study other HPV-associated cancers using adoptive T-cell therapy.

Don’t Miss These Important Reports Inside this Issue of

The ASCO Post Josep Tabernero, MD, PhD, on the CALGB/SWOG 80405 trial see page 3 G.S. Raju, MD, FACG, FASGE, on colon cancer prevention see page 78

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ASCO Annual Meeting Hematology

Ibrutinib Surpasses Ofatumumab as Second-Line Treatment of Chronic Lymphocytic Leukemia

By Alice Goodman

I

brutinib (Imbruvica) significantly improved progression-free survival, overall survival, and response when compared with ofatumumab (Arzerra) as second-line treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in the phase III RESONATE study. The study

John C. Byrd, MD

results were presented at the 50th ASCO Annual Meeting and published online in The New England Journal of Medicine to coincide with the ASCO presentation.

“Ibrutinib beat a standard comparator in CLL for the first time,” stated John C. Byrd, MD, principal investigator of the study and Director of Hematology at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus.

The impact of ibrutinib was similar regardless of what types of pretreatment patients had received and molecular features of the disease. “The improvement in survival remained significant despite the crossover of 57 patients who had disease progression on ofatumumab,” Dr. Byrd said.

Ibrutinib is a first-in-class irreversible inhibitor of Bruton’s tyrosine kinase, and the drug has been given Breakthrough Therapy designation by the U.S. Food and Drug Administration.

The RESONATE study randomly assigned previously treated CLL/SLL patients in a 1:1 ratio to oral ibrutinib (n = 195) or to intravenous ofatumumab (n = 196). Median follow-up was 9.4 months. The study included patients with a short response to first-line therapy, elderly patients (over age 65), and those with deletions in 17p; these patients have poor outcomes and limited treatment options, he said.

Key Results “At a median follow-up of 9.4 months, 86% of patients on ibrutinib had durable responses and were continuing on treatment with minimal side effects. This is

remarkable, especially considering that standard CLL therapies typically produce a 35% to 40% response rate,” Dr. Byrd commented.

At 6 months, 83% of the ibrutinib arm experienced progression-free survival compared with 49% of those on the ofatumumab arm. At the time the data were presented, median progression-free survival had not yet been reached in the ibrutinib arm vs 8.08 months in the ofatumumab arm (P < .0001). This represents a 78% reduction in the risk of progression with ibrutinib.

The impact on progression-free survival was observed in all patient groups, including the elderly and those with deletions in chromosome 17p, Dr. Byrd said. Richter’s transformation, which is a concern, occurred in only two patients in each arm.

While median overall survival had not yet been reached in either treatment arm, the investigators found a significant improvement in overall survival for ibrutinib vs ofatumumab. There was a 57% re-

Ibrutinib vs Ofatumumab in CLL ■■ This was the first head-to-head comparison of ibrutinib with a standard second-line therapy for chronic lymphocytic leukemia (CLL).

■■ Ibrutinib significantly improved progression-free survival, overall survival, and response rate compared with ofatumumab, with modest, manageable toxicities.

duction in risk of death for the ibrutinib arm (P < .0049). At 12 months, the overall survival rate was 90% with ibrutinib vs 81% with ofatumumab.

Treatment with ibrutinib led to a 78% reduction in the risk of disease progression or death vs ofatumumab treatment. Overall response rate was 42.6% for ibrutinib vs 4.1% for ofatumumab (P < .001). These positive results were achieved despite the crossover of 57 patients from ofatumumab to ibrutinib, Dr. Byrd commented.

The safety profiles of both drugs were acceptable, with similar rates of major hemorrhage and renal toxicities, and higher rates of atrial fibrillation with ibrutinib and neuropathy with ofatumumab. Ibruti-

EXPERT POINT OF VIEW

“I

t is impressive to see an overall survival benefit in chronic lymphocytic leukemia (CLL),” said Gregory A. Masters, MD, FASCO, who moderated an ASCO press conference where the RESONATE study data were discussed. “Patients treated with [ibrutinib] have a long survival. Ibrutinib can be an encouraging option because of its manageable toxicity. This drug’s efficacy

nib does carry the risk of diarrhea, (48% vs 18% with ofatumumab), but it is modest and manageable in most patients, he said. Other nonhematologic adverse events included fatigue, pyrexia, and nausea in the ibrutinib group and cough in the ofatumumab group.

For Most Relapsed, Refractory CLL “If I were a patient with CLL, I would want this drug. In the relapsed and refractory setting after one prior therapy, there is no good reason not to give this drug outside of a few circumstances; those exceptions include patients on warfarin, because of an early safety signal regarding bleeding, hematomas, inflammatory bowel disease, and sarcoidosis,” Dr. Byrd commented. “The findings of phase II and the confirmatory phase III study show ibrutinib should be used for all relapsed, refractory CLL. Patients can go back to regular life and be productive.”

Looking Ahead

Gregory A. Masters, MD, FASCO

Olatoyosi Odenike, MD

Lee Greenberger, PhD

can potentially transform the treatment of CLL, replacing more toxic therapy,” added Dr. Masters, who is Attending Physician at the Helen F. Graham Cancer Center and Research Institute, Newark, Delaware.

Olatoyosi Odenike, MD, Associate Professor at the University of Chicago and University of Chicago Comprehensive Cancer Center, said, “The issue is how to best use ibrutinib and move it into the front-line setting. It is truly a transformative drug.”

Lee Greenberger, PhD, Chief Scientific Officer of the Leukemia & Lymphoma Society, White Plains, New York, said that ibrutinib can hold the disease in check for many years. “Ibrutinib is one of a few emergent drugs that will change the landscape of how CLL is treated, making CLL look more like chronic myelogenous leukemia after the advent of imatinib.” n Disclosure: Drs. Masters, Odenike, and Greenberger reported no potential conflicts of interest.

Dr. Byrd told The ASCO Post that ibrutinib is about to undergo phase III testing in mantle cell lymphoma with bendamustine (Treanda)/rituximab (Rituxan) as the comparator. Ibrutinib is also in phase III study as first-line therapy for CLL. Envisioning how all the new agents for CLL will be deployed, Dr. Byrd said younger patients could be treated with several of the active drugs for CLL to achieve remission; these include ibrutinib, idelalisib, ABT-199, and obinutuzumab (Gazyva). Older, more infirm patients with a life expectancy of 2 to 3 years could receive ibrutinib because of its benign side-effect profile. n Disclosure: Dr. Byrd has received research funding from Pharmacyclics. For full disclosures of all study authors, visit abstracts.asco.org.

Reference 1. Byrd JC, Brown JR, O’Brien SM, et al: Results from the phase III RESONATE trial. ASCO Annual Meeting. Abstract LBA 7008. Presented June 3, 2014.

ASCOPost.com | JUNE 25, 2014

PAGE 13

ASCO Annual Meeting Thoracic Oncology

Pieces of the Puzzle in Treating Early Non–Small Cell Lung Cancer

By Alice Goodman

S

eparate studies in early-stage non– small cell lung cancer (NSCLC) found that the addition of consolidation chemotherapy to concurrent chemoradiotherapy did not improve survival and that adjuvant erlotinib (Tarceva) did not improve survival. There was a suggestion of benefit for adjuvant erlotinib in patients with EGFR-mutant disease, but this was found in an exploratory subset analysis, and experts said a phase III trial is needed to clarify that finding.

RADIANT Trial Results Karen Kelly, MD, Associate Director for Clinical Research at UC Davis Comprehensive Cancer Center, Sacramento, California, presented the long-awaited results of the phase III RADIANT trial of adjuvant erlotinib vs placebo following complete resection in patients with stage Ib to III EGFRpositive NSCLC.1 “Adjuvant erlotinib did not prolong disease-free survival in patients with early-stage, completely resected EGFR-

expressing NSCLC. In a subset of tumors with del19 and L858R mutations, disease-free survival favored adjuvant erlotinib, but this was not statistically significant due to hierarchical testing,” Dr. Kelly told the audience.

Erlotinib has proven efficacy in second- and third-line therapy for NSCLC, as well as in first-line maintenance therapy in unselected patients and first-line therapy in patients with EGFR-activating mutations, she explained. Although adjuvant chemotherapy for early-stage NSCLC has improved the 5-year survival rate from 60% to 64%, not all patients are candidates for cisplatin-based regimens due to toxicity concerns.

Some exploratory analyses of previous studies suggested that EGFR protein expression by immunohistochemistry (IHC) and EGFR high copy number or amplification by fluorescence in situ hybridization (FISH) may be predictive markers of benefit for EGFR tyrosine kinase inhibitors.

RADIANT was designed to test this hypothesis and included patients with

Adjuvant erlotinib did not prolong disease-free survival in patients with early-stage, completely resected EGFRexpressing NSCLC. —Karen Kelly, MD

EGFR IHC-positive and EGFR FISH– positive stage IB to IIIA early NSCLC. Following complete resection, 973 patients, regardless of whether they received adjuvant chemotherapy, were randomly assigned 2:1 to erlotinib at 150 mg/d or placebo for 2 years. The primary endpoint was disease-free survival, and secondary endpoints were overall survival, and both disease-free and overall survival in patients with del19/L858R EGFR mutation–positive disease.

The study was conducted from September 2006 to July 2010. Per the

EXPERT POINT OF VIEW

F

ormal discussant of the study by Park et al, Nasser H. Hanna, MD, Associate Professor of Medicine at the Indiana University Simon Cancer Center, Indianapolis, said that the

dation therapy], and all studies have failed,” he stated.

I believe that the available evidence does not support additional chemotherapy, induction or con-

Consolidation therapy did not improve disease-free or overall survival and caused significantly more toxicity.

—Nasser H. Hanna, MD

trial confirms the difficulty of giving consolidation therapy, since less than two-thirds of patients were able to get the three planned cycles.

“Consolidation therapy did not improve disease-free or overall survival and caused significantly more toxicity. Many studies have tried to demonstrate improved outcomes with additional therapy beyond concurrent chemoradiotherapy [including induction therapy and consoli-

solidation therapy. [Concurrent chemoradiotherapy] should remain the standard of care in the most fit patients, and the [National Comprehensive Cancer Network] guidelines should reflect all the negative studies,” he said.

Most Significant Finding Turning to the RADIANT trial, Dr. Hanna pointed out that no difference in disease-free or overall survival was

observed with erlotinib (Tarceva) in the overall trial and in [fluorescence in situ hybridization]–positive patients.

“The most significant finding was the secondary endpoint showing that patients with EGFR mutations have the most benefit from erlotinib in the advanced-disease setting. There was an 18-month difference in median disease-free survival and few events at this time point,” Dr. Hanna continued.

He said that three additional datasets (from the National Cancer Institute of Canada, Memorial Sloan Kettering Cancer Center, and in the phase II SELECT trial) suggest that adjuvant erlotinib achieves a magnitude of gain in disease-free survival in patients with an activating EGFR mutation that he considers clinically important.

“Do we need phase III trials to use erlotinib? I believe the magnitude of gain in disease-free survival in patients with EGFR mutations is consistent in three datasets; it is persuasive and compelling and appears to be far better than without adjuvant chemotherapy,” Dr. Hanna stated. n

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

hierarchical testing procedure, if the primary endpoint was not met, then all subsequent endpoints would be deemed not significant.

Baseline characteristics were well balanced in both arms. The average age was 62 years, 80% were white, and 17% were Asian; 20% were never smokers, and the majority of patients had stage IB adenocarcinoma.

For the primary endpoint of disease-free survival, there was no significant difference between the two arms. Median disease-free survival was 48.2 months in the placebo arm and 50.5 months in the erlotinib arm.

At the time of Dr. Kelly’s ASCO presentation, overall survival data was immature.

The median duration of treatment was shorter with erlotinib at 11.9 months compared to 21.9 months for placebo. Adverse events were more common with erlotinib, including rash (86.4%), diarrhea (52.2%), pruritus (26.4%), dry skin (20.8%), and fatigue (19/3%).

EGFR-Mutated Disease A subset analysis of the RADIANT population with EGFR-mutated disease (n = 161 patients) showed a similar treatment duration for erlotinib (21.2 months) and placebo (21.9 months).2 Treatment was completed as planned in 47% and 50% of patients, respectively. Adverse events were similar to those seen in the overall trial.

Disease-free survival favored erlotinib in patients with EGFR mutations.

Median disease-free survival was 46.4 months for erlotinib vs 28.5 months for placebo, but this could not be deemed statistically significant due to hierarchical analysis. Overall survival data are immature.

Additional biomarker analyses are ongoing, Dr. Kelly said. continued on page 17

NOW

IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

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

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

Important Safety Information

• In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

• Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Rare cases of StevensJohnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Lifethreatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

• Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57).

Perform the assessment for KRAS mutational 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 treatment with Vectibix®.

• Progressively decreasing serum magnesium levels leading to severe (Grade 3-4) hypomagnesemia occurred in up to 7% in Study 2.

Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

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

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

Discontinue Vectibix® therapy if ILD is confirmed.

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

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

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4 • The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who

were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone • Prespecified major efficacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02) • Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC • Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm (n = 331) (HR = 0.83; 95% CI: 0.70, 0.98) • There were no OS or PFS benefits in Vectibix®-treated patients with mutant KRAS mCRC

• Keratitis and ulcerative keratitis, known risk factors for corneal • Because many drugs are excreted into human milk and because of

perforation, have been reported with Vectibix® use. Monitor for evidence the potential for serious adverse reactions in nursing infants from of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for Vectibix®, a decision should be made whether to discontinue nursing acute or worsening keratitis. or to discontinue the drug, taking into account the importance of • In an interim analysis of an open-label, multicenter, randomized the drug to the mother. If nursing is interrupted, it should not be clinical trial in the first-line setting in patients with mCRC, the resumed earlier than 2 months following the last dose of Vectibix®. addition of Vectibix® to the combination of bevacizumab and ® chemotherapy resulted in decreased OS and increased incidence • Women who become pregnant during Vectibix treatment are of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC encouraged to enroll in Amgen’s Pregnancy Surveillance Program. grade 3-4 adverse reactions occurring at a higher rate in Vectibix®- Women who are nursing during Vectibix® treatment are encouraged treated patients included rash/acneiform dermatitis (26% vs 1%), to enroll in Amgen’s Lactation Surveillance Program. Patients or diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring their physicians should call 1-800-77-AMGEN (1-800-772-6436) in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/ to enroll. mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). ® • NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate • In Study 1, the most common adverse reactions (≥ 20%) with Vectibix in Vectibix®-treated patients (7% vs 3%) and included fatal events were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in three (< 1%) Vectibix®-treated patients.

• As a result of the toxicities experienced, patients randomized to in the Vectibix® arm were general physical health deterioration and Vectibix®, bevacizumab, and chemotherapy received a lower mean intestinal obstruction. relative dose intensity of each chemotherapeutic agent (oxaliplatin, • In Study 3, the most commonly reported adverse reactions (≥ 20%) irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first in patients with wild-type KRAS mCRC receiving Vectibix® 24 weeks on study, compared with those randomized to bevacizumab (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were and chemotherapy.

• Advise patients of the need for adequate contraception in both males diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, and females while receiving Vectibix® and for 6 months after the last anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, dose of Vectibix® therapy. Vectibix® may be transmitted from the pruritus, and dry skin. Serious adverse reactions (≥ 2% difference mother to the developing fetus, and has the potential to cause fetal between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. harm when administered to pregnant women.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-aflibercept) prescribing information, sanofi-aventis.

Avastin is a registered trademark of Genentech, Inc. Erbitux is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap is a registered trademark of Regeneron Pharmaceuticals, Inc. Please see Brief Summary of full Prescribing Information on adjacent page. ©2014 Amgen Inc. All rights reserved. 05/14 80389-R1-V1

Visit www.vectibix.com

Vectibix® (panitumumab) Brief Summary of full PreScriBing information Warning: Dermatologic toXicity Dermatologic toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (nci-ctc grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. inDicationS anD uSage metastatic colorectal cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies 14.2 in Full Prescribing Information].

• As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1) in Full Prescribing Information]. limitation of use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1) in Full Prescribing Information].

DoSage anD aDminiStration Patient Selection Prior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes.

Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)].

Dose modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

• Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.

Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose.

• Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at 80% of the original dose.

• Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose.

• Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®.

Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.

Preparation and administration Do not administer Vectibix® as an intravenous push or bolus. contrainDicationS None.

WarningS anD PrecautionS Dermatologic and Soft tissue toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. increased tumor Progression, increased mortality, or lack of Benefit in Patients with KRAS-mutant mcrc Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1), and Clinical Studies (14) in Full Prescribing Information]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57).

Perform the assessment for KRAS mutational 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 Vectibix®. electrolyte Depletion/monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. infusion reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4).

Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1), 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. acute renal failure in combination with chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

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

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

Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. ocular toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. increased mortality and toxicity with Vectibix® in combination with Bevacizumab and chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. aDVerSe reactionS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)]

• Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)] • Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] clinical trials experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are available from two clinical trials in which patients received Vectibix®: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.

The most frequently reported (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).

For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). table 1: adverse reactions (≥ 5% Difference) observed in Patients treated with Vectibix® monotherapy and Best Supportive care compared to Best Supportive care alone (Study 1)

SyStem organ claSS Preferred Term eye DiSorDerS Growth of eyelashes gaStrointeStinal DiSorDerS Nausea Diarrhea Vomiting Stomatitis general DiSorDerS anD aDminiStration Site conDitionS Fatigue Mucosal inflammation infectionS anD infeStationS Paronychia reSPiratory, tHoracic, anD meDiaStinal DiSorDerS Dyspnea Cough SKin anD SuBcutaneouS tiSSue DiSorDerS Erythema Pruritus Acneiform dermatitis Rash Skin fissures Exfoliative rash Acne Dry skin Nail disorder Skin exfoliation Skin ulcer

Study 1 Vectibix® Plus Best Supportive care Best Supportive care (n = 234) (n = 229) Any Grade Grade 3-4 Any Grade Grade 3-4 n (%) n (%) n (%) n (%) 13 (6) 52 (23) 49 (21) 43 (19) 15 (7)

2 (< 1) 4 (2) 6 (3)

37 (16) 26 (11) 28 (12) 2 (< 1)

1 (< 1)

60 (26) 15 (7)

10 (4) 1 (< 1)

34 (15) 2 (< 1)

7 (3)

57 (25)

4 (2)

41 (18) 34 (15)

12 (5) 1 (< 1)

30 (13) 17 (7)

8 (3)

150 (66) 132 (58) 131 (57) 51 (22) 45 (20) 41 (18) 31 (14) 23 (10) 22 (10) 21 (9) 13 (6)

13 (6) 6 (3) 17 (7) 3 (1) 3 (1) 4 (2) 3 (1)

2 (< 1) 4 (2) 2 (< 1) 2 (< 1) 1 (< 1)

2 (< 1)

2 (< 1) 1 (< 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).

In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)].

In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration (2.3)].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.

Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®. table 2: adverse reactions (≥ 5% Difference) observed in Patients with Wild-type (Wt) KRAS tumors treated with Vectibix® and folfoX chemotherapy compared to folfoX chemotherapy alone (Study 3)

SyStem organ claSS Preferred Term eye DiSorDerS Conjunctivitis gaStrointeStinal DiSorDerS Diarrhea Stomatitis general DiSorDerS anD aDminiStration Site conDitionS Mucosal inflammation Asthenia infectionS anD infeStationS Paronychia inVeStigationS Weight decreased metaBoliSm anD nutrition DiSorDerS Anorexia Hypomagnesemia Hypokalemia Dehydration reSPiratory, tHoracic, anD meDiaStinal DiSorDerS Epistaxis

Vectibix® Plus folfoX (n = 322) Any Grade Grade 3-4 n (%) n (%)

folfoX alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

58 (18)

5 (2)

10 (3)

201 (62) 87 (27)

59 (18) 15 (5)

169 (52) 42 (13)

29 (9) 1 (< 1)

82 (25) 79 (25)

14 (4) 16 (5)

53 (16) 62 (19)

1 (< 1) 11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

116 (36) 96 (30) 68 (21) 26 (8)

46 (14)

14 (4) 21 (7) 32 (10) 8 (2)

SyStem organ claSS Preferred Term SKin anD SuBcutaneouS tiSSue DiSorDerS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

Vectibix® Plus folfoX (n = 322) Any Grade Grade 3-4 n (%) n (%)

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

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1) 10 (3) 4 (1)

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

30 (9)

4 (1)

9 (3)

30 (9)

6 (2) 1 (< 1) 15 (5) 5 (2)

24 (7)

1 (< 1)

2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).

Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix ® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies.

Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®.

In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®.

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

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

Postmarketing experience The following adverse reactions have been identified during post-approval use of Vectibix ®.

Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, skin necrosis, angioedema [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] Drug interactionS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. uSe in SPecific PoPulationS Pregnancy Pregnancy category c. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. nursing mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)].

Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-7726436) to enroll.

Pediatric use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. geriatric use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy.

Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. oVerDoSage Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

Patient counseling information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

22 (7)

85 (26) 26 (8) 42 (13) 10 (3)

folfoX alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

This brief summary is based on the Vectibix® Prescribing Information v20, 5/14.

Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2014 Amgen Inc. All rights reserved. v20 05/14

ASCOPost.com | JUNE 25, 2014

PAGE 17

ASCO Annual Meeting Treating Early NSCLC

It is urgent that we develop newer strategies that will improve the outcome of inoperable stage III NSCLC, such as the incorporation of novel agents including immunotherapy or molecular targeted therapy.

continued from page 13

Adding Consolidation Chemotherapy For patients with locally advanced stage III inoperable NSCLC, three cycles of consolidation therapy with cis­ platin and docetaxel made no difference in overall survival or progression-free survival, according to a phase III trial reported at the 2014 ASCO Annual Meeting.3 “The primary endpoint of this trial was not met. Concurrent chemoradiotherapy should remain the standard of care for stage III inoperable NSCLC,” stated lead author Keunchil Park, MD, PhD, Professor at the Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

From October 2005 to April 2011, 437 patients with stage III NSCLC and no evidence of progression on concurrent chemoradiotherapy with radiation, cisplatin, and docetaxel were screened; 437 were randomly assigned to consolidation therapy with cisplatin and docetaxel or observation. Due to consent withdrawal, adverse events, disease progression, or death, however, about one-third of patients in the consolidation arm did not receive any consolidation treatment, and accrual to the trial was slow, Dr. Park said. An interim analysis in 2009 showed no safety issues.

For the final analysis, 171 patients were evaluable in the observation arm and 173 in the consolidation arm. The median age was 61 years, the majority

—Keunchil Park, MD, PhD

were males, about 50% had adenocarcinoma, and about one-third had squamous cell histology. About 80% were Korean, 17.4% were Chinese, and 1.4% were from Taiwan; 25% had stage IIIA, and 75% had stage IIIB disease.

At a median follow-up of more than 50 months, median progressionfree survival was 8.1 months in the observation arm and 9.1 months in the consolidation arm, a nonsignificant difference. Similarly, no significant difference was observed between arms for median overall survival,

which was 20.6 and 21.8 months, ­respectively.

About 54% of patients in each arm experienced treatment failure: the locoregional failure rate was 49.6% with observation vs 44.6% with consolidation therapy; distant failure rate was 43.5% and 50%, respectively. The brain and lung were the most common sites of metastasis.

There were no unexpected toxicities during consolidation therapy, and those that occurred were tolerable and manageable, Dr. Park said. The rates of adverse events were higher in the consolidation arm.

Treating Early Non–Small Cell Lung Cancer ■■ Adjuvant erlotinib did not improve disease-free survival in patients with early NSCLC, but may be of benefit in patients with EGFR-activating mutations.

■■ The role of adjuvant erlotinib in EGFR-mutated NSCLC needs to be established in a prospective, randomized phase III trial.

■■ The addition of consolidation chemotherapy to concurrent chemoradiotherapy did not improve disease-free survival in patients with inoperable stage III NSCLC. ■■ Concurrent chemoradiotherapy should remain the standard of care in this group of patients.

“It is urgent that we develop newer strategies that will improve the outcome of inoperable stage III NSCLC, such as the incorporation of novel agents including immunotherapy or molecular targeted therapy,” Dr. Park told listeners. n

Disclosure: Dr. Park is an advisor/consultant for AstraZeneca, Astellas, AVEO, Boehringer Ingelheim, Clovis, Daiichi Sankyo, Eli Lily, Hanmi, Kyowa Hakko Kirin, Novartis, and Roche. He has received research funding from AstraZeneca and Sanofi-Aventis. Dr. Kelly reported no potential conflicts of interest.

For full disclosures of all study authors, visit abstracts.asco.org.

References 1. Kelly K, Altorki NK, Eberhardt WE, et al: A randomized, double-blind phase 3 trial of adjuvant erlotinib versus placebo following complete tumor resection with or without adjuvant chemotherapy in patients with stage IB-IIIA EGFR positive (IHC/FISH) non-small cell cancer: RADIANT results. ASCO Annual Meeting. Abstract 7501. Presented June 2, 2014.

2. Shepherd F, Altorki NK, Eberhardt WE, et al: Adjuvant erlotinib versus placebo in non-small cell lung cancer patients with tumors carrying EGFR-sensitizing mutations form the RADIANT trial. ASCO Annual Meeting. Abstract 7513. Presented June 1, 2014.

3. Park K, Ahn YC, Ahn JS, et al: A multinational phase III randomized trail with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small cell cancer. ASCO Annual Meeting. Abstract 7500. Presented June 2, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Cora N. Sternberg, MD, FACP, on Metastatic Castration-Resistant Prostate Cancer see page 5

Karen Lisa Smith, MD, MPH, and Vered Stearns, MD, on HER2+ Breast Cancer see page 64

Patrick M. Boland, MD, and Michael J. Hall, MD, MS, on Physician Attitudes on Genomics see page 87

Halle Moore, MD, on Goserelin/Chemotherapy and Fertility in Young Women With Breast Cancer see page 98

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | JUNE 25, 2014

PAGE 18

Announcements

Barbara L. McAneny, MD, to Serve as Chair of the AMA Board of Trustees

B

arbara L. McAneny, MD, a practicing oncologist from Albuquerque, New Mexico, has been re-elected to the Board of Trustees of the American Medical Association (AMA) and will assume the position of Board Chair when the trustees gather for their first post-

President of the New Mexico Chapter of the American College of Physicians. She served as Chair of the AMA Council of Medical Service from 2009 to 2010.

Dr. McAneny is the cofounder of her multidisciplinary oncology practice, New Mexico Oncology Hematol-

ogy Consultants Ltd. She also built and manages the New Mexico Cancer Center, which provides comprehensive outpatient medical and radiation oncology care and imaging at several underserved rural areas across New Mexico including sites in Albuquerque, Gallup, Ru-

idoso, Silver City, and Las Cruces.

The ASCO Post recently interviewed Dr. McAneny for inclusion in the publication’s annual edition of “Narratives in Oncology.” Portions of that interview are included on page 19. For the full text, visit http://bit.ly/1vt3lGF n

Barbara L. McAneny, MD

election meeting. Dr. McAneny, who has been a Board member since 2010, has been Chair-elect of the Board for the past year. Her re-election to the AMA Board affirms her transition to Board Chair.

“I am honored to be re-elected to the American Medical Association Board of Trustees,” said Dr. McAneny. “I hope to help AMA to continue to lead the way in providing the support and structures needed to unleash the creativity of American physicians to provide the highest possible level of patient and physician satisfaction.”

Leadership Roles in ASCO, AMA, NMMS Prior to her election to the AMA Board, Dr. McAneny served on the Board for ASCO and was the delegate to the AMA from ASCO. She has held many leadership roles including President of the New Mexico Medical Society (NMMS), President of the Greater Albuquerque Medical Association, and NAME: Barbara L. McAneny, MD TITLE: CEO, New Mexico Oncology

Hematology Consultants; Chair, AMA Board of Trustees

MEDICAL DEGREE: MD,

University of Iowa College of Medicine

RESEARCH INTERESTS:

Health-care policy, community oncology, organized medicine, hematology/oncology NOTABLE HONORS: Health Care Innovation Award, U.S. Centers for Medicare and Medicaid Services (2012); ASCO Statesman Award (2010); ASCO Board (2005-2008); Council on Medicine Service (2003-2010); Governors Award for Outstanding New Mexico Women (1996)

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ASCOPost.com | JUNE 25, 2014

PAGE 19

Announcements

Barbara McAneny, MD, on the Collective Power of Doctors Excerpts from “Narratives in Oncology,” The ASCO Post, June 10, 2014

D

r. McAneny took over the practice management side of her growing clinic, a transition that was partly related to her serendipitous

career move into organized medicine, she noted. “I was in the hospital’s doctor’s lounge after a consult with a young lung cancer patient,

bemoaning the fact that so many people still smoke. A urologist came over and said, ‘So, are you just going to bitch about smoking, or are you

going to do something about it?’”

The urologist was president of the local medical society, which worked with the Department of Health on smoking cessation initiatives. He invited Dr. McAneny to join the committee and push for antismoking legislation. She jumped at the opportunity. “It took about 15 years of hard work but we got a clean indoor air act passed city-by-city in New Mexico. The experience taught me that when doctors organize together they could accomplish some pretty remarkable things,” said Dr. McAneny.

“I’ve been as ASCO member, from the day I decided to become an oncologist,” she continued. “ASCO is essential in moving forward everything related to oncology. But I’ve also been a long-time member of the American Medical Association [AMA]. The current situation in health care does a very good job at dividing doctors and keeping us relatively powerless as we fight over pieces of a decreasing pie.”

Designing a Better System

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In 2012, Dr. McAneny was awarded a $19.8 million Health Care Innovation Award from the Centers for Medicare and Medicaid Services to test how private practices could provide better cancer care at a lower cost.

To that end, she created Innovative Oncology Business Solutions, serving as its Medical Director and CEO. The project, titled COME HOME (“Community Oncology Medical Homes”), aims to replicate the care and cost-saving practices that Dr. McAneny created at the New Mexico Cancer Center at six practices across the nation.

In regard to her role as AMA’s Chair of the Board of Trustees, Dr. McAneny said “I hope to help AMA to continue to lead the way in providing the support and structures needed to unleash the creativity of American physicians to provide the highest possible level of patient and physician satisfaction.” n

The ASCO Post | JUNE 25, 2014

PAGE 20

ASCO Annual Meeting Gynecologic Oncology

Oral Two-Drug Regimen Appears Promising in Phase II Trial of Recurrent Platinum-Sensitive Ovarian Cancer

By Alice Goodman

A

n all-oral combination of the investigational agents olaparib and cediranib nearly doubled progressionfree survival in platinum-sensitive recurrent ovarian cancer in a National Cancer Institute (NCI)-sponsored randomized phase II trial reported at the 2014 ASCO Annual Meeting.1 The toxicity profile of the combination was acceptable.

“This is the first study to explore the activity of the combination of a PARP inhibitor and antiangiogenesis drug in ovarian cancer, and we found that the combination is more active than olaparib alone. The progression-free survival compares favorably with standard-ofcare chemotherapy. And we saw activity in both carriers and noncarriers of BRCA [mutations],” said lead investigator Joyce F. Liu, MD, MPH, a medical oncologist at Dana-Farber Cancer Center, Boston.

Still Investigational “This combination is not yet ready for clinical practice, as neither of these drugs is currently [U.S. Food and Drug Administration]-approved for ovarian or for any other cancer.

We also need additional clinical studies to confirm the findings and see how this combination compares to

standard treatment,” Dr. Liu said.

Olaparib is an oral PARP inhibitor that blocks DNA repair, and cediranib is an oral angiogenesis inhibitor that blocks vascular endothelial growth factor (VEGF) receptor. Clinical trials were mounted based on preclinical evidence of synergy in ovarian cancer between PARP inhibitors and antian-

high-grade serous, endometrioid, or other histologic subtypes with known germline BRCA mutation. Median age was 58.

The combination of olaparib plus cediranib significantly improved progression-free survival vs olaparib alone.

Median progression-free survival was 17.7 months for the combination vs

This is the first study to explore the activity of the combination of a PARP inhibitor and antiangiogenesis drug in ovarian cancer, and we found that the combination is more active than olaparib alone.

—Joyce F. Liu, MD, MPH

giogenesis drugs, Dr. Liu explained.

This is the first time this combination has been explored in a clinical trial, she added.

The randomized, open-label phase II study was conducted from October 2011 to June 2013 in 90 patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer treated at nine different cancer centers. All patients enrolled in the trial had experienced disease recurrence at least 6 months after their last platinum-based therapy. They had

EXPERT POINT OF VIEW

A

t an ASCO press conference held during the Annual Meeting, moderator Gregory A. Masters, MD, FASCO, who is Attending Physician at the Helen F. Graham Cancer Center and Research Institute, Newark, Delaware, commented on the study presented by Liu et al. “This new combination demonstrates how combining active therapies can build on improving treatment.

The cumulative understanding of cancer biology and clinical research can link these steps in progress in cancer care over the last 50 years,” he said.

Don S. Dizon, MD, FACP, a medical oncologist and the Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, Boston, said, “Women with platinum-sensitive ovarian cancer are the patients we would consider for surgical debulking or reoperation. We believe that there is a survival advantage if we can further resect platinum sensitive disease, but this has not been proved. This oral combination takes repeat surgery off the table.”

Regarding the present study, Dr. Dizon offered the following takeaway points: “(1) olaparib and cediranib represent a nonchemotherapy orally based combination that appears active in platinum-sensitive ovarian cancer, (2) we need to be cautiously enthusiastic because we don’t have overall survival data, and (3) we need a phase III trial.” n Disclosure: Drs. Masters and Dizon reported no potential conflicts of interest.

9 months for olaparib alone, representing an 8.7-month improvement (P = .005). To put this into context, studies with standard chemotherapy in platinum-sensitive patients show progression-free survival between 8 and 13 months.

Stratified by BRCA Status Dr. Liu said that previous studies have suggested that women with BRCA mutations may be more sensitive to PARP inhibition, so they stratified patients according to BRCA status.

In patients with BRCA mutations, a trend was observed toward increased activity for the combination, but the progression-free survival difference was much more robust for the combination in noncarriers and patients with unknown BRCA status.

Median progression-free survival in BRCA mutation carriers was 19.4 months for the combination vs 16.5 months for olaparib alone (nonsignificant); in noncarriers or those of unknown BRCA status, median pro-

gression-free survival was 16.7 months for the combination vs 5.7 months for olaparib alone (P = .008).

See page 6

“This was a post hoc exploratory analysis of a phase II trial showing the difference in activity was most pronounced in non-BRCA mutation carriers. This was an unexpected finding and needs to be confirmed,” she noted.

Toxicity was higher with the combination. The most common adverse events related to the combination were hypertension, diarrhea, and fatigue.

Dr. Liu said these toxicities were manageable with aggressive symptom management and dose reductions.

Further Study “Results support additional clinical evaluation of this combination in ovarian cancer,” she stated. Two phase III trials are being planned for platinumsensitive and platinum-resistant ovarian cancer by one of NCI’s new National Cancer Trial Network Groups (NRG Oncology Group), the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Liu J, Barry WT, Birrer M, et al: A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. ASCO Annual Meeting. Abstract LBA5500. Presented May 31, 2014.

Olaparib/Cediranib in Recurrent Ovarian Cancer ■■ A combination of two investigational oral drugs yielded a median progression-free survival of 17.7 months in recurrent platinum-sensitive ovarian cancer in a phase II trial.

■■ This is the first time that olaparib and cediranib have been studied in combination in ovarian cancer.

■■ Phase III trials are being planned with the combination in both platinumsensitive and platinum-resistant ovarian cancer.

G N I L ROL STUDY

N 3 E E S

A OW ZED PH

N ANDOMI A R

A phase 3 study of ceritinib (LDK378) in adults with advanced ALK+ non-small cell lung cancer (NSCLC) previously treated with chemotherapy and crizotinib Aged 18 years or older Stage IIIB or IV histologically or cytologically confirmed ALK+ NSCLC Prior treatment with crizotinib and 1 regimen of platinum doublet chemotherapy for the treatment of locally advanced or metastatic ALK+ NSCLC At least 1 measurable lesion as defined by RECIST 1.1

Additional inclusion/exclusion criteria apply.

Study Design Randomization (1:1)

Ceritinib

Chemotherapya

Primary endpoint: Progression-free survival Key secondary endpoint: Overall survival Investigatorâ&#x20AC;&#x2122;s choice: pemetrexed or docetaxel

a

ALK, anaplastic lymphoma kinase; ALK+, ALK-positive; RECIST, Response Evaluation Criteria In Solid Tumors.

For more information, please call 1-855-338-1820, or visit www.ascendtrials.com or www.clinicaltrials.gov (NCT01828112) Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

Š 2014 Novartis

4/14

LCD-1086930

The ASCO Post | JUNE 25, 2014

PAGE 22

ASCO Annual Meeting Breast Cancer

Goserelin With Chemotherapy Prevents Early Menopause, Helps Preserve Fertility in Younger Women With Hormone Receptor–Negative Breast Cancer

By Alice Goodman

T

he good news for younger women during chemotherapy. LHRH analogs with hormone receptor–negative are also used to control ovarian cycles for early breast cancer is that adding goserelin infertility procedures, and as hormonal (Zoladex), a luteinizing hormone–releas- therapies for prostate and breast cancer. ing hormone (LHRH) agonist, to chemotherapy can prevent sudden menopause, POEMS Design The primary endpoint of the study better preserve ovarian function and fertility, and lead to successful pregnancies after was ovarian failure, defined as amenorrhea for the prior 6 months cancer treatment, compared and postmenopausal levels of with standard chemotherapy. follicle-stimulating hormone.

These findings of the Southwest The investigators also assessed Oncology Group (SWOG)disease-free survival and overled international Prevention all survival. of Early Menopause Study From February 2004 to (POEMS) were presented as a See page 6 May 2011, POEMS randomly late-breaking oral abstract at the assigned 218 eligible and evaluable pre50th ASCO Annual Meeting.1 “Goserelin use led to consistent evi- menopausal women with stage I to IIIA dence of better-preserved ovarian function hormone receptor–negative breast cancer across multiple endpoints. This is the first to treatment with cyclophosphamidedemonstration of improved fertility pros- containing chemotherapy (standard arm) pects and more successful pregnancies in or the same chemotherapy plus goserelin

This is the first demonstration of fertility prospects and more successful pregnancies in women with breast cancer. Premenopausal women being treated with curative intent should consider this new option to prevent premature ovarian failure.

—Halle Moore, MD

women with breast cancer when goserelin was used with chemotherapy. Premenopausal women being treated with curative intent should consider this new option to prevent premature ovarian failure,” said lead author Halle Moore, MD, a Staff Physician at Cleveland Clinic. “Goserelin appears to be not only highly safe but also effective, as it increased the odds of becoming pregnant and delivering a healthy baby following chemotherapy.”

Goserelin and other LHRH analogs temporarily shut down ovarian function putting patients into a postmenopausal state. The idea is to protect the ovaries

given as monthly injections starting 1 week before chemotherapy. Dr. Moore said the trial was designed to enroll 416 patients but was closed prematurely due to loss of funding for distribution of the study drug.

Median age was 38 years. More than 90% got anthracycline-containing chemotherapy, and cancer stage distribution was similar in the two study arms. Endocrine toxicity was twice as high in the goserelin arm compared with the standard chemotherapy arm and included hot flashes, mood swings, dry vagina, and dyspareunia.

Ovarian failure was identified in 22% of the chemotherapy arm vs 8% of the gos-

Preventing Early Menopause in Breast Cancer Patients ■■ Goserelin added to chemotherapy reduced the rate of ovarian failure and ovarian dysfunction, and improved chances of pregnancy and successful birth in premenopausal women with hormone receptor-negative breast cancer.

■■ Although this study had some limitations, experts believe that goserelin should be offered to this group of women for ovarian preservation.

EXPERT POINT OF VIEW

F

ormal discussant Sharon H. Giordano, MD, MPH, Professor of Medicine and Chair of Health Services Research at The University of Texas MD Anderson Cancer Center, Houston, emphasized how important it is to preserve fertility in these younger patients with breast cancer.

“The main downside is an increase in menopausal symptoms during treatment,” she said.

Because of the missing data on 38% of particiSharon H. Giordano, MD, MPH pants, low accrual rates, and early termination of the trial, Dr. Giordano could not consider these results definitive.

“Having said that, I would be comfortable offering this option to my young patients who desire fertility preservation,” Dr. Giordano stated. n Disclosure: Dr. Giordano reported no potential conflicts of interest.

erelin arm (P = .04). After adjustment for stratification factors, goserelin achieved a significantly lower rate of ovarian failure.

Key Findings “Patients who got goserelin [plus chemotherapy] were about two-thirds less likely to develop ovarian failure at 2 years,” Dr. Moore said. The 2-year rate of ovarian dysfunction was also significantly lower in the goserelin arm: 33% vs 13% (P = .03).

Pregnancy was attempted by 18 patients treated with chemotherapy alone and 25 who received goserelin in addition to chemotherapy. Women in the goserelin arm were about 2.5 times more likely to have a successful pregnancy: 12 (11%) in the chemotherapy arm and 22 (21%) in the chemotherapy-plus-goserelin arm became pregnant (P = .03). Pregnancies resulting in live births were reported by 8 patients in the chemotherapy arm (7%, 12 babies) and 16 patients (15%) in the goserelin arm (18 babies, P = .05).

The use of goserelin did not increase the risk of miscarriages, delivery complications, or need for pregnancy terminations compared with chemotherapy alone. Goserelin also positively impacted disease-free and overall survival, which was an unexpected finding, Dr. Moore said. Survival rates were adjusted for age, regimen, and stage. After adjustment, the 4-year diseasefree survival rate was 78% in the chemotherapy arm and 88% in the goserelin arm (P = .04). Four-year overall survival was 82% vs 92%, ­respectively (P = .06).

Study Limitations Dr. Moore cited the following limitations of the trial: failure to complete accrual, missing data for 38% of patients, and

lack of stratification for disease risk factors including stage, HER2 status, and nodal status. That said, this is the largest randomized study of LHRH agonist use for ovarian protection in hormone receptor–negative breast cancer, and it is the most informative study reporting pregnancy outcomes with an LHRH analog during chemotherapy.

Senior author Kathy S. Albain, MD, FACP, Professor of Medicine at Loyola University Chicago Stritch School of Medicine in Maywood, Illinois, said, “We found that, in addition to reducing the risk of early

Kathy S. Albain, MD, FACP

menopause, and all of the symptoms that go along with early menopause, goserelin was very safe and may even improve survival. I think these findings are going to change our clinical practice.… This study was much more than a fertility preservation study—as important as that finding is—­in that it impacts a large number of women who can potentially be spared the early onset of menopause.” n

Disclosure: Drs. Moore and Albain reported no potential conflicts of interest.

Reference 1. Moore HCF, et al: Phase III trial of LHRH analog during chemotherapy to reduce ovarian failure in early-stage, hormone receptornegative breast cancer. ASCO Annual Meeting.

Abstract LBA505. Presented May 31, 2014.

ASCOPost.com | JUNE 25, 2014

PAGE 23

ASCO Annual Meeting Breast Cancer

Immune-Related Genes Predictive of Trastuzumab Benefit

By Caroline Helwick

I

mproved relapse-free survival following treatment with adjuvant trastuzumab (Herceptin) appears to be associated with a heightened state of immunologic function, according to genomic analysis that resulted in a 14-gene profile predictive of outcomes in the landmark NCCTG (Alliance) N9831 trial.1 “We have identified a predictive model for adjuvant trastuzumab, using an approach that integrates genomics, biology, and clinical outcome data. This genomic analysis reveals a major immunologic component that is predictive of the clinical benefit of adjuvant trastuzumab,” said Edith A. Perez, MD, Deputy Director at Large at the Mayo Clinic Cancer Center, Jacksonville, Florida, and the principal investigator of N9831, which helped establish the benefit of adjuvant trastuzumab.

The findings suggest that breast cancer could join the ever-growing list of malignancies that might be subject to immune modulation.

“We are very enthusiastic about the results,” Dr. Perez told The ASCO Post. “We validated the findings with 100 replications, and they all led to the same 14-gene panel, with all genes associated with immune function. Our work has taken 4 years. It is very solid.

We have a prognostic panel of 87 genes and a 14-gene predictive panel.”

At the 2014 ASCO Annual Meeting, Dr. Perez presented the findings of a genomic analysis of N9831 tissue samples. The study’s aim, she said, was to identify biologic principles that underlie the clinical outcomes of earlystage HER2-positive breast cancer. To this end, her team developed, evaluated, and validated a multigene predic-

Immune Genes and Trastuzumab ■■ Genomic analysis of the N9831 adjuvant trastuzumab trial identified 87 genes related to prognosis, and 14 genes related to outcomes.

■■ Patients with “immune-enriched” tumors were significantly more likely to be relapse-free at a median follow-up of about 6 years.

This genomic analysis reveals a major immunologic component that is predictive of the clinical benefit of adjuvant trastuzumab.

—Edith A. Perez, MD

tive signature for response to adjuvant trastuzumab.

Genomic Analysis The investigatgors used Illumina’s 24K DASL whole-transcriptome technology to quantify mRNA abundance in 1,282 tumor samples. They identified 473 genes in the chemotherapy-alone arm associated with recurrence-free survival and 510 in the trastuzumab/ chemotherapy combined arms, independent of nodal status, tumor size, hormone receptor status, age, and tumor grade. Using the genes that were significantly associated with outcome, they used pathway enrichment statistics to assess the biologic significance of

four functional “interactome” models.

In the trastuzumab-treated patients, six biologic pathways were associated with increased relapse-free survival. These pertained to cytokine-cytokine receptor interaction, T-cell receptor signaling in CD8-positive T-cells, the interferongamma pathway, tumor necrosis factor receptor signaling pathway, cell surface interaction at the vascular endothelium, and class 1 PI3K signaling events.

“Four of these significant pathways are linked to immunologic function,” she noted. “This was the first indication that there is an important immunologic component to benefit from adjuvant trastuzumab.” continued on page 26

EXPERT POINT OF VIEW

S

herene Loi, MD PhD, Head of the Translational Breast Cancer Genomics Lab at the Peter McCallum Cancer Centre, Victoria, Australia, commented on the N9831 study presentation and referred to her group’s own work on tumor-infiltrating lym-

lymphocytes to be related to pathologic complete response to trastuzu­ mab in the GeparQuattro study.2 “There is increasing evidence that immunity is important in certain subtypes of breast cancer, particularly HER2-positive and triple-negative dis-

The study needs further validation, but now we have two biomarker studies from randomized clinical trials [FinHER and N9831] supporting the concept that immunity is important for trastuzumab efficacy.

—Sherene Loi, MD PhD

phocytes. These investigators have shown a positive association between the presence of tumor-infiltrating lymphocytes in the tumor at baseline and response to adjuvant trastuzumab (Herceptin) in the FinHER trial.1 They also found tumor-infiltrating

ease,” she said in her discussion.

“Dr. Perez’s group used a large randomized landmark trial showing the benefit of adjuvant trastuzumab, sequentially or concurrently with chemotherapy.

Randomization allows us to discern predictive effects,” she said. “The study needs

further validation, but now we have two biomarker studies from randomized clinical trials [FinHER and N9831] supporting the concept that immunity is important for trastuzumab efficacy.”

Unanswered Questions Questions include how to bring this approach into the clinical setting, and what are the implications for biomarkers and therapeutic drug development?

Importantly, which immune biomarker will be most important in breast cancer?

“Can we just use [tumor-infiltrating lymphocytes] or do we need the immune gene signature? I think we don’t know yet. Ultimately, clinical utility will define the biomarker,” she predicted.

A biomarker will likely not be used to select patients for trastuzumab, she pointed out, as all HER2-positive patients warrant treatment. But it may be useful in determining which patients can limit treatment to trastuzumab alone, and who requires dual anti-HER2 treatment. If HER2 signaling is found to promote immunosuppression, perhaps dual

blockade will most help patients without lymphocytic infiltration, she said.

“The most tantalizing possibility is that we could select patients more suitable for immune modulation,” she said, referring to the anti–PD-1/PD-L1/ CTLA-4 inhibitors. The global phase Ib/II PANACEA trial of the anti–PD-1 monoclonal antibody pembrolizumab (MK-3475) in advanced trastuzumabresistant HER2-positive patients with confirmed PD-L1 expression will try to answer this question. The trial, which Dr. Loi heads up, starts this summer. n

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

References 1. Loi S, et al: Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer. Ann Oncol. April 29, 2014 (early release online).

2. Loi S, et al: Tumor infiltrating lymphocytes indicate trastuzumab benefit in earlystage HER2-positive breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S1-05. Presented December 11, 2013.

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 | JUNE 25, 2014

PAGE 26

ASCO Annual Meeting Immune-Related Genes continued from page 23

Dr. Perez and her team did not stop there: They assigned each of the 510 genes a gene ontology identifier, resulting in 13 biologic process descriptors with different distribution in patients treated only with chemotherapy, compared with those also receiving trastu-

zumab. Of these, 10 descriptors were associated with increased relapse-free survival. These 10 processes defined a cohort of 87 immune function genes.

“These 87 genes were prognostic for outcomes in patients who got chemotherapy plus trastuzumab,” she said. Of these 87 genes, 14 demonstrated a significant interaction with trastuzumab treat-

ment vs chemotherapy alone, and these formed the predictive gene signature.

“Our interest went beyond identifying a prognostic signature. We wanted to identify a predictive signature. Of the 87 genes, we found 14 that had significant interaction P values (P < .05) in the trastuzumab arms vs the nontrastuzumab arms,” Dr. Perez said. “These 14 genes were inte-

grated into a voting scheme model that predicts trastuzumab response.”

The model labels patients as “immuneresponse enriched” or not and predicts for trastuzumab response, independent of nodal or hormone receptor status. About 50% of both the trastuzumab-treated and chemotherapy-alone cohorts in the N9831 sample had immune-response enriched tumors.

Immune-Enriched Patients

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.

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.

Most importantly, patients with immune-enriched tumors experienced a favorable outcome when treated with trastuzumab. “We found that immune enrichment predicts response to trastuzumab,” Dr. Perez reported.

Among immune-enriched patients, the hazard ratio (HR) for relapse-free survival for those receiving trastuzumab was 0.36 (P < .0001), compared with chemotherapy treatment alone. When tumors were not immune-enriched, trastuzumab conferred no benefit over chemotherapy alone (HR = 0.99, P = .91). “Those curves were the same,” she observed. “For those not enriched, there were no differences in relapse-free survival whether they received adjuvant trastuzumab or not.”

To confirm that this 14-gene signature was generalizable, the investigators conducted a fivefold cross-validation and repeated it 100 times. “In each of the 100 tests, we got the same data, showing that patients whose tumors were immune-enriched did the best when receiving chemotherapy plus trastuzumab vs all the other patients and tumors.”

“This observation may define a significant biologic process that is linked to the efficacy of HER2-targeted therapy, may provide a means of predicting probability of relapse following adjuvant trastuzumab, and suggests possible routes of therapeutic enhancement,” she said.

“We feel there are significant implications for our 14-gene predictive immune signature,” she said at the ASCO session. “It can help us evaluate and understand the mechanisms of sensitivity and resistance to trastuzumab and it has potential implications for enrollment criteria in future clinical trials.”

Dr. Perez suggested that patients presumed to be HER2-negative by central testing but who respond to trastuzumab may be responsive because they express these immune-related genes. n

Disclosure: Dr. Perez reported no potential conflicts of interest. For full disclosures of all study authors, visit abstracts.asco.org.

Reference 1. Perez EA, et al: Association of genomic analysis of immune function genes and clinical outcome in the NCCTG (Alliance) N9831 adjuvant trastuzumab trial. ASCO Annual Meeting. Abstract 509. Presented May 31, 2014.

ASCOPost.com | JUNE 25, 2014

PAGE 27

ASCO Annual Meeting Thoracic Oncology

Chemotherapy Plus Ramucirumab Provides Survival Advantage Over Chemotherapy Alone in Non–Small Cell Lung Cancer

By Alice Goodman

R

amucirumab (Cyramza) added to docetaxel improved overall survival compared to chemotherapy alone in patients with stage IV non–small cell lung cancer (NSCLC) that has progressed on one prior therapy, according to results of a phase III trial presented at the 50th ASCO Annual Meeting.1 The improvement in survival was consistent across multiple prognostic factors, including squamous cell and non–squamous cell histology, suggesting that the combination may turn out to be valuable in all subtypes of NSCLC. Overall

survival was modestly improved by a median of 1.4 months in patients treated with the combination.

This is the first treatment to have shown a significant survival advantage over chemotherapy alone in secondline therapy of NSCLC, and the first treatment in approximately a decade to improve outcomes in the secondline setting.

New Second-Line Option “This is the first treatment to have shown a significant survival advantage over chemotherapy alone in second-line therapy of NSCLC, and the first treatment in approximately a decade to improve outcomes in the second-line setting,” stated lead author Maurice Pérol, MD, Head of Thoracic Oncology at Cancer Research Centre

Ramucirumab in Lung Cancer ■■ The combination of ramucirumab plus docetaxel improved overall survival compared with docetaxel alone by a median of 1.4 months in advanced pretreated non–small cell lung cancer.

■■ The combination also improved progression-free survival and tumor shrinkage vs chemotherapy alone.

■■ This is the first treatment in many years to show a survival improvement in the second-line lung cancer setting.

—Maurice Pérol, MD

of Lyon in France. “Ramucirumab represents a potential new option for treatment in the second-line setting.”

“Despite advances in NSCLC and genomics, the majority of patients with NSCLC cannot benefit from targeted therapy, and chemotherapy is still the treatment of choice,” Dr. Pérol said. Approved second-line chemotherapy includes docetaxel, pemetrexed (Alimta), and erlotinib

(­ Tarceva), and median overall survival with these agents is 7 to 9 months.

Ramucirumab is a monoclonal antibody that targets the vascular endothelial growth factor (VEGF) receptor 2, blocking the formation of new blood vessels to feed the tumor. Currently ramucirumab is approved only for advanced gastric cancer treatment.

No other antiangiogenic drugs are apcontinued on page 28

EXPERT POINT OF VIEW

“T

his combination shows good activity in the difficult-to-treat second-line setting of NSCLC,” said Gregory A. Masters, MD, FASCO, about the results of the REVEL study reported at the ASCO Annual Meeting.

Dr. Masters, who is Attending Physician at the Helen F. Graham Cancer

meaningful outcomes for clinical trial endpoints. As an example, they have stated that a meaningful improvement in overall survival in the first-line setting for advanced NSCLC should be at least 2.5 months (squamous) to 3.25 months (non-squamous). ASCO did not comment on what improvement would be

Progess is slow and stepwise, and we build one step at a time. The cumulative progress is what we find encouraging.

—Gregory Masters, MD, FASCO

Center and Research Institute, Newark, Delaware, moderated a press conference where these data were presented.

Dr. Masters was asked whether this treatment represents true “value” at the press conference, since it improved survival by a modest 1.4 months and will probably be costly. These data must also be viewed in the context of ASCO’s recent position paper on

meaningful in the second-line setting.

Also, it is important to point out that the paper by Ellis et al was intended to “encourage patients and investigators to demand more from clinical trials” and to “help guide the development of definitive, randomized phase III trials”—rather than being intended to decide what we do with trial results already completed.

Dr. Masters replied that investigators of clinical trials are focusing on developing more effective therapies based on improved science and targeting therapies to mechanisms of tumor growth and progression.

“Progress is slow and stepwise, and we build one step at a time. The cumulative progress is what we find encouraging. A study is only one piece of a puzzle.

A study like REVEL may not change the way we treat NSCLC, but it can influence our design of further studies,” he said.

“Ramucirumab is not yet available for treatment of NSCLC. Our understanding of using targeted drugs will build on our ability to improve treatment for patients. We want to balance benefit with cost, and figure out how best to treat patients,” Dr. Masters said.

Three Key Considerations Don S. Dizon, MD, FACP, a medical oncologist and the Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, Boston, weighed in on the discussion of “value” at the press briefing. “The 3-month improvement in overall survival is a good threshold for the first-line setting in advanced NSCLC,

and it provides guidance, but we don’t consider that as the be-all and end-all of every scientific presentation. As with the results of any investigational treatment, we should consider three key things: efficacy, toxicity, and cost.”

Commenting on the trial results, Roy S. Herbst, MD, PhD, Ensign Professor of Medicine and Chief of Medical Oncology at Yale Cancer Center, New Haven, Connecticut, said he was impressed by the activity of the combination in both squamous and adenocarcinoma subtypes and by the toxicity profile of the combination.

“It is hard to give other drugs with docetaxel. The study showed a signal of improved overall and progression-free survival without patient selection for the combination of ramucirumab plus docetaxel. The results are not a home run, but I would say they are a single.

Right now, in squamous NSCLC cancer, we need a few doubles. We need to get men and women with advanced lung cancer on base,” Dr. Herbst said. “Further studies to identify a biomarker are clearly needed,” Dr. Herbst added. n Disclosure: Drs. Masters, Dizon, and Herbst reported no potential conflicts of interest.

The ASCO Post | JUNE 25, 2014

PAGE 28

ASCO Annual Meeting Chemotherapy/ Ramucirumab continued from page 27

proved in the second-line setting for advanced NSCLC.

Study Details The double-blind, placebo-controlled, phase III REVEL trial enrolled 1,253 patients with stage IV NSCLC (26% had squamous histology) that progressed on standard platinum-based therapy. Patients were randomly assigned to treatment with ramucirumab plus docetaxel or docetaxel plus placebo.

The combination significantly improved response rate, progression-free survival, and overall survival compared with docetaxel alone. Tumor shrinkage was observed in 22.9% of those who received ramucirumab/docetaxel vs 13.6% of those in the docetaxel-alone arm (P < .001). Median progressionfree survival was 4.5 vs 3.0 months (P < .0001), respectively, and median overall survival was 10.5 vs 9.1 months (P = .0235).

“This study met the primary endpoint of overall survival, reducing the risk of death by 14% and prolonging median survival by 1.4 months,” Dr. Pérol noted. The combination also reduced the risk of progression by 24%.

The safety profile was as expected for an antiangiogenic agent combined with docetaxel chemotherapy. The most common (≥ 5% incidence) of grade 3 or higher adverse events included neutropenia, febrile neutropenia, fatigue, leukopenia, hypertension, and pneumonia.

No increase in pulmonary hemorrhage was observed with the combination. n

Disclosure: Dr. Pérol is a Consultant or Advisor for Boehringer Ingelheim, Genentech, Lilly, Pfizer, and Roche, and has received honoraria or other remuneration from Genentech, Lilly, Pfizer, and Roche. For full disclosures of all study authors, visit abstracts.asco.org.

Reference 1. Pérol M, Ciuleanu T-E, Arrieta O,

et al: REVEL: A randomized, doubleblind, phase III study of docetaxel and ramucirumab versus docetaxel and placebo in the second-line treatment of stage IV non-small cell lung cancer following disease progression after one prior platinum-based therapy. ASCO Annual Meeting. Abstract LBA8006. Presented June 2, 2014.

Activated T Cell Inactivated T Cell

PD-L1

PD-1 Receptor PD-L2

PD-1 Receptor PD-L1

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

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

Artist’s interpretation based on scanning electron microscopy.

ASCOPost.com | JUNE 25, 2014

PAGE 29

FDA Update

FDA Approves Magnetic Resonance Contrast Agent for Evaluation of Breast Cancer

T

he U.S. Food and Drug Administration has approved a new indication for gadobutrol (Gadavist) injection for intravenous use with magnetic resonance imaging (MRI) of the breast to assess the

presence and extent of malignant breast disease. The approval is based on priority review of two multicenter phase III studies (GEMMA-1 and GEMMA-2) conducted in 13 countries.

Gadobutrol is a gadolinium-based extracellular contrast agent for MRI. It was first approved in the United States in March 2011 for intravenous use in diagnostic MRI in adults and children to

Discover PD-1: An immune checkpoint pathway1 Some tumor cells can evade the body’s immune response, which may result in disease progression2,3 • One function of the body’s immune response is to detect and destroy tumor cells through activated T cells and other mechanisms; tumor cells express multiple antigens that are not expressed in normal tissue.1—3 • However, some tumor cells may evade the body’s immune response by exploiting the PD-1 checkpoint pathway through expression of the dual PD-1 ligands PD-L1 and PD-L2.1,2,4—7 • PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate T cells, which may allow tumor cells to evade the immune response.1,2,8 Merck is committed to furthering the understanding of immunology in cancer, including the role of the PD-1 pathway.

TO DISCOVER MORE ABOUT THE PD-1 CHECKPOINT PATHWAY IN CANCER AND TO REGISTER FOR UPDATES, VISIT WWW.DISCOVERPD1PATHWAY.COM.

PD-1=programmed cell death protein 1; PD-L1=programmed cell death ligand 1; PD-L2=programmed cell death ligand 2.

References: 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264.

2. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 4. Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer. 2013;108(8):1560–1565.

5. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–477.

6. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–862. 7. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151–2157. 8. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–268.

Copyright © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1105870-0000 02/14 merck.com

detect and visualize areas with disrupted blood-brain barrier and/or abnormal vascularity of the central nervous system.

“The phase III GEMMA studies demonstrate that [gadobutrol]-enhanced breast MRI provided a statistically significant improvement in the identification of the extent of breast cancer vs unenhanced MRI,” said principal investigator Gillian Newstead, MD, FACR, from

the University of Chicago Medical Center. “This is an important diagnostic tool for health-care professionals with breast cancer patients. Breast MRI with [gadobutrol] provides important visibility for assessment of malignant breast disease and for treatment planning.”

GEMMA Studies Two multicenter phase III clinical trials with identical design (GEMMA-1 and GEMMA-2) were used to investigate the diagnostic efficacy of gadobutrol-enhanced breast MRI. In total, 787 patients with recently diagnosed breast cancer from 13 countries were enrolled.

In each study, MRI images were analyzed by three independent radiologists. These readers confirmed that gadobutrol-enhanced breast MRI improved ability to assess the presence and extent of breast cancer when compared to images from unenhanced breast MRI. Gadobutrol-enhanced breast MRI demonstrated superior sensitivity (range, 80%–89%) for the presence and extent of malignant disease compared to unenhanced breast MRI (range, 37%–73%) for all six readers. A true-negative rate (specificity) of > 80% for breasts without malignant disease was confirmed for gadobutrolenhanced breast MRI by five of six readers.

The studies did reveal that in breasts with malignancy, gadobutrol-enhanced breast MRI overestimated the histologically confirmed extent of malignancy in the diseased breast in up to 50% of patients. Three additional radiologists in each study read x-ray mammography alone. For these readers, over both studies, sensitivity for the presence and extent of malignancy ranged from 68% to 73% and specificity ranged from 86% to 94% in nonmalignant breasts.

Final study findings will be presented at an upcoming medical meeting. n

The ASCO Post | JUNE 25, 2014

PAGE 30

American Association for Cancer Research Special Conference Gastrointestinal Oncology

Research Insights From the AACR Special Conference on Pancreatic Cancer

By Caroline Helwick

P

ancreatic cancer still kills 40,000 Americans a year out of approximately 44,000 diagnosed. While advances in diagnosis and treatment are extending the lives of patients with other cancers, pancreatic ductal adenocarcinoma remains the second most lethal tumor (behind lung cancer).

While a magic bullet is not on the horizon, a very positive energy was felt at the American Association for Cancer Research (AACR) special conference, Pancreatic Cancer: Innovations in Research and Treatment. Close to 500 pancreatic cancer researchers from around the world gathered at the 3-day meeting in New Orleans to exchange insights, the highlights of which were described by three Conference leaders.

Novel Diagnostics David Tuveson, MD, PhD, Director of Research for The Lustgarten Foundation, and the Roy J. Zuckerberg

David Tuveson, MD, PhD

Professor of Cancer Research and Deputy Director of the Cancer Center at Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, focused on ways to diagnose and monitor pancreatic ductal adenocarcinoma.

Only about 10% of pancreatic cancers are diagnosed while the disease is still localized, leading to a dismal 1-year survival rate of less than 20%. The potential for early diagnosis via bloodbased biomarkers now seems possible, Dr. Tuveson said.

One method has identified circulating tumor DNA in about 75% of patient with various solid tumors, including pancreatic ductal adenocarcinoma. In the case of tumors with KRAS mutations, which are common in pancreatic ductal adenocarcinoma, the sensitivity of circulating tumor DNA approached 90% and specificity exceeded 99%.1 Researchers at The University of Texas MD Anderson Cancer Center, Houston, are also working on a cancer-spe-

cific marker on cell fragments called exosomes that are present in the blood of pancreatic ductal adenocarcinoma patients.2 This also holds promise for the early, blood-based detection of cancer, according to Dr. Tuveson.

A third blood test combines the known pancreatic cancer biomarker CA19-9 with three other putative pancreatic cancer biomarkers.3 Approximately 90% of the time, the biomarker panel accurately distinguished individuals with pancreatic ductal adenocarcinoma from healthy controls, or persons with chronic pancreatitis or pancreatic cysts. Its negative predictive value was 98%.

Other researchers found a way to improve upon the current unsatisfactory use of positron-emission tomography (PET) in differentiating and staging pancreatic cancer by incorporating the CA19-9 antigen, which is elevated in the disease.4 The recombinant monoclonal antibody 5B1 potently binds an extracellular epitope on the CA19-9 protein, providing a platform for developing an immuno-PET agent for imaging of pancreatic ductal adenocarcinoma. The result has been exceptional PET images, Dr. Tuveson noted.

“The CA19-9 antibody test has not yet been tested in patients, but we are excited about that possibility,” he commented.

Dr. Tuveson also highlighted research regarding the alterations in systemic metabolism that are a defining feature of pancreatic ductal adenocarcinoma. This is an important area of investigation because the risk for pancreatic ductal adenocarcinoma is known to be increased among persons with chronic obesity, hyperglycemia, and hyperinsulinemia; weight loss and newonset diabetes frequently develop in the 2 years prior to diagnosis; and cachexia and sarcopenia are often observed in these patients.

Researchers from Dana-Farber Cancer Institute, Boston, profiled circulating metabolites in prediagnostic plasma from approximately 1,500 pancreatic patients and matched controls. They found that 5 to 6 years before developing cancer, individuals ultimately diagnosed with pancreatic ductal adenocarcinoma had elevations in three particular branch chain amino acids.5 “This may give us an early warning sign

for [pancreatic ductal adenocarcinoma],” Dr. Tuveson indicated.

Inflammation and Immunity Alec Kimmelman, MD, PhD, Assistant Professor of Radiation Oncology at Harvard Medical School and the Dana-Farber Cancer Institute, Boston, highlighted inflammation and immunity as being of high interest at the meeting.

Researchers developed a state-ofthe-art mouse model of diet-induced obesity and pancreatic cancer that resembles important clinical features of human obesity.6 Compared to control animals, the high-fat diet–fed animals showed signs of marked inflammation in and around the pancreas, with increased numbers of infiltrating inflammatory cells, infiltrating natural killer cells, myeloid-derived suppressor cells, regulatory T cells and tumor-infiltrating macrophages, along with a significant change in the pancreatic cytokine profile. Most importantly, the high-fat

the antitumor effects of gemcitabine by increasing its concentration within the tumor, researchers reported here.7 Researchers from the United Kingdom have been attempting to decipher why pancreatic ductal adenocarcinoma does not respond to the T-cell checkpoint antagonists—anti–CTLA-4 and anti–PD-L1—and they have been able to attribute this largely to the chemokine CXCL12, which is secreted by a type of fibroblast in the tumor, as the mediator of immune suppression. They reported that CXCL12 protein selectively coats the cancer cells, and T cells are excluded from cells in the region where this occurs.8 Treatment of pancreatic ductal adenocarcinoma–bearing mice with the small-molecule CXCL12 receptor antagonist plerixafor (Mozobil), alone or together with anti–PD-L1, suppressed tumor growth, reduced tumor volume, and was associated with the presence of numerous T cells within the tumors.

“The tumor can elicit an immune re-

The significance of these and other findings are yet to be determined, but they are examples of steps we are taking to understanding the complexity of [pancreatic ductal adenocarcinoma] and make inroads.

—Christine Iacobuzio-Donahue, MD, PhD

diet led to accelerated development of the cancer precursor, pancreatic intraepithelial neoplasia, he noted.

“This research is about the development of a system that allows us to understand whole-body metabolism, and the importance of obesity on the inflammatory response,” he said.

Dr. Kimmelman also emphasized the importance of the dense stromal tissue surrounding and infiltrating many pancreatic tumors, which impedes both imaging and drug delivery. Stellate cells are a component of the stroma, and they secrete factors that can reprogram tumor cells to express key genes that are important for tumor growth. These stellate cells express the vitamin D receptor, which acts as a master transcriptional regulator of the stellate cell. In vivo, a synthetic vitamin D receptor agonist induced remodeling of the tumor stroma, and this enhanced

sponse from the body, but there is a barrier for the T cell to get into the tumor because of this coating from CXCL12.

Plerixafor can block the interaction of this secreted factor with the receptor, and in preclinical models can eradicate the tumor,” Dr. Kimmelman noted.

Disease Complexity Christine Iacobuzio-Donahue, MD, PhD, Associate Director of Translational Research at the David M. Rubenstein Center for Pancreatic Research at Memorial Sloan Kettering Cancer Center, New York, was struck by new findings concerning the complexity and heterogeneity of pancreatic ductal adenocarcinoma.

“We learned at this meeting that pancreatic cancer is complex at a level that has not been appreciated before,” she said.

“We heard some very exciting but

ASCOPost.com | JUNE 25, 2014

PAGE 31

American Association for Cancer Research Special Conference preliminary data about heterogeneity, specifically, that there are RNA and DNA differences within the same cell that can potentially impact on signaling and therapeutic pathways.9 We also heard about heterogeneity in terms of the types of cells in [pancreatic ductal adenocarcinoma],” Dr. Iacobuzio-Donahue said.

An emerging part of this story involves acinar cell transdifferentiation, which sets the stage for early tumor heterogeneity. This process involves tuft cells, which have stem cell–like properties and which were recently identified as being potential initiators of pancreatic intraepithelial neoplasia.10 At the conference, Dr. Iacobuzio-­ Donahue discussed the genetic evolution of pancreatic ductal adenocarcinoma from the time of its inception to its dissemination to distant sites, including evidence for the role of the microenvironment as a selective force in clonal evolution.11 She alluded to new insights regarding pancreatic intraepithe-

lial neoplasia—in particular, the timing and order of the known founder genetic alterations that drive progression.

She also cited evidence in support of distinct biologic subsets of pancreatic ductal adenocarcinoma and drew from whole-genome sequencing data to describe “the first estimation of the extent of heterogeneity among different metastases in the same distant organ.”

“The significance of these and other findings are yet to be determined, but they are examples of steps we are taking to understanding the complexity of [pancreatic ductal adenocarcinoma] and make inroads,” she added. n Disclosure: Dr. Tuveson is a consultant for Bethyl Laboratory, Pfizer, Millennium, and Celgene, and he has received licensing royalties from Novartis. Dr. Kimmelman is a consultant for Forma Therapeutics. Dr. Iacobuzio-Donahue reported no potential conflicts of interest.

References 1. Diaz LA: Circulating tumor DNA.

AACR Special Conference on Pancreatic Cancer. Abstract IA12. Presented May 20, 2014.

2. Kalluri R: Diagnosis and treatment of pancreas cancer. Lecture. AACR Special Conference on Pancreatic Cancer. Presented May 20, 2014.

3. Taguchi A, Capello M, Zhao Y, et al: Development and validation of diagnostic biomarker model for detection of early stage pancreatic cancer. AACR Special Conference on Pancreatic Cancer. Abstract B20. Presented May 20, 2014.

4. Lewis JS: New methods of PET imaging pancreas cancer. AACR Special Conference on Pancreatic Cancer. Abstract IA16.

Presented May 20, 2014.

5. Wolpin BM: Pancreatic adenocarcinoma and altered whole-body metabolism.

AACR Special Conference on Pancreatic Cancer. Abstract IA26. Presented May 21, 2014.

6. Eibl G: Obesity, inflammation, and pancreatic cancer. AACR Special Conference on Pancreatic Cancer. Abstract IA18.

Presented May 20, 2014.

7. Sherman MH, Ding N, Collisson EA, et al: Vitamin D: Shining light on pancreatic cancer. Abstract IA9. Presented May 19, 2014.

8. Fearon DT: The basis of immune suppression in murine pancreatic ductal adenocarcinoma. AACR Special Conference on Pancreatic Cancer. Abstract IA21. Presented May 21, 2014.

9. Rhim A: Generation of intratumoral heterogeneity via RNA-DNA differences in pancreatic cancer. Lecture. AACR Special Conference on Pancreatic Cancer. Presented May 19, 2014.

10. Takeuchi KK, Delgiorno KE, Halbrook CJ, et al: Acinar cell transdifferentiation sets the stage for early tumor heterogeneity. AACR Special Conference on Pancreatic Cancer. Abstract IA13. Presented May 19, 2014.

11. Iacobuzio-Donahue CA: Dynamics and evolution of pancreatic cancer from inception to invasive. AACR Special Conference on Pancreatic Cancer. Abstract IA1.

Presented May 18, 2014.

Announcement

Lung-MAP Launches: First Precision Medicine Trial From National Clinical Trials Network

A

public-private collaboration among the National Cancer Institute (NCI), SWOG Cancer Research, Friends of Cancer Research, the Foundation for

Ellen V. Sigal, PhD

the National Institutes of Health (FNIH), five pharmaceutical companies (Amgen, Genentech, Pfizer, AstraZeneca, and AstraZeneca’s global biologics R&D arm, MedImmune), and Foundation Medicine recently announced the initiation of the Lung Cancer Master Protocol (LungMAP) trial.

Lung-MAP is a multidrug, multiarm, biomarker-driven clinical trial for patients with advanced squamous cell lung cancer. The trial will use genomic profiling to match patients to one of several different investigational treatments that are designed to target the genomic alterations found to be driv-

ing the growth of their cancer. This innovative approach to clinical testing aims to improve access to promising drugs for patients and ease the significant recruitment and infrastructure burdens on researchers involved in traditional clinical trials.

“This diverse, collaborative approach, with support from leading lung cancer advocacy organizations, helps to ensure that the needs of patients, clinicians, developers, and regulators are all considered in the design and operation of the trial,” said Ellen V. Sigal, PhD, Chair and Founder of Friends of Cancer Research.

First Five Drugs The trial will initially test five experimental drugs—four targeted therapies and an anti–PD-L1 immunotherapy. It is anticipated that between 500 and 1,000 patients will be screened per year for over 200 cancerrelated genes for genomic alterations.

The results of this test will be used to assign each patient to the trial arm that is best matched to their tumor’s genomic profile.

“Lung-MAP represents the first of several planned large, genomically

driven treatment trials that will be conducted by NCI’s newly formed National Clinical Trials Network (NCTN),” said Jeff Abrams, MD, Associate Director of NCI’s Cancer Therapy Evaluation Program. “The restructuring and consolidation of NCI’s large trial treatment program, resulting in the formation of the NCTN, is quite timely, as it now can offer an ideal platform for bringing the benefits of more precise molecular diagnostics to cancer patients in communities large and small.”

More Efficient Model Lung-MAP aims to establish a model of clinical testing that more efficiently meets the needs of both patients and drug developers. Whereas a typical clinical trial for a targeted therapy tests each potential patient for a single biomarker and enrolls only a portion—sometimes a very small portion—of patients tested, Lung-MAP will simultaneously test patients for many biomarkers including selected base substitutions and small in/dels, gene fusions, and amplifications in order to assess compatibility with several different experimental treatments. All

patients tested will then be enrolled into one of Lung-MAP’s five trial arms.

Lung-MAP will make it easier for patients and researchers to find one another. It will also be more flexible than traditional clinical trial models.

Where typical clinical trials require the development of new protocols for each new drug tested, Lung-MAP uses a single “master protocol,” which can be amended as needed as drugs enter and exit the trial, preserving infrastructure and patient outreach efforts.

Over 200 Medical Centers The trial will be conducted at over 200 medical centers by NCI’s NCTN, led by SWOG, and partly funded by NCI through its Cancer Therapy Evaluation Program. Significant additional funding will be provided by the participating companies as part of a partnership managed by FNIH that also involves the Food and Drug Administration[www.fda.gov], Friends of Cancer Research, and other patient advocacy organizations. The trial infrastructure is capable of testing as many as five to seven additional drugs over the next 5 years, and will cost up to $160 million. n

Now FDA Approved For patients with advanced gastric or gastroesophageal (GE) junction adenocarcinoma who have progressed after prior fluoropyrimidine- or platinum-containing chemotherapy, CYRAMZA is the only FDA-approved antiangiogenic to significantly extend overall survival CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo.

Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

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

Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred

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

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery.

Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

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

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

CYRAMZA monotherapy significantly extended overall survival (OS)1

CYRAMZA significantly improved progression-free survival (PFS)1 MAJOR OUTCOME MEASURE

OS PROBABILITY

OVERALL SURVIVAL: MEDIAN – MONTHS (95% CI)1 1.0

CYRAMZA

Placebo

0.8

months

months

(4.4, 5.7)

(2.8, 4.7)

5.2

0.6

The phase III REGARD trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma who had progressed on or after prior fluoropyrimidine- or platinumcontaining chemotherapy. Major efficacy outcome measure was overall survival. Supportive efficacy outcome measure was progression-free survival. All patients were ECOG PS 0 or 1. Prior to enrollment, 85% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease, and 15% of patients progressed during treatment or within 6 months after the last dose of adjuvant chemotherapy. Patients were randomized 2:1 to CYRAMZA 8 mg/kg q2w + BSC (n=238) or placebo + BSC (n=117).1

3.8

Hazard Ratio=0.78 (0.60, 0.998); P=0.047

0.4

CYRAMZA Placebo

0.2

0.0 0

1

2

3

238 117

5

6

7

8

9

10 11 12 13

14 15 16 17 18 19

20

26

27

28

0 1

0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk CYRAMZA Placebo

4

154 66

92 34

49 20

17 7

7 4

3 2

37%

• Median PFS with CYRAMZA was 2.1 months (95% CI: 1.5, 2.7) vs 1.3 months (95% CI: 1.3, 1.4) with placebo (hazard ratio 0.48 [95% CI: 0.38, 0.62]; P<0.001)1

CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; PS=performance status; BSC=best supportive care.

INCREASE IN MEDIAN OS

Most Common Adverse Reactions

Use in Specific Populations

• The most commonly reported adverse reactions (all grades) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%), diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs 2%).

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. 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 a fetus.

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

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

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

• As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZA-treated patients with post-baseline serum samples tested positive for antiramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting antiramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

Drug Interactions • No formal drug interaction studies have been conducted.

• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant.

• Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on next page.

RB HCP ISI 21APR2014 Reference: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

RB89001 05/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED. CYRAMZA™ is a trademark of Eli Lilly and Company.

Visit CYRAMZANowApproved.com

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

WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

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

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

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

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

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

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

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

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

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.

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

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo Adverse Reactions N=236 N=115 a (MedDRA) All Grades Grade 3-4 All Grades Grade 3-4 System Organ Class (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a MedDRA Version 15.0.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. 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 a fetus.

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

Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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

Geriatric Use Clinical Trials of CYRAMZA as a single agent did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 236 patients who received CYRAMZA in Study 1, 35% were 65 and over, while 9% were 75 and over.

Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab.

Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab.

Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility.

Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Recommended Dose and Schedule The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes.

Continue CYRAMZA until disease progression or unacceptable toxicity. Do not administer CYRAMZA as an intravenous push or bolus.

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

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

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

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

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

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

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Of increased risk of an arterial thromboembolic event.

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

• To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

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

• Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment.

Additional information can be found at www.CYRAMZAhcp.com.

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

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions.

In Study 1, according to laboratory assessment, 8% of CYRAMZA–treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) of CYRAMZAtreated patients with post baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No formal drug interaction studies have been conducted.

TM

CYRAMZA (ramucirumab) injection

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2014, Eli Lilly and Company. All rights reserved.

RB HCP BS 21APR2014

PA000IPAM00 – BS 9.25x13.25

CYRAMZATM (ramucirumab) injection

PA000IPAM00 – BS 9.25x13.25

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PAGE 35

European Multidisciplinary American Roentgen Ray Society Cancer Annual Congress Meeting Breast Cancer

Preoperative Breast MRI: Does Higher Sensitivity Equal Better Outcomes?

By Shalmali Pal

B

reast magnetic resonance imaging (MRI) is superior to more commonly used imaging modalities in preoperative breast cancer staging and should be a key element in routine workup. But despite its high sensitivity for catching cancers, breast MRI still does not deliver maximum value for the patient. Those were the respective

(ACRIN) 6666 trial, which found that the addition of screening MRI to mammography in women at increased risk of breast cancer resulted in a higher cancer detection yield at 14.7 extra cancers per 1,000.2 He also noted that breast MRI can detect additional ipsilateral and contralateral disease, evaluate axillary and extra-axillary

Why wouldn’t we want to use the test that’s proven to be the most sensitive and just as specific [as mammography]? … There are many benefits to breast MRI that are really not debatable.

—Christopher E. Comstock, MD

T:14 in

B:14.25 in

S:13 in

[Breast MRI is a] promising tool.

As radiologists, we want it to be successful. But this debate is not about radiologists, it’s about the patient … and delivering maximum value to the patient.

—Peter R. Eby, MD

arguments two radiologists made during a debate on presurgical breast MRI at the American Roentgen Ray Society 2014 Annual Meeting in San Diego.1 Arguing in favor of routine preoperative breast MRI was Christopher E. Comstock, MD, a breast-imaging specialist at Memorial Sloan Kettering Cancer Center in New York. Making the argument against was Peter R. Eby, MD, a breast-imaging specialist at Virginia Mason Medical Center in Seattle.

Pro: Benefits ‘Not Debatable’ Dr. Comstock pointed out that mammography, with all its limitations, is the standard for preoperative imaging. But breast MRI has proven itself to be a higher-caliber imaging tool, so “why wouldn’t we want to use the test that’s proven to be the most sensitive and just as specific [as mammography]? Why wouldn’t we want to use the test that is not inhibited by breast density to define the extent of disease? There are many benefits to breast MRI that are really not debatable,” he said.

As proof of breast MRI’s sensitivity, Dr. Comstock cited data from the American College of Radiology Imaging Network

adenopathy, and evaluate pectoralis and chest wall involvement, all of which is important for treatment planning.

Critics of breast MRI will claim that the additional disease found with the modality is “clinically insignificant” because it will be treated with radiation therapy.

“But if the additional disease is never clinically significant, that implies surgery is not needed in the first place—that you can treat everything with radiation therapy— and that’s clearly not the case,” Dr. Comstock argued.

Not relying on breast MRI to find contralateral disease could lead to inadequate treatment of occult cancers, he said. In ad-

dition, the ability to assess the axilla can help direct full axillary dissection and help guide treatment for women with significant adenopathy.

Finally, breast MRI can reveal distant metastases of the pectoralis muscle and chest wall, which is key for effective disease staging. Dr. Comstock cited results from a study that used breast MRI to assess disease extent in patients with posterior breast masses with suspected tumor invasion into the underlying muscle.3 The study authors reported that MRI results showed enhancing masses in all cases, with more than a quarter of the patients having masses that “abutted the muscles, with obliteration of the fat plane and muscle enhancement. All five had muscle involvement at surgery,” he said.

“Finding that extra disease may benefit survival, not to mention alleviate the psychological stress a woman can experience when the additional disease is found and she has to undergo treatment again,” Dr. Comstock pointed out.

Dr. Comstock addressed some of the criticisms leveled at breast MRI, most notably that it has a high false-positive rate.

But he noted that the positive predictive value of the modality is in the 20% to 40% range, which is similar to that of mammography, and much better than than of breast ultrasound at 8% to 9%.

Lastly, there are the claims that breast MRI leads to overdiagnosis and overtreatment. Dr. Comstock called overdiagnosis a “misnomer.” “Overdiagnosis is not the problem, it’s the overtreatment,” Dr. Comstock said. “Overtreatment is not the fault of the radiologists, we’re just the messenger. It’s our colleagues in the medical and oncology communities who need to decide if treatment is required and what constitutes appropriate treatment.”

Con: Measuring Breast MRI’s Value Dr. Eby called breast MRI a “promising tool. As radiologists, we want it to be suc-

Pros and Cons of Breast MRI ■■ Breast MRI offers higher sensitivity than mammography, and equal specificity, for preoperative breast cancer staging.

■■ Breast MRI can detect additional ipsilateral and contralateral disease, evaluate axillary and extra-axillary adenopathy, and evaluate pectoralis and chest wall involvement, all of which is important for treatment planning.

■■ Preoperative MRI for breast cancer staging does not reduce the risk of local or disease recurrence and has been shown to result in a higher conversion rate from breast-conservation therapy to mastectomy.

■■ Breast MRI can determine disease extent more accurately than standard mammography, but whether that leads to better outcomes is unknown.

cessful. But this debate is not about radiologists, it’s about the patient … and delivering maximum value to the patient. How do we measure that value? We should do that based on a set of outcomes that matter to the patient.” Those outcomes are service, treatment outcomes, cost, and appropriateness, he explained.4 Dr. Eby acknowledged that breast MRI can find additional disease, and that constitutes a potentially beneficial service given that breast cancer is often a multifocal disease. But the data have shown that MRI will detect ipislateral lesions in 16% of patients and contralateral disease in 4%.

“MRI is more sensitive to finding [additional disease], but it’s not finding all of it,” Dr. Eby cautioned. In terms of outcomes, do results with this sensitive tool translate into improvements in survival, recurrence, margin status, and reoperation rates? In general, the answer is “no,” Dr. Eby said.

“Survival is something that, as breast imagers, we really try to hang our hats on. Screening mammography has been shown to improve survival,” he said, pointing out that based on Surveillance, Epidemiology, and End Results data, 5-year survival rates approach 99% for localized disease and 90% for all cancer stages combined.5 On the other hand, studies have yet to show a survival benefit with breast MRI, he stated.

A 2014 meta-analysis of “individual person data” found that preoperative MRI for breast cancer staging did not reduce the risk of local recurrence or disease recurrence, Dr. Eby pointed out.

And results from another study demonstrated a higher MRI-related conversion rate from breast-conservation therapy to mastectomy.6,7 As for recurrence, research has shown that for 8-year local recurrence, there is no significant decrease in recurrence rates for patients who have had a preoperative breast MRI, Dr. Eby said.6,8 The same can be said for reoperation rates, with no difference between patients who did or did not undergo breast MRI.9,10 In terms of cost, Dr. Comstock mentioned that the price tag for breast MRI is dropping, with the current Medicare reimbursement rate at around $800. He also stressed that more expensive studies, such as whole-body MRI for cancer staging or lumbar MRI for back pain, don’t receive as much financial scrutiny as breast MRI. Dr. Eby countered that there is more to the cost of a breast MRI than the single continued on page 38

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; JUNE 25, 2014

PAGE 38

European Multidisciplinary American Roentgen Ray Society Cancer Annual Congress Meeting Preoperative Breast MRI continued from page 35

study, including the cost of callbacks for additional studies, biopsies, treatment delays, and anxiety for the patient.

Dr. Eby questioned the appropriateness of breast MRI in terms of its contribution to patient management. Even among radiologists, the answer to the question of

appropriateness is not clear: According to a 2013 revision of the American College of Radiologyâ&#x20AC;&#x2122;s practice guideline, breast MRI determines the extent of disease more accurately than standard mammography, but it remains to be shown conclusively that the increase in accuracy results in any reduction in recurrence rates following surgery, radiation, or systemic therapy.11

Dr. Eby and Dr. Comstock said they are looking forward to results from the newly launched ACRIN 6694 trial that will evaluate the effect of preoperative breast MRI on surgical outcomes, costs, and quality of life in breast cancer patients. Dr. Comstock, a coâ&#x20AC;&#x201C;prinicipal investigator, emphasized that the trial will be powered to look at long-term recurrence at 5 years.12 n

Disclosure: Drs. Comstock and Eby reported no potential conflicts of interest.

References 1. Comstock CE, Eby PR: 2nd Annual Great Debate: The Role of Breast MRI in Preoperative Staging. American Roentgen Ray Society Annual Meeting. Presented May 4, 2014.

2. Berg WA, et al: Detection of breast cancer with addition of annual screening ultrasound

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 | JUNE 25, 2014

PAGE 39

European Multidisciplinary American Roentgen Ray Society Cancer Annual Congress Meeting or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA 307:1394-1404, 2012.

3. Morris EA, et al: Evaluation of pectoralis major muscle in patients with posterior breast tumors on breast MR image. Radiology 214:67-72, 2000.

4. Rona JM: 97.1 percent perfect. J Healthc Manag 50:87-93, 2005.

5. Cancer of the Breast—SEER Stat Facts

Sheets. Available at seer.cancer.gov/statfacts/ html/breast.html.

6. Houssami N, et al: An individual person data meta-analysis of preoperative magnetic resonance imaging and breast cancer recurrence. J Clin Oncol 32:392-401, 2014.

7. Gonzalez V, et al: Preoperative MRI of the breast (POMB) influences primary treatment in breast cancer. World J Surg. May 12, 2014 (early release online).

8. Pilewskie M, et al: Perioperative breast MRI is not associated with lower locoregional recurrence rates in DCIS patients treated with or without radiation. Ann Surg Onc 21:15521560, 2014.

9. Turnbull L, et al: Comparative effectiveness of MRI in breast cancer trial. Lancet 375:563-571, 2010.

10. Houssami N, et al: Preoperative magnetic resonance imaging in breast cancer. Ann

Surg 257:249-255, 2013.

11. ACR Practice Guideline for the Performance of Contrast Enhanced Magnetic Resonance Imaging (MRI) of the Breast. Available at www.acr.org.

12. Alliance for Clinical Trials in Oncology/American College of Radiology Imaging Network: Alliance A011104/ACRIN 6694.

NCI version date: April 1, 2013. Available at www.acrin.org.

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; JUNE 25, 2014

PAGE 40

Digestive Disease Week Gastrointestinal Oncology

Gastric Cancer Detected in a Breath Test

By Caroline Helwick

B

y detecting certain volatile organic compounds in exhaled breath, NanoArtificial Nose technology (NA-NOSE) was able to differentiate patients with gastric cancer from those with benign lesions,

with high accuracy, in a poster that earned a merit award at Digestive Disease Week 2014, the largest gathering of gastroenterology specialists in the world.1 â&#x20AC;&#x153;The detection of volatile markers in

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.

human breath is an emerging field of research for screening, surveillance, and monitoring different diseases, including cancer,â&#x20AC;? said Marcis Leja, MD, MBA, PhD, of the University of Latvia in Riga.

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:

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

The studyâ&#x20AC;&#x2122;s first author was Haitham Amal, a PhD candidate in the research group led by Hossam Haick, BSc, PhD, at Technionâ&#x20AC;&#x201C;Israel Institute of Technology, Haifa.

The NA-NOSE, which was designed and developed by Prof. Haickâ&#x20AC;&#x2122;s group, relies on electrical signals from sensors that correspond with more than 20 components in the breath. Dr. Leja reported the results of this novel sensor technology for

If the results are validated in a wider patient population, this could be a very good and inexpensive tool that could be used for screening. â&#x20AC;&#x201D;Marcis Leja, MD, MBA, PhD

both detecting gastric cancer and differentiating it from peptic ulcer disease and precancerous lesions in the stomach mucosa.

The study involved 99 gastric cancer patients, 53 with peptic ulcer disease and 342 controls, who underwent upper endoscopy. For differentiating cancer from noncancerous conditions, the sensitivity of the test was found to be 70%, the specificity, 98%, and accuracy, 92%. â&#x20AC;&#x153;The device is really performing well,â&#x20AC;?

Dr. Leja said in an interview. â&#x20AC;&#x153;If the results are validated in a wider patient population, this could be a very good and inexpensive tool that could be used for screeningâ&#x20AC;&#x201D; even for the simultaneous detection of a number of different diseases from the same breath sample.â&#x20AC;Ś We are showing that we can discriminate high-risk premalignant lesions from low-risk ones.â&#x20AC;? n Disclosures: Dr. Leja has received compensation for speaking and teaching from AstraZeneca and Krka Pharmaceuticals.

Reference 1. Amal H, Leja M, Funka K, et al: Nanomaterial-based sensor technology can detect gastric cancer and peptic ulcer disease with a high accuracy from an exhaled air sample. Digestive Disease Week 2014. Abstract Sa1896.

Presented May 3, 2014.

ASCOPost.com | JUNE 25, 2014

PAGE 41

Digestive Disease Week Gastrointestinal Oncology

Colorectal Cancer Screening Poised for Change

By Caroline Helwick

N

ew screening modalities and the customization of the screening population could soon change the way that screening for colorectal cancer is done. At Digestive Disease Week 2014, the largest gathering of gastrointestinal disease specialists in the world, researchers presented data suggesting that at least some of these changes are just around the bend.

Stool DNA vs Fecal Immunochemical Testing There was much buzz about the noninvasive multitarget stool DNA testing (Cologuard), which was recently rec-

(92.3% vs 73.8%; P = .002), advanced precancerous lesions (42.4% vs 23.8%; P < .001), polyps with high-grade dysplasia (69.2% vs 46.2%; P = .004) and serrated sessile polyps measuring ≥ 1 cm (42.4% vs 5.1%; P = .001), though fecal immunochemical testing is more specific (94.9%–96.4% vs 86.6%– 89.8%). These results were recently published in The New England Journal of Medicine.1 At Digestive Disease Week, the DEEP-C investigators presented the prespecified analysis for sessile serrated polyps ≥ 1 cm. These lesions are frequent precursors to cancer and are

We are hoping the stool DNA test will become a legitimate part of our armamentarium.

—David A. Ahlquist, MD

ommended by the U.S. Food and Drug Administration (FDA)’s Molecular and Clinical Genetics advisory committee. The new test involves quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and beta-actin, plus a hemoglobin immunoassay.

Co-investigator for the studies, ­David A. Ahlquist, MD, the Carol Gatton Professor of Gastrointestinal Research at the Mayo Clinic, Rochester, said that should multitarget stool DNA testing become FDA-approved, many may choose to use this test because of its user-friendly features and high earlydetection accuracy.

“We are hoping the stool DNA test will become a legitimate part of our armamentarium,” he said in a panel discussion at Digestive Disease Week.

Compared with colonoscopy, the test is noninvasive but would be performed more often—probably every 3 years— with referral to colonoscopy for patients with positive findings. “Fine-tuning of this algorithm will require additional observation,” he added.

Data from the DEEP-C trial of nearly 10,000 individuals suggests multitarget stool DNA testing is more effective than currently available fecal immunochemical testing in detecting adenocarcinoma

often missed by colonoscopy as well as by fecal immunochemical testing, since they do not bleed. For detecting these challenging lesions, multitarget stool DNA testing was almost 10 times better than fecal immunochemical testing, the study found.2 Of the whole study population, 7.6% had an advanced precancerous lesion as the most advanced finding on colonoscopy and 13.1% of these individuals

testing] for [sessile serrated polyps] ≥ 1 cm was significantly higher than that of fecal immunochemical testing, which was not effective for identifying patients with large [sessile serrated polyps],” said Barry M. Berger, MD, Chief Medical Officer of EXACT Sciences, Madison, Wisconsin, who presented the subset analysis.

“Stool DNA testing really is the only noninvasive approach to detecting these lesions,” Dr. Ahlquist agreed.

Integration Into Screening Algorithm The detection of 92% of colon cancer is considered extremely high for a noninvasive test and spares these patients colonoscopy, expert endoscopists commented. One of these was Douglas Rex, MD, Professor of Medicine at the University of Indiana, Indianapolis, who often speaks about the potential “disruption” of colonoscopy as the preferred screening approach.

Dr. Rex called the sensitivity “remarkable for a noninvasive test,” but he indicated that the test might be expensive (the price has not yet been set).

While this may not be a factor for individuals who can pay for it, it could be problematic in terms of its widespread uptake and for the health-care system at large, he maintained.

“I don’t think colonoscopy is off the map as a screening option. We are wrestling with several legitimate strategies right now,” he said in a panel discussion.

Thomas F. Imperiale, MD, Professor of Medicine at Indiana University

Colorectal Cancer Screening Advances ■■ The multitarget stool DNA test, currently being considered for approval by the FDA, is significantly more sensitive than fecal immunochemical testing and is the only noninvasive screening test that can detect sessile serrated polyps ≥ 1 cm.

■■ Risk stratification as a means of timing colonoscopy screening is an active area of research.

■■ The EndoRings device, which fits on the end of a colonoscope, improves visualization around colonic folds and greatly improves the detection of adenomas and polyps, vs standard colonoscopy.

had a sessile serrated polyp ≥ 1 cm, for an overall incidence in the population of 1%.

“The detection of patients with [sessile serrated polyps] is a clinically important issue in the consideration of noninvasive screening techniques. The sensitivity of [multitarget stool DNA

School of Medicine, Indianapolis, who authored the pivotal study, added, “How this new test integrates into the current options for colorectal cancer screening will depend on its comparative effectiveness and cost-effectiveness— metrics that may be best delineated through the use of microsimulation

modeling. Based on test characteristics alone, [multitarget stool DNA testing] may be best for persons between 50 and 64 years old for whom the prevalence of disease is lower and test specificity is higher, characteristics that minimize the false-positive risk and optimize the positive-predictive value of the test.”

Risk Stratification for Screening Screening colonoscopy may not always be a “one size fits all” situation, according to a number of specialists who suggest that risk stratification makes sense. Several adverse risk factors have been established, but only age (50 as the threshold) and family history (one or more first-degree relatives with colorectal cancer or adenoma) are used in clinical decision-making. This leaves out black race, male sex, cigarette smoking, high body mass index, heavy ethanol use, diet (red meat), and diabetes.

Dr. Imperiale pointed out that while colorectal cancer screening of averagerisk individuals reduces colorectal cancer–related morbidity and mortality, it is inefficient and expensive. More than half the population is never screened, many low-risk persons are screened unnecessarily, and many high-risk persons are never examined.

A tailored colorectal cancer screening design would adjust the intensity of screening to the individual’s risk and optimize the balance between benefit and risk. Screening would be more aggressive for high-risk groups, and could be delayed or performed with noninvasive tests in low-risk persons, said Dr. Imperiale.

Dr. Imperiale and his colleagues, therefore, constructed a risk-based model using literature-derived risk factors and correlated the scores with endoscopic and pathologic findings among 4,500 individuals.3 With the application of the model, they were able to stratify risk for three-fourths of an average-risk cohort, resulting in a highrisk group in which colonoscopy had a high yield for advanced neoplasia, and a low-risk group that could be screened less invasively.

“If validated in independent cohorts, this strategy could improve the efficiency and uptake of [colorectal cancer] screening,” Dr. Imperiale said.

Could individuals simply be stratified by age and race? Age-adjusted continued on page 42

The ASCO Post | JUNE 25, 2014

PAGE 42

Digestive Disease Week Colorectal Cancer Screening continued from page 41

colorectal cancer risk is higher in men than in women—a 10-year lag in cancer risk is observed in women, with the exception of black women, whose risk is comparable to that of men the same age.

Black individuals have higher colorectal cancer incidence and mortality, possibly because of an earlier onset of cancer precursors, more aggressive tumor biology, or less access or adherence to screening. Therefore, they may warrant earlier or more intensive screening, experts have suggested.

David Lieberman, MD, Head of Gastroenterology at Oregon Health & Science University, Portland, who has conducted much of the research in this area, said risk-based screening is rational. However, he worries that it would only complicate efforts at colorectal cancer prevention.

“We showed in a screening cohort that a few simple things—age, sex, race/ ethnicity—were strongly associated with the risk of advanced neoplasia,” he said. “But in discussing the guidelines for screening, our sense was that we are

already delivering a complicated message by offering a menu of screening options, and that by further complicating it—stratifying by risk—we might paradoxically adversely affect screening rates,” he continued.

“We have been making progress, and we don’t want to complicate things, but I am suggesting that now, perhaps, the clouds have opened, and it’s time to start thinking about a more customized approach,” he said in a panel discussion.

New Colonoscopy Technology The addition of a small rubber tip with flexible, circular rings to the distal end of a colonoscope resulted in substantially greater detection of polyps and adenomas in a randomized, tandem study of 106 patients evaluating the EndoRings device.4 In a per-lesion analysis, the adenoma miss rate was 13% when patients underwent an EndoRings colonoscopy followed by a standard colonoscopy and 53% when standard colonoscopy was done before the EndoRings colonoscopy (P > .001). Similarly, the miss

rates for polyps were 11% and 58% (P > .001), investigators of the Dutch CLEVER study reported.

This is a big improvement over the current adenoma miss rate of 25% to 40% with standard colonoscopy techniques. Lack of detection is largely due to inadequate visualization of proximal aspects of folds and inner curves of flexures, which can be overcome by the EndoRings device, which improves visualization by engaging and stretching colonic folds during withdrawal, explained Peter D. Siersema, MD, PhD, Director of Gastroenterology and Hepatology at University Medical Center Utrecht, the Netherlands. The EndoRings device will soon be available in the United States and Europe. n Disclosure: Dr. Ahlquist, as co-developer of the multitarget stool DNA test, will receive inventor’s share of royalties coming to the Mayo Clinic from Exact Sciences; he is also a scientific advisor to an research collaborator with Exact Sciences. Dr. Berger is an employee of Exact Sciences Corporation. Dr. Rex reported consulting and board membership with Exact Sciences Corporation. Dr. Siersema reported

grant/research support from EndoAid Ltd. Dr. Imperiale had no relevant disclosures.

References 1. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al: Multi-target stool DNA testing for colorectal-cancer screening. N Engl J Med 370:1287-1297, 2014.

2. Berger BM, Imperiale TF, Hilsden RJ, et al: Non-invasive detection of sessile serrated polyps in an average risk colorectal cancer screening population: Comparison of multi-target stool DNA and fecal immunochemical testing. Digestive Disease Week 2014. Abstract 113. Presented May 3, 2014.

3. Imperiale TF, Monahan PO, Stump TE, et al: A risk stratification strategy for colorectal cancer screening: sequential application of two clinical prediction rules.

Digestive Disease Week 2014. Abstract 225.

Presented May 3, 2014.

4. Dik VC, Grainek IM, Segol O, et al: Comparing standard colonoscopy with EndoRings colonoscopy: A randomized, multicenter tandem colonoscopy study— interim results of the CLEVER study. Digestive Disease Week 2014. Abstract 929b.

Presented May 6, 2014.

Many Patients With Colorectal Cancer Fail to Receive Adjuvant Chemotherapy

By Caroline Helwick

D

ata from the National Cancer Data Bank (2010–2011) suggest that 30% of patients with colorectal cancer who are eligible for adjuvant chemotherapy fail to receive it, but their odds increase by 30% when surgery is performed by laparoscopy, rather than laparotomy.1 “In this large national database of almost 20,000 patients, we found that the use of evidence-based adjuvant chemotherapy after resection of nodepositive colon cancer is disturbingly low, with over 30% of patients not receiving therapy,” said Brian Englum, MD, of Duke University. Dr. Englum and colleagues presented their findings at Digestive Disease Week 2014.

Study Details Adjuvant chemotherapy is recommended within 2 to 3 months of surgery for patients with lymph node-positive disease. Laparoscopy is a safe alternative to laparotomy for colon cancer resection, however, its benefits in achieving higher rates of appropriate adjuvant chemotherapy use have not been established.

Dr. Englum and colleagues examined the National Cancer Data Bank, which

captures 70% of newly diagnosed cancer cases from 1,500 U.S. centers, for patients treated in 2010 and 2011. They identified 19,531 patients with N1-2 disease and no distant metastasis, which made them eligible for chemotherapy, ideally within 90 days of surgery. The patients had 12,088 open procedures and 7,443 laparoscopies.

Patients who underwent an open procedure were found to be older and to have larger tumors. There was no evidence for an oncologic benefit for one type of surgery over the other.

appropriately timed adjuvant chemotherapy,” he indicated.

Predictors of failure to receive adjuvant chemotherapy included older age, increased comorbidities, racial minority status, nonprivate insurance, pro-

Chemotherapy Not Delivered to One-Third of Candidates

longed hospital stay (≥10 days), and unplanned readmission.

“Our thought is that patients who have complications are much less likely to receive adjuvant chemotherapy. They develop complications after surgery and have difficulty recovering from them. When they continue to have problems, the window for chemotherapy often closes. They may never get to the point where they are robust enough to tolerate chemotherapy,” Dr. Englum observed.

“We know from other studies that

The overall rate of receiving adjuvant chemotherapy was only 65%, but this rose higher in patients having laparoscopies. The rates for adjuvant chemotherapy at 60 and 90 days postoperatively were 53% and 62% after laparoscopy compared to 44% and 54% after laparotomy, Dr. Englum ­reported.

“Laparoscopic colon resection is associated with a nearly 30% higher odds (OR = 1.27; P < .001) of undergoing

the complication rates after laparoscopic surgery are significantly less than with open procedures, so it makes sense more of these patients received adjuvant chemotherapy in our study,” he said. “Certainly, in our center, we prefer

Certainly, in our center, we prefer laparoscopic surgery where possible. If we have a choice, that’s what we recommend and what we do.

—Brian Englum, MD

laparoscopic surgery where possible. If we have a choice, that’s what we recommend and what we do.” n Disclosure: Dr. Englum reported no potential conflicts of interest.

Reference 1. Englum BR, Speicher PJ, Ganapathi AM, et al: Optimizing the utilization of adjuvant chemotherapy following surgical resection of colon cancer: A comparison of laparoscopic vs open approach. Digestive Disease Week 2014. Abstract Mo1072. Presented May 5, 2014.

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 100 800 1st dose reduction 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 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (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 8 4 Severe Symptomsd Asthenia Any Symptoms 47 39 8 3 Severe Symptomsd 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 2 25 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 227 (54%) 70 (17%) 51 (13%) 3 (1%) neuropathya 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 47 (11%) 10 (2%) 20 (5%) 1 (<1%) infectionsb 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 | JUNE 25, 2014

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Director’s Corner Immune Checkpoint ­Targeting continued from page 1

experiments and identified CTLA-4 as an inhibitory checkpoint molecule, which acted to restrict activated T-cell responses. Dr. Allison then proposed blockade of CTLA-4 as a way to enhance activated T-cell responses against cancer.

In laboratory studies with an antibody to CTLA-4, Dr. Allison found that 90% of cancers in treated mice disappeared. In 2011, ipillimumab (Yervoy), an antibody to human CTLA-4, proved successful in human clinical trials in the treatment of melanoma and was approved by the U.S. Food and Drug Administration as standard therapy for patients with metastatic melanoma.

While statistics show that about 20% of patients with late-stage melanoma who took ipilimumab in clinical trials have lived 5 years or longer, Dr. Allison said that recent studies actually show prolonged immune response and longer overall survival in some patients. “That tail of the survival curve appears to be quite durable,” said Dr. Allison.

Today, immune checkpoint targeting in which the immune system is used to destroy cancer has become the new paradigm for cancer treatment and is a major component of MD Anderson Cancer Center’s “Moon Shots” program, an ambitious endeavor to reduce cancer deaths over the next decade. In an interview with The ASCO Post, Ronald DePinho, MD, President of MD Anderson Cancer Center, cited Dr. Allison’s research with helping to achieve that goal. “Thanks to the work of many, particularly Jim Allison’s, there is a solid likelihood that we will reach our goal of reducing mortality from advanced melanoma by at least 50% in the next 5 to 10 years,” said Dr. DePinho. (See “Conversation With Ronald DePinho, MD,” in the May 15, 2014, issue of The ASCO Post.)

Dr. Allison has been recognized for his contribution to 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.

This year, Dr. Allison was the recipient of the Szent-Györgyi Prize, the Canada Gairdner International Award, and the American Association for Cancer Research GHA Clowes Memorial Award.

The ASCO Post talked with Dr. Allison about the Moon Shots program and the

Ronald DePinho, MD

role of the Immunotherapy Platform to achieve its goals, the promise of immune checkpoint targeting in a variety of cancers, and his unforgettable one-night gig playing harmonica with Willie Nelson.

Immunotherapy Platform Components Please talk about the goals of the Immunotherapy Platform in MD Anderson’s Moon Shots program.

The whole purpose of the immunotherapy platform is to perform in-depth immune monitoring studies, including immunopathology analyses, in the context of patient samples obtained from clinical trials of immunotherapeutic drugs such as anti–CTLA-4 and anti– PD-1 agents. Data from these studies will generate hypotheses regarding mechanisms that contribute to tumor rejection, which can be tested in preclinical models. Studies in preclinical models provide data to help in the development of novel immunotherapy strategies to hopefully benefit even more patients with cancer.

We tried to put together a unified array of experimental approaches to understand—on the cellular and molecular level—the consequences of giving drugs that impact the human immune system. The goal of that is to guide the development of treatment combinations to increase therapeutic efficacy.

We knew, for example, that CTLA-4 blockade and PD-1 blockade impacted antitumor immune responses differently in preclinical models, which indicated that combined blockade of CTLA-4 and PD-1 may be beneficial clinically.

The immunologic monitoring component is tasked with performing cytometry techniques to define different subsets of cells within the immune system and to perform functional studies on selected subsets. But this component also takes that process a step further, using expression arrays and NanoString technology to get an idea on the message level of the changes in specific cells, such as T cells. We are currently in the process of setting up a system to do mass cytometry analysis as well.

The second component is molecular pathology. We wanted to do very spe-

cialized immunopathology, not diseasebased pathology, because it’s becoming apparent that there are multiple immune inhibitory pathway checkpoints, and the expression of these inhibitory molecules (such as PD-1 or LAG-3 on T cells and B7-H3 or B7-H4 on tumor cells) may be clues as to what combination treatments need to be considered for eliciting effective antitumor immune responses.

We also want to look for patterns of expression of different immunologic molecules in the different types of cancer. We want to know whether there are specific patterns associated with certain types of cancer or whether any patterns are random. Also, we want to know how treatment changes the tumor micro­ environment.

The third component—the preclinical studies part—is meant to achieve two goals. One is to determine the impact of different agents, such as targeted therapies and chemotherapies, on the immune system. The second is to test hypotheses that are generated as a result of data obtained from the immune monitoring studies performed in the context of the different clinical trials, as previously mentioned.

Can you offer an example of the preclinical studies component?

My colleague, Padmanee Sharma, MD, PhD [Scientific Director of the Immunotherapy Platform], noticed in one of her presurgical trials that there was a great amplification of a kind of T cell (CD4-positive/ICOS-high) that expresses a molecule called ICOS (inducible T-cell costimulator). Dr. Sharma designed a presurgical study to treat 12 localized bladder cancer patients with anti–CTLA-4 to evaluate the impact of anti–CTLA-4 on human immune responses in both peripheral blood and tumor samples obtained from scheduled surgeries that removed the patients’ bladders.1 The purpose of the study was to obtain data regarding human immune responses after treatment with anti–CTLA-4 and, most importantly, to understand the impact of the drug on the immune responses with the tumor microenvironment.

In her study, Dr. Sharma found that these ICOS-positive cells can act as effector T cells, which produce the Th1 cytokine interferon-gamma. In collaboration with Dr. Sharma, we found that melanoma patients who had sustained levels of ICOS-positive cells had longer survival rates than patients without sustained levels of CD4-positive/ ICOS-high T cells. This raises the pos-

sibility that ICOS-positive cells might be important in the therapeutic effects of anti–CTLA-4 agents.

To test that hypothesis, Dr. Sharma studied ICOS or its ligand (ICOSL) in mouse models treated with CTLA-4 and found that the treatment was much less effective in mice that lack either ICOS or ICOSL.2 These data raised the possibility that targeting ICOS might enhance the efficacy of anti–CTLA-4, which we recently showed to be the case.

These types of studies that combine expertise in clinical trials, translational research, and basic science form the foundation of the Immunotherapy Platform. We are taking an integrated scientific approach to really understand what is going on in the immune system and tumor microenvironment and see if we can gain insight into biomarkers and new targets. We are also working with several drug manufacturers to develop immunology-based therapies and study them in both preclinical models and clinical trials.

Clinical Trials As part of the Immunotherapy Platform initiative you are launching clinical trials in melanoma, breast, lung, colon, and pancreatic cancers. What is the goal of those studies?

To determine whether the blockade of CTLA-4 or PD-1, or both, is efficacious in all those tumor types. That’s one goal. Another goal is to investigate the combination of an immunotherapy with other drugs, such as a tyrosine kinase inhibitor, or treatment modalities, such as radiation therapy.

Role of Ipilimumab Ipilimumab is effective in about onequarter of patients with late-stage melanoma. Do you know why the drug works really well in some patients and not in others?

One possibility is that there are multiple checkpoint molecules in melanoma, so some patients who do not respond to ipilimumab do respond to nivolumab, an investigational anti–PD-1 antibody, and vice versa. For patients who don’t respond to either agent alone, combining the two drugs might be more effective. A study presented at last year’s ASCO Annual Meeting found that patients with advanced melanoma who were treated with a combination of ipilimumab and nivolumab had a nearly 50% response rate.3 Some melanoma patients have very long, durable responses. While “cure” is a loaded term, I know a patient from an early phase I trial of ipilimumab who has been in remission for almost 14 years after just a single injection. Is she

ASCOPost.com | JUNE 25, 2014

PAGE 51

Director’s Corner

cured? I don’t know, but she thinks she is cured. Another melanoma patient, while not in complete remission, has had stable disease for 9 years without subsequent treatment and has had two children during that time.

Since ipilimumab treats the immune system rather than the tumor directly, it is also showing effectiveness in the treatment of other cancers, including prostate, renal, and some lung cancers.

We also have anecdotal evidence that the drug may work in ovarian and pancreatic cancers, but we have to do the clinical trials.

stage, accompanying him on “Blue Eyes Crying in the Rain.” It was only that one song and that one night, but I’ll never forget it. n

Disclosure: Dr. Allison is an inventor of intellectual property owned by the University of California, Berkeley, and licensed to BristolMeyers Squibb, and is the recipient of royalties.

He is also a founder and member of the Scientific Advisory Board of Jounce Therapeutics.

References 1. Carthon BC, Wolchok JD, Yuan J, et al: Preoperative CTLA-4 blockage: Tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res 16:2861-2871, 2010.

2. Fu T, He Q, Sharma P: The ICOS/ ICOSL pathway is required for optimal antitumor responses mediated by anti-CT-

LA-4 therapy. Cancer Res 71:5445-5454, 2011.

3. 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 3, 2013.

Long-Term Goal What is the long-term promise of immune checkpoint targeting in cancer therapy? To increase durable remissions?

Yes, that’s the goal. To be slightly controversial, I think the goal of cancer clinical trials should not be to get an increase in median survival of just a few months.

We know we can do much better than that with both anti–CTLA-4 and anti– PD-1 therapies since they can provide durable antitumor responses. I think we have to focus on how to increase the durable effect of cancer therapies, and it’s going to require some thinking about how to combine immunotherapies with other agents to improve durable antitumor responses. We also need to consider what endpoints need to be evaluated for a drug or drug combination to become approved, because we can’t take a lot of years to test all the combinations for survival ­benefit.

The bigger point becomes, if you have a therapy or combination strategy that is showing objective responses in a phase I trial, there has to be an acceptable way of shortening the study process, so that the drugs can get to patients faster.

Musical Sidelight In 1975, during your postdoctoral fellowship at Scripps Clinic and Research Foundation, you found yourself on stage playing harmonica with country legend Willie Nelson. Was that experience as exciting as the research you were doing?

Oh, yes. I had been a Willie Nelson fan for years—and I still am. For a couple of years, I had played harmonica with Clay Baker and the Texas Honky Tonk Band at the Stingaree bar in San Diego. I got an invitation to a party Willie’s record label was throwing to celebrate the sale of over a million copies of his hit album The Red Headed Stranger. When Willie asked me where he could play some music the next night, I suggested Stingaree. I joined Willie on

Julie M. Vose, MD President-Elect

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Allen S. Lichter, MD

ASCO Chief Executive Officer

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PAGE 52

Inside the Black Box FDA Approval of Siltuximab for Multicentric Castleman’s Disease

A Conversation With Albert Deisseroth, MD, PhD INSIDE THE BLACK BOX is an occasional column providing insight into the FDA and its policies and procedures.

In this installment, FDA hematologist/oncologist Albert Deisseroth, MD, PhD, discusses the recent approval of siltuximab for patients with multicentric Castleman’s disease who are human immunodeficiency virus (HIV)– and human herpesvirus-8 (HHV-8)–negative. Dr. Deisseroth is a Clinical Team Leader in the Division of Hematology Products, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research.

resembles multicentric Castleman’s disease. Treatment of these mice with an antibody to the IL-6 receptor reduces the severity of the multicentric Castleman’s disease–like disease.

Siltuximab is a human-mouse chimeric IgG1 monoclonal antibody that binds human IL-6, thereby preventing its interaction with the IL-6 receptor.

A phase I study of siltuximab in 37 patients with Castleman’s disease demonstrated one complete and eight partial responses in patients treated with the 11 mg/kg dose.

FDA Clinical Reviewer

Albert Deisseroth, MD, PhD

Study Design

O

n April 22, 2014, the U.S. Food and Drug Administration (FDA) approved the interleukin-6 (IL-6) antagonist siltuximab (Sylvant) for the treatment of patients with multicentric Castleman’s disease who are HIV-negative and HHV-8–negative. The ASCO Post spoke to Dr. Deisseroth about this uncommon lymphoproliferative disorder and the trial that led to siltuximab’s approval.

Rare Disorder What is Castleman’s disease, and what are its clinical manifestations?

Castleman’s disease, also known as angiofollicular lymph node hyperplasia, is a very rare disorder characterized by hyperplasia of lymphoid tissue that results in lymphadenopathy (unicentric or multicentric) and is often associated with HIV and HHV8 infections. The lymphadenopathy is associated with symptoms of fatigue, fever, weakness, day or night sweats, anorexia, pruritus, pain, and/ or dyspnea. In addition, patients with Castleman’s disease have physical findings of weight loss, fluid retention, edema, effusions, ascites, neuropathy, skin rashes, skin nodules, anemia, and/or splenomegaly and hepatomegaly.

There are three different histopathologic variants: the plasmacytic variant, the hyaline vascular variant, and the mixed subtype. Castleman’s disease, especially the hyaline vascular form, has been reported to progress into a clonal proliferation of lymphocytes and may evolve into non-Hodgkin lymphoma.

Treatment Options What therapies are available to treat patients with multicentric Castleman’s disease?

Prior to siltuximab’s approval, there were no approved therapies in the United States for multicentric Castleman’s disease. Palliative treatment with chemotherapy and steroids has been tried. Rituximab (Rituxan) has been used in multicentric Castleman’s

What were the most important design features of the trial used to support marketing approval of siltuximab?

The randomized placebo-controlled trial of siltuximab enrolled patients with multicentric Castleman’s disease and excluded patients with known HIV or HHV-8 infections. A total of 79 men and women with symptomatic and measurable multicentric Castleman’s disease were allocated (2:1) to best supportive care with sil-

This is the first treatment approved by the FDA for this very rare disease and the first approval of an anti-IL-6 antibody in the United States.

—Albert Deisseroth, MD, PhD

disease alone and in combination with chemotherapy (eg, liposomal doxorubicin). Initial responses occur but may be followed by relapse and progression of disease.

There have been case reports of responses to bortezomib (Velcade), thalidomide (Thalomid), and the thalidomide/rituximab combination.

Autologous bone marrow transplantation following high-dose chemotherapy has also been tried.

Underlying Mechanism What is the rationale for testing siltuximab in multicentric Castleman’s disease?

Excessive secretion of IL-6 is thought to play a role in the generation of the signs and symptoms of the disease. Transgenic mice with the human IL-6 gene have high levels of IL-6 from birth and develop a disease that

tuximab (n = 53) or to best supportive care with placebo (n = 26).

Patients were treated with siltuximab at 11 mg/kg or placebo intravenously every 3 weeks until treatment failure, discontinuation of treatment, withdrawal from the study, or 48 weeks after the last subject started study treatment. Patients who met the criteria for treatment failure were allowed to cross over from the placebo arm to the siltuximab arm. The primary endpoint of the trial was the proportion of patients in each arm achieving a durable tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure.

One of the most interesting parts of the clinical trial design was the definition of the primary endpoint: a composite of tumor response (reduction of lymphadenopathy on computed tomg-

raphy [CT] scans by independent review), response as measured by clinician-reported severity of symptoms, and response as measured by physical signs of the disease as reported by the investigator.

Tumor response was defined as a complete or partial response of the lymph node masses as assessed by independent review of CT scans using the International Working Group response criteria for malignant lymphoma. Symptomatic response was defined as complete resolution or stabilization of 34 Castleman’s disease– related signs and symptoms as defined by the multicentric Castleman’s disease–related overall symptom score.

This score was calculated as the sum of the investigator-determined severity (NCI-CTCAE) grades of the multicentric Castleman’s disease–related signs and symptoms. The percentage change from baseline was calculated at the beginning of each cycle of therapy.

If the difference of the primary endpoint (proportion of patients achieving a durable tumor and symptomatic response) on each arm achieved statistical significance, the following secondary endpoints were analyzed in a fixed order: tumor response by central review, time to treatment failure, the percentage of patients on each arm in whom the hemoglobin level increased ≥ 1.5 g/dL over baseline at week 13, the median time to improvement in the Multicentric Castleman’s Disease Symptom Scale (as reported by patients), the median time to improvement in the Functional Assessment of Chronic Illness Therapy–Fatigue score, and the proportion of patients

ASCOPost.com | JUNE 25, 2014

PAGE 53

Inside the Black Box who were corticosteroid-free for at least 9 consecutive weeks during the blinded treatment period.

Why were patients with HIV or HHV8 infections excluded from the trial?

Siltuximab was not studied in this patient population because the drug did not bind to virally produced IL-6 in a nonclinical study.

among 18 patients in the hyaline vascular subset, 8 responses among 13 patients in the plasmacytic subset, and 10 responses among 22 patients in the mixed subsets. The median duration of response was 383 days.

The results of three of the six secondary endpoints were statistically significant. The percentage of patients on the siltuximab and placebo arms with a partial response or better was 38% and 4%, respectively. With 424 days of follow-up, the time to treatment failure was not reached on the siltuximab arm and was 134 days on the placebo arm. For the hyaline vascular subset, the time to treatment failure was 206 days on the siltuximab arm and 70 days on the placebo arm.

Approximately 61% of patients treated with siltuximab experienced an increase in hemoglobin ≥ 1.5g/dL at 13 weeks, whereas no patient on the placebo arm did. Additionally, 17% of patients in the hyaline vascular subset experienced an increase in hemoglobin level ≥ 1.5 g/dL at 13 weeks of treatment with siltuximab, compared to none on the placebo arm.

Key Findings

Adverse Events

What were the results of the trial?

The durable tumor and symptom response rate was 34% on the siltuximab arm compared to no response on the placebo arm, a result that was statistically and clinically significant.

This difference was seen across all subsets except for subsets defined by histopathology. There were no responses

What were the safety issues?

The most common adverse reactions (> 10% compared to placebo) with siltuximab in the randomized trial were pruritis, increased weight, rash, hyperuricemia, and upper respiratory tract infection.

Overall, about 750 patients have been treated with siltuximab. One pa-

Baseline Data What were the disease and demographic characteristics of patients enrolled on the trial?

Only patients with multicentric Castleman’s disease were eligible. Of all patients enrolled, 33% had the hyaline vascular subtype, 23% had the plasmacytic subtype, and 44% had the mixed subtype. About 19% had one to three symptoms of multicentric Castleman’s disease prior to initiation of therapy, 81% had four or more symptoms, and 58% had received at least one prior treatment. As mentioned before, patients positive for HIV or HHV-8 infection were excluded.

tient was reported to have experienced an anaphylactic reaction. Among 249 patients treated with siltuximab monotherapy, infusion reactions were reported in 4.8%.

The median number of completed infusions was more than double in the siltuximab group (19 infusions) compared with the placebo group (8 infusions). The median duration of treatment was 375 days in the siltuximab arm and 152 days in the placebo arm.

There were no adverse events leading to death, and the percentage of patients who discontinued treatment due to adverse events was 23% on the siltuximab arm and 39% on the placebo arm.

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.

Risk-Benefit Assessment How would you characterize the risks and potential benefits of siltuximab for multicentric Castleman’s disease?

Multicentric Castleman’s disease is a disease of lymphadenopathy accompanied by signs and symptoms associated with elevated levels of IL-6. Infusions of siltuximab are well tolerated, and many patients remain on therapy for years. There is no other FDA-approved therapy for patients with multicentric Castleman’s disease, and for patients with multicentric Castleman’s disease and no HIV or HHV-8 infection, siltuximab provides symptomatic relief to a substantial number of patients with acceptable toxicity.

Closing Thoughts What are your concluding thoughts

about the approval of siltuximab for multicentric Castleman’s disease?

There are several notable features of the FDA approval of siltuximab for multicentric Castleman’s disease. This is the first treatment FDA-approved for this very rare disease and the first approval of an anti-IL-6 antibody in the U. S. In addition, the treatment targets the basic pathophysiologic mechanism of the disease. Despite the rarity of the disease and the many hurdles that had to be overcome in launching this global randomized trial, sufficient numbers of patients were enrolled and the trial met its prespecified primary endpoint as well as three secondary endpoints. n Disclosure: Dr. Deisseroth reported no potential conflicts of interest.

FDA Update

FDA Approves Radioactive Diagnostic Imaging Agent to Help Determine the Extent of Head and Neck Cancer in the Body

T

he U.S. Food and Drug Administration has approved a new use for technetium 99m tilmanocept (Lymphoseek Injection), a radioactive diagnostic imaging agent used to help doctors determine the extent to which squamous cell carcinoma has spread in the body’s head and neck region.

In 2013, tilmanocept was approved to help identify lymph nodes closest to a primary tumor in patients with breast cancer or melanoma. With today’s approval, the agent may now be used to guide sentinel lymph node biopsy in patients with cancer of the head and

neck. This new indication will allow for the option of more limited lymph node surgery in patients with sentinel nodes negative for cancer.

“For some patients with head and

Marzella, MD, PhD, Director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research. “To use [tilmanocept], doctors inject the drug into the tumor area and later, using a handheld radiation detector, find the sentinel lymph nodes that have taken up [tilmanocept]’s radioactivity.”

Clinical Trial Results neck cancer, removal and pathological examination of lymph nodes draining a primary tumor is an important diagnostic evaluation,” said Libero

For this new indication, tilmanocept’s safety and effectiveness were established in a clinical trial of 85 patients with squamous cell carcinoma

of the lip, oral cavity, and skin. All patients were injected with tilmanocept. Surgeons subsequently removed suspected lymph nodes—those identified by the imaging agent and those based upon tumor location and surgical practice—for pathologic examination. Results showed that tilmanocept–guided sentinel lymph node biopsy accurately determined if the cancer had spread through the lymphatic system.

The most common side effect identified in the clinical trial was pain or irritation at the injection site. n

The ASCO Post | JUNE 25, 2014

PAGE 56

Direct From ASCO

Conquering Cancer With 2013 Career Development Award Recipient Rebecca A. Gardner, MD

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ebecca A. Gardner, MD is an Assistant Professor at the University of Washington and Attending Physician at Seattle Children’s Hospital. She received a 2013 Conquer Cancer Foundation

Rebecca A. Gardner, MD

of ASCO Career Development Award (CDA) for her project “Autologous T cells genetically modified to express a CD19 specific chimeric antigen receptor to treat pediatric relapsed acute lymphoblastic leukemia.” She was also named Geek of the Year in 2012 by GeekWire, an independent technology news site based in Seattle, Washington. Read more about Dr. Gardner’s Geek of the Year award at www. geekwire.com/2012/geek-week-dr-rebecca-gardner-reprogramming-cancer/ ASCO recently spoke with Dr. Gardner about the impact of the Career Development Award on her research.

Career Development Award What is the focus of your research?

The focus of my research is developing

clinical trials where we use T-cell therapy to treat pediatric leukemia.

Describe your 2013 Career Development Award (CDA) research project.

The CDA provides support for me to conduct two clinical trials for patients with recurrent acute lymphoblastic leukemia (ALL). The first trial is for patients who have recurrent disease and have never made it to a stem cell transplant and the second trial is for patients whose disease recurs after their stem cell transplant.

Does your research have any direct or future impact on patient care?

The really exciting thing about this research is that it has direct impact on patient care right now! We’re taking patients who have no other treatment options and offering them a chance at a new therapy.

Our preliminary results are very promising. Several patients who are refractory to other therapies have gone into remission after they received the T cells. When we look ahead, I think this research is going to change the way we treat not only leukemia but also other types of cancer. I really hope we’re able to make this paradigm shift where we rely less on chemotherapy and radiation and more on targeted therapy.

What impact did your grant have on your career and your ability to pursue your research?

Congress Salutes ASCO’s 50th Anniversary on House Floor

O

n May 8, 2014, the House of Representatives held a Special Order in honor of ASCO as it celebrates its 50th anniversary. Representatives Leonard Lance (R-NJ), Brian Higgins (DNY), Chuck Fleischmann (R-TN), and Sheila Jackson Lee (D-TX) spoke during the Special Order, which took place on the House Floor following the close of the legislative session. House Members applauded oncologists for their commitment to cancer patients and several spoke to the impact of ASCO’s work on driving progress and innovation in cancer care over the last 50 years.

“When ASCO was founded cancer was widely regarded as an untreatable disease with fewer than one half of patients alive five years after diagnosis,” said Rep. Lance. “Because of the work of passionate advocates and tireless champions, and of

the expertise of talented medical professionals, including those at the American Society of Clinical Oncology, today the survival rate is higher than two thirds.”

Speakers also addressed key challenges in oncology today including prevention and federal funding for research and encouraged fellow members to support actions

that would spur progress in cancer care and drive future advancements. Watch the Special Order CSPAN clip at www. asco.org/advocacy/house-special-orderhonors-asco’s-mid-century-anniversary. n © 2014. American Society of Clinical Oncology. All rights reserved.

It’s very important! Basically the CDA grant allows me to have protected time to actually be doing this research which otherwise would be very difficult to find the time to do. It allows me to focus my professional effort on taking care of the patients on these clinical trials.

Adoptive T-Cell Therapy What is the purpose of T cells and how does modifying these T cells to express a chimeric antigen receptor (CAR) help patients with ALL? T cells are one of the more important types of cells in your immune system. We extract the T cells from the patient, modify them in the lab with a gene to express this new type of receptor, then we then grow the cells in the lab, and finally, reinfuse the T cells back into the patient. T cells are a “living therapy” so once you modify the T cells and give them back to the patient, they should be capable of reproducing.

After you give one dose of T cells, hopefully those T cells get rid of the cancer cells that are present at that time and also stick around to survey and prevent a recurrence if the leukemia were to come back.

Are there any negative side effects of adoptive T-cell therapy?

The most common negative side effects are typical of those seen with a cold or flu virus, such as fever, body aches, and chills. The patients typically recover within

a few days. We’re not sure about long-term effects of T-cell therapy yet.

How do you determine if the treatment is successful?

We monitor patients by their peripheral blood and bone marrow to see if we can (1) detect the T cells that we gave the patient and (2) detect the presence of any remaining leukemia cells. The measures of success include being able to make a T-cell product for a patient, being able to detect the T cells in the patient after we infuse them, and then hopefully having patients go into remission.

Learning From Young Patients How does helping children with cancer motivate you?

Children don’t complain. One minute they feel really awful from chemotherapy or their treatment and the next minute they’re like “Hey, I’m going to go ride my bike.” It’s that resilient spirit that they have that really motivates me to keep doing this.

And I think everyone in pediatric oncology is here because we don’t want to see kids diagnosed with or suffering from cancer.

What’s the most extraordinary response you’ve seen in your years as a pediatric oncologist?

This clinical study that I’m doing has led to the most impactful moment that I’ve continued on page 57

Cancer Organizations Honor Congressmen for Cancer Research Advocacy

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SCO joined three other organizations on May 7 to honor U.S. Senator Tom Harkin (D-IA) and Representative Charlie Dent (R-PA) for their support of cancer research. With the American Association for Cancer Re-

search, Association of American Cancer Institutes, and Friends of Cancer Research, ASCO lauded the lawmakers’ leadership on supporting the nation’s investment in biomedical research.

Both members of Congress said the work of ASCO and its members has been important in continuing to support

federal funding for cancer research. Read their comments at www.asco.org/advocacy/cancer-organizations-honor-senharkin-and-rep-dent-research-advocacy The awards program was held the day before a cancer research advocacy day during which scientists, clinicians, and research advocates spoke to members of Congress and staff about how the federal investment in research sustains progress in the fight against cancer and provides economic benefits for the nation. The cancer organizations are advocating for at least $32 billion in federal funding for the National Institutes of Health for fiscal year 2015. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | JUNE 25, 2014

PAGE 57

Direct From ASCO Rebecca A. Gardner, MD continued from page 56

had in my career so far. The first patient that enrolled on our study had refractory leukemia and wasn’t responsive to chemotherapy. We gave her the T-cell therapy and

quer Cancer Foundation Grants and Awards program to support programs like the CDA? Research funding right now is so tight, and one of the things that moves the oncology field forward is research and innovation. The Conquer Cancer Foundation Grants and Awards program, particularly the CDA, really enables young investigators to have that protected time

to jumpstart their career. Without young investigators getting into research, it’s really hard to move research, diagnosis, and therapies forward.

Is there any message you’d like to pass on to our donors?

It’s always important to know when you’re donating your money that it is making a difference and that it is being used

a week later we couldn’t find any detectable leukemia at all. To me that was like “Wow!” You do all this planning and you have these ideas about how things are going to work, but you don’t know it’s going to work until you try it. And then you try it and it works beyond your best expectations. It’s just really amazing! She is 9 months out from therapy now and still disease-free.

wisely. You want to make sure it is going to something meaningful. The Conquer Cancer Foundation Grants and Awards program is really meaningful in terms of allowing physicians to do impactful research. n © 2014. American Society of Clinical Oncology. All rights reserved.

We Will

Watching children in this realm, what have they taught you?

It puts life in perspective. When bad things happen, you have to ask yourself, “Is it really that bad or is it just an annoyance?” Watching families with a child who has cancer, it makes you really grateful for everything you have in your own life.

exhaust all possibilities.

Message to Donors Why should people donate to the Con-

Help Your Patients Catch Up on the Latest Research From the 2014 ASCO Annual Meeting

D

irect your patients to www.cancer .net/blog for podcasts with ASCO experts discussing the research that was presented at the 2014 ASCO Annual Meeting. This series of “Research Round Up” podcasts provides the latest information on treatment and care for people with cancer and will help your patients understand how it affects them. These podcasts will continue throughout the summer and cover new research on several different types of cancer. n

© 2014. American Society of Clinical Oncology. All rights reserved.

We will…because patients are our priority.

Celgene Patient Support ® provides free and personalized assistance with patients’ access and reimbursement needs.

With continual communication and consistent follow-through, your dedicated Celgene Patient Support ® Specialist will streamline access to Celgene products by helping you and your patients with: • Benefits investigation

To Contact Celgene Patient Support®:

• Prior authorization

Call: 1-800-931-8691

• Appeal support

E-mail: patientsupport@celgene.com

• Medicare

Fax: 1-800-822-2496

• Co-pay assistance – Celgene Commercial Co-pay Program – Co-pay assistance through third-party organizations

Visit: www.CelgenePatientSupport.com Monday through Friday, 8:00 am to 7:00 pm ET

• Prescription status • Celgene free medication program • Celgene products and restricted distribution programs 4 out of 5 patients who requested assistance from Celgene Patient Support ® received their medication.

Celgene Patient Support® is a registered trademark of Celgene Corporation. © 2013 Celgene Corporation 09/13 US-CELG110059(1)

The ASCO Post | JUNE 25, 2014

PAGE 58

Direct From ASCO

ASCO’s Patient Information Website, Cancer.Net, Undergoes Redesign

A

SCO is committed to providing people with cancer and their caregivers with top quality educational information and resources to help them manage their cancer care, treatment, and survivorship.

This ongoing commitment is best reflected in its patient-facing educational website, Cancer.Net (www.cancer.net), which has just completed its latest redesign.

“The redesign continues to provide visitors with all of the same great information

Robert S. Miller, MD, FACP

that has always been available on Cancer.

Net, but it makes navigating the site easier and makes information more accessible to patients and the general audience,” said Robert S. Miller, MD, FACP, editor-inchief of the website. “The redesign now features our content in a way that will make people want to keep coming back to the site, and cements Cancer.Net’s reputation as one of the definitive sources for cancer information.”

New Blog Platform The website, which was originally launched in 2002, underwent its last redesign in 2009. Oncologists are no strangers

to the amount of change and innovation that can take place in 5 years in the cancer research arena and the same is true when it comes to online innovation, including the explosion of social media.

One of the first components to the website redesign was the launch of the Cancer.Net Blog in December. According to Dr. Miller, the blog was designed as a way to communicate important and relevant information to patients and caregivers in a timely and responsive manner.

Guided by Anas Younes, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, the blog features a wide variety of content including updates on cancer research, interviews with health-care professionals, and focused posts and podcasts discussing topics that are important to patients and caregivers.

Blog authors include ASCO members, survivors, patient advocates. In addition, there is a Comments section that will encourage community dialogue on each entry. Patients can subscribe to the Cancer.Net blog at www.cancer.net/blog “ASCO and Cancer.Net have recognized that patients are heavily involved in social media, and in order to remain relevant in terms of patient education, we have to be in that space as well,” said Dr. Miller, who is a Clinical Associate in the Breast Cancer Program at the Johns Hopkins University School of Medicine, Department of Oncology. He is also Oncology Medical Information Officer and Epic Physician Champion at the Sidney Kimmel Comprehensive Cancer Center.

Other Social Media Channels The blog is one part of Cancer.Net’s efforts to more easily engage with patients and others looking for cancer information online. During the last few years, ASCO as a whole has become very active on Twitter and Facebook. As part of this comprehensive effort, Cancer.Net’s social media channels are aimed specifically at the patient/survivor community and the public at large.

These channels offer a simple way for patients to stay up to date with new information and resources as they become available on Cancer.Net, or ask questions and provide feedback. Now instead of seeking out information through an often time-consuming search, patients can have information pushed out to them via social media. Patients can follow the website on Facebook (www.facebook.com/ CancerDotNet), Google+ (plus.google. com), YouTube (www.youtube.com/ CancerDotNet), and at CancerDotNet on Twitter (www.twitter.com/ CancerDotNet).

Highlighting Spanish Content The redesign of Cancer.Net also incorporated improvements to the delivery of Spanish language content available on the website.

Spanish language patient information

was first made available in 2005, with the amount of translated content growing each year. In 2013, Cancer.Net’s awardwinning app also became available in Spanish. With the website redesign, there is a toggle feature to switch between English and Spanish on each webpage where Spanish content is available. In addition, Cancer.Net has a Spanish version of its homepage for the first time. All of the information presented in Spanish goes through professional translation so that patients can be assured that the information is reliable and accurate.

Intuitive, Visually Appealing Design Finally, the most recent component of continued on page 59

The 2014 Conquer Cancer Foundation Grants and Awards

Promising Researchers Receive More Than $5 Million in Grants and Awards

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he Conquer Cancer Foundation of ASCO presented more than $5 million in grants and awards to more than 250 promising oncology researchers at the 2014 ASCO Annual Meeting, held May 30 to June 3 in Chicago, Illinois. The Conquer Cancer Foundation and ASCO congratulate the 2014 grant and award recipients on their contributions to the field of oncology and offer their profound thanks to all the generous organizations that supported these awards.

The Foundation is proud to provide funding opportunities for oncology professionals at various stages in their careers across the globe through the Grants and Awards Program. The awards that were presented at the Annual Meeting include: • Eight Medical Student Rotation Awards (MSR) for Underrepre-

sented Populations • Nine Resident Travel Awards (RTA) for Underrepresented Populations • 50 Young Investigator Awards (YIA), a 1-year grant of $50,000 that provides funding to promising investigators to encourage and promote quality research in clinical oncology.

• Nine Career Development Awards (CDA), a 3-year, $200,000 grant that provides funding to clinical investigators who have received their initial faculty appointment to establish an independent clinical cancer research program • One Advanced Clinical Research Award in Breast Cancer (ACRA), a 3-year, $450,000 grant that funds investigators who are in their fourth to ninth year of faculty appointment,

and who are committed to clinical cancer research in an area not currently funded. Vandana Abramson, MD, of Vanderbilt University Medical Center received the award for her project “Developing targeted therapies for triple negative breast cancer”.

• 23 International Development and Education Awards (IDEA) and six International Development and Education Awards in Palliative Care (IDEAPC) to young oncologists from low and middle-income countries • Three Long-Term International Fellowships (LIFe) to early-career oncologists from Armenia, China, and Brazil.

• 103 Merit Awards including four Special Merit Awards in recognition of high-quality abstracts sub-

mitted to the Annual Meeting • Nine Clinical Trials Participation Awards (CTPA) to community-based practices in recognition of their outstanding efforts to increase awareness of and participation in clinical trials.

• 36 Oncology Trainee Travel Awards For the complete list of grant and award recipients, visit www.conquercancerfoundation.org/awardrecipients and conquercancerfoundation.org/ grantrecipients.

Donate today at www.conquercancerfoundation.org/donate to help the Conquer Cancer Foundation accelerate breakthroughs, launch careers, and improve cancer care. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | JUNE 25, 2014

PAGE 59

Direct From ASCO Cancer.Net’s Redesign continued from page 58

the redesign is updating the visual appearance of the website.

“We redesigned Cancer.Net to give it a uniformity of visual appearance with other ASCO websites,” Dr. Miller said.

The website’s home page has been fully updated and streamlined in line with the latest knowledge in the field of website usability and user preferences. The structure of the website has also gone through a comprehensive review, to make Cancer.

Net’s vast amount of content easier to find with fewer links for site visitors.

Together, these design changes make the website easier to use and navigate, and will get people to the information they are seeking quicker. In addition, multimedia components—including Cancer.Net vid-

eos and podcasts—are more easily integrated into written articles thanks to the redesign.

Cancer.Net’s redesign will not affect its popular content, all of which is reviewed and approved by the site’s 150-member editorial board. For instance, patients will still have access to the Types of Cancer section that includes comprehensive information such as risk factors, symptoms, diagnosis and treatment on 124 different types of cancer and related syndromes.

Patients and caregivers will also still be able to take advantage of the website’s Find a Cancer Doctor database, a very popular feature of the site. This database includes the names of ASCO members who have agreed to be identified publicly. With the redesign, website users will now have

Videos Tell Stories of 50 Years of Progress Against Cancer

N

early 3 years ago, ASCO launched CancerProgress.Net to mark the 40th anniversary of the signing of the U.S. National Cancer Act, which led to major new investments in cancer research and significant increases in cancer survival.

The site provides a dynamic and interactive history of progress against cancer and expert perspective on future of care.

In honor of the Society’s anniversary, the site features numerous stories about ASCO’s evolution, an upgraded timeline of advances in cancer, aggregated news and views on ASCO’s anniversary and progress, social media features, and an opportunity to vote on the most significant milestones in the field.

Interviews With Oncology Luminaries Videos on the site feature past ASCO presidents and other oncology luminaries discussing the founding of ASCO, the early days of cancer treatment, and the notable changes that have occurred since then— both in the care of people with cancer and in our understanding of the disease. Those

interviewed include ASCO Immediate Past President Clifford A. Hudis, MD, FACP; Emil J Freireich, MD; Vincent T. DeVita, MD; George Sledge, MD; Robert C. Young, MD; Clara D. Bloomfield, MD; Samuel Hellman, MD; Karen H. Antman, MD; and George P. Canellos, MD. Patients and cancer advocates are at the front lines of progress against cancer. The site includes inspiring videos highlighting their experiences with a diagnosis of cancer and their important contributions to clinical research.

In a third set of interviews, editors of the site’s Cancer Progress Timeline and ASCO’s Blueprint and Clinical Cancer Advances reports, among others, discuss progress, the importance of clinical trials, and recommendations for transforming the nation’s research system to deliver more effective and personalized cancer therapies, faster. Some of those interviewed include Bruce J. Roth, MD; Neal Meropol, MD; Ghassan Abou-Alfa, MD; Sonali Smith, MD; Lidia Schapira, MD; Carolyn Runowicz, MD; Derek Raghavan, MD; and Jennifer Obel, MD. Watch the CancerProgress.Net videos at www.cancerprogress.net/ stories/history-cancer-care n © 2014. American Society of Clinical Oncology. All rights reserved.

greater access to this important feature because the Find a Cancer Doctor option is highlighted prominently on the home page and is included in the footer area of each page within the site.

An ‘Information Prescription’ People who find themselves suddenly immersed in the world of cancer— whether it is as a patient or caregiver— frequently turn to the Internet, which is overflowing with information about the disease, including many questionable or outright fraudulent sites. Faced with such a wide array of information sources, it can often be difficult to sort out quality information.

For this reason, it is important that ASCO members encourage patients to take advantage of the valuable information

Volume 7, Issue 3

May 2011

Journal of oncology Practice

available on Cancer.Net. The site brings the expertise and resources of ASCO to people living with cancer and those who care for and about them.

“Oncologists cannot provide patients with all the information they might need in the context of a single visit,” Dr. Miller said. “My vision is to see oncologists writing ‘information prescriptions’ as part of the same visit where they might give patients a prescription for a nausea drug.”

Patients will always have questions, Dr. Miller said. Oncologists should encourage them to turn to Cancer.Net as the only patient resource that is part of ASCO’s trusted online offerings. n © 2014. American Society of Clinical Oncology. All rights reserved.

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by Eytan Ben-Ami, et al

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www.IMBRUVICA.com CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IMBRUVICATM is indicated for the treatment of patients with CLL who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

MANTLE CELL LYMPHOMA (MCL) IMBRUVICATM is indicated for the treatment of patients with MCL who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage – Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria).

Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

The mechanism for the bleeding events is not well understood. IMBRUVICA™ may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA™ for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA™ therapy.

At least 25% of patients with MCL and 35% 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.

Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity - Fatal and serious cases of renal failure have occurred with IMBRUVICA™ therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

Second Primary Malignancies - Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA™. Four percent of patients with MCL, had skin cancers, and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

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 – MCL: The most commonly occurring adverse reactions (≥20%) in the clinical trial were thrombocytopenia*, diarrhea (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%). *Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

IMBRUVICATM: the first-in-class covalent BTK inhibitor

DISCOVERING HOW FAR THERAPY CAN GO Encouraging response rates in previously treated CLL and MCL1 Durable responses1:

Most common adverse reactions (ARs) (≥20%)1:

• Median duration of response (DOR) not reached in CLL —Range: 5.6 to 24.2+ months • 17.5 months median duration of response (95% CI: 15.8, NR) in MCL Phase 2 MCL Trial:

open-label, multi-center, single-arm 1

100

100

80

80

60 40

ORR 58.3%

PR 58.3%

20 0

Response (%)

Response (%)

CLL Trial: open-label, multi-center 1

ORR 65.8%

60 40

PR 48.6%

20

CLL (N=48)

0

CR 17.1% MCL (N=111)

None of the patients achieved a complete response.

CLL: 95% CI (43.2, 72.4) MCL: 95% CI (56.2, 74.5) CR=complete response; ORR=overall response rate; PR=partial response.

ORR and DOR were assessed using a modified version of the International Workshop on CLL (iwCLL) criteria by an Independent Review Committee.

ORR was investigator-assessed according to the revised International Working Group (IWG) non-Hodgkin lymphoma (NHL) criteria.

The most common Grade 3 or 4 nonhematological adverse reactions (≥5%) were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. 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.

CLL: The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%).

© Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 05/14 PRC-00300

• CLL: thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%) • MCL: thrombocytopenia†, diarrhea (51%), neutropenia†, anemia†, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%)

*Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions. † Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

The most common Grade 3 or 4 non-hematological ARs (≥5%) were1:

• CLL: pneumonia (8%), hypertension (8%), atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), dehydration (6.4%), and musculoskeletal pain (6%). Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48).

These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients. Treatment-emergent Grade 3 or 4 cytopenias were reported in 35% of patients • MCL: pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111)

*Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions.

The most common Grade 3 or 4 nonhematological adverse reactions (≥ 5%) were pneumonia (8%), hypertension (8%), atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), dehydration (6.4%), and musculoskeletal pain (6%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 35% of patients.

Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48).

These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas.

Adverse reactions leading to dose reduction occurred in 13% 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.

SPECIAL POPULATIONS - Hepatic Impairment - Avoid use in patients with baseline hepatic impairment.

Reference: 1. IMBRUVICATM (ibrutinib) Prescribing Information. Pharmacyclics, Inc. 2014.

Please review the Brief Summary of full Prescribing Information on the following page.

Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules TM (ibrutinib) capsules, for oral use IMBRUVICA TM IMBRUVICA (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, See package insert for Full Prescribing Information Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) INDICATIONS AND USAGE or Neutrophils in Patients with MCL (N=111) INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have Percent of Patients (N=111) IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have Percent of Patients (N=111) received at least one prior therapy. This indication is based on overall response rate. An improvement received at least one prior therapy. This indication is based on overall response rate. An improvement All Grades (%) Grade 3 or 4 (%) in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full All Grades (%) Grade 3 or 4 (%) in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full Prescribing Information].

Platelets Decreased 57 17 Prescribing Information].

Platelets Decreased 57 17 CONTRAINDICATIONS Neutrophils Decreased 47 29 CONTRAINDICATIONS Neutrophils Decreased 47 29 None None Hemoglobin Decreased 41 9 Hemoglobin Decreased 41 9 WARNINGS AND PRECAUTIONS WARNINGS AND PRECAUTIONS * Based on laboratory measurements and adverse reactions Hemorrhage: Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher * Based on laboratory measurements and adverse reactions Hemorrhage: Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most bleeding events including bruising of any grade occurred in 48% of patients with MCL treatedTen with frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%).

560 mg daily and 63% of patients with CLL treated at 420 mg daily.

Adverse reactions leading to dose reduction occurred in 14% of patients.

560 mg daily and 63% of patients with CLL treated at 420 mg daily.

Adverse reactions leading to dose reduction occurred in 14% of patients.

The mechanism for the bleeding events is not well understood.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial The mechanism for the bleeding events is not well understood.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the therapies. setting of disease progression. therapies. setting of disease progression.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery Forty percent of patients had elevated uric acid levels on study including 13% with values above Consider the benefit-risk of the withholding least to 7 days[see pre and post-surgery of patients had elevated uric acid levels on study including 13% with values above depending upon type of IMBRUVICA surgery and for theatrisk of 3bleeding Clinical Studies (14) Forty in fullpercent 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. dependingPrescribing upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

Information].

Prescribing Information].

Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in a Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of Lymphocytic Chronic Leukemia: The data described below reflect exposure to IMBRUVICA in a Infections:patients Fatal andwith non-fatal infections occurred withhad IMBRUVICA 25%NCI of Common clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a MCL and 35% of have patients with CLL infectionstherapy.

Grade 3Atorleast greater clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common median treatment of 15.6 months.

Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for treatment duration ofduration median 15.6 months.

Terminology Criteria for Adverse (CTCAE) [See Adverse Reactions]. Monitor patients for The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, fever and infections andEvents evaluate promptly.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, fever and infections and evaluate promptly. neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 with MCL (17%) and 35% patients CLL. These thrombocytopenia and 4). and of anemia (9%)with in patients with included MCL andneutropenia neutropenia (29%), (27%) and thrombocytopenia and (10%) 4).

(17%) and in anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) patients with CLL. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, in patients with CLL. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Monitor complete blood counts monthly. hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Monitor complete blood counts monthly.

Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at Renal Toxicity: Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy.

Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at Renal Toxicity: Fatal and serious cases ofin renal failure haveupoccurred withtheIMBRUVICA therapy. a rate of ≥ 10% are presented in Table 3.

Treatment-emergent increases creatinine levels to 1.5 times upper limit of normal occurred a rate of ≥ 10% are presented in Table 3.

Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the in 67% of patients withofMCL andoccurred 23% of patients CLL. Increases in creatinine 1.5 to with 3 times the Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with upper limit normal in 9% ofwith patients with MCL and 4% of patients CLL. Periodically Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with upper limitmonitor of normal occurredlevels. in 9%Maintain of patients with MCL and 4% of patients with CLL. Periodically Chronic Lymphocytic Leukemia (N=48) creatinine hydration.

Chronic Lymphocytic Leukemia (N=48) monitor creatinine levels. Maintain hydration.

All Grades Grade 3 or 4 Second Primary Malignancies: Other malignancies have occurred in 5% of patients with MCL and Grade 3 or 4 System Organ Class Preferred Term All Grades Second Primary malignancies occurred in 5% of patients MCLofand Preferred Term (%) (%) 10% ofMalignancies: patients with Other CLL who have beenhave treated with IMBRUVICA. Four with percent patientsSystem with Organ Class (%) (%) 10% of patients with CLL who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL had skin 4 63 Gastrointestinal disorders Diarrhea MCL, had skin cancers and 1% had other carcinomas.

Eight percent of patients with CLL had skin 4 63 Gastrointestinal disorders Diarrhea cancers and 2% had other carcinomas.

2 23 Constipation cancers and 2% had other carcinomas.

2 23 Constipation 2 21 Nausea Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when 2 21 Nausea Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when 0 21 Stomatitis administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times 0 21 Stomatitis 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 2 19 Vomiting those reported in patients with MCL and 20 times those reported in patients with CLL, receiving 2 19 Vomiting the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were 0 15 Abdominal pain the ibrutinib dose of 560 mg per day and 420 mg per day, respectively.

Reduced fetal weights were 0 15 Abdominal pain observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. 0 13 Dyspepsia observed atIf lower exposures.

Advise women to avoid becoming pregnant while taking IMBRUVICA. 0 13 Dyspepsia this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the Infections and infestations Upper respiratory If this drugpatient is usedshould duringbe pregnancy or if the patient becomes pregnant while taking this drug, the Upper respiratory apprised of the potential hazard to a fetus [see Use in Specific Populations]. Infections and infestations 2 48 patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. tract infection 2 48 tract infection ADVERSE REACTIONS 6 21 Sinusitis ADVERSE REACTIONS 6 21 Sinusitis The following adverse reactions are discussed in more detail in other sections of the labeling: 6 17 Skin infection The following adverse reactions are discussed in more detail in other sections of the labeling: 6 17 Skin infection 8 10 Pneumonia • Hemorrhage [see Warnings and Precautions] 8 10 Pneumonia • Hemorrhage [see Warnings and Precautions] 0 10 Urinary tract infection • Infections [see Warnings and Precautions] 0 10 Urinary tract infection • Infections [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] 4 31 General disorders and administrative Fatigue • Myelosuppression [see Warnings and Precautions] 4 31 General disorders and administrative Fatigue • Renal Toxicity [see Warnings and Precautions] 2 25 site conditions Pyrexia • Renal Toxicity [see Warnings and Precautions] 2 25 site conditions Pyrexia 0 23 Peripheral edema • Second Primary Malignancies [see Warnings and Precautions] 0 23 Peripheral edema • Second Primary Malignancies [see Warnings and Precautions] 4 13 Asthenia Because clinical trials are conducted under widely variable conditions, adverse event rates 4 13 Asthenia Because clinical trials are conducted widely variable conditions, event rates trials of 0 13 Chills observed in clinical trials of aunder drug cannot be directly comparedadverse with rates of clinical 0 13 Chills observed in clinical trials a drug cannotthe berates directly compared with rates of clinical trials of 2 54 Skin and subcutaneous tissue disorders Bruising another drug andofmay not reflect observed in practice.

2 54 Skin and subcutaneous tissue disorders Bruising another drug and may not reflect the rates observed in practice.

0 27 Rash Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial 0 27 Rash Mantle Cell Lymphoma: described below reflect exposure IMBRUVICA in mg a clinical trial a median 0 17 Petechiae that included The 111 data patients with previously treated MCL to treated with 560 daily with 0 17 Petechiae that included 111 patients with previously treatment duration of 8.3 months. treated MCL treated with 560 mg daily with a median 0 19 Respiratory, thoracic and mediastinal Cough treatment duration of 8.3 months.

0 19 Respiratory, thoracic and mediastinal Cough The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, 0 15 disorders Oropharyngeal pain The most neutropenia, commonly occurring adverse reactions (≥ 20%) were thrombo cytopenia, diarrhea, 0 15 disorders Oropharyngeal pain anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract 0 10 Dyspnea neutropenia, anemia, fatigue, musculo skeletal pain, peripheral edema, upper respiratory tract 0 10 Dyspnea infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased 6 27 Musculoskeletal and connective tissue Musculoskeletal pain infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased 6 27 Musculoskeletal and connective tissue Musculoskeletal pain appetite (See Tables 1 and 2).

0 appetite (See Tables 1 and 2).

23 disorders Arthralgia 0 23 disorders Arthralgia The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, 2 19 Muscle spasms The most abdominal common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, 2 19 Muscle spasms pain, atrial fibrillation, diarrhea, fatigue, and skin infections. abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

0 21 Nervous system disorders Dizziness 0 21 Nervous system disorders Dizziness Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring 2 19 Adverse reactions the MCL trial (N=111) agent IMBRUVICA 560 mg daily occurring Headache at a ratefrom of ≥ 10% are presented in using Table single 1.

2 19 Headache at a rate of ≥ 10% are presented in Table 1.

0 10 Peripheral 0 10 Peripheral neuropathy Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with neuropathy Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) Metabolism and nutrition disorders Decreased appetite 17 2 Mantle Cell Lymphoma (N=111) Metabolism and nutrition disorders Decreased appetite 17 2 All Grades Grade 3 or 4 Neoplasms benign, malignant, Second 10* 0 Grade 3 or 4 System Organ Class Preferred Term All Grades Neoplasms benign, malignant, Second 10* 0 System Organ Class Preferred Term (%) (%) unspecified malignancies* (%) (%) unspecified malignancies* 5 51 Gastrointestinal disorders Diarrhea Injury, poisoning and procedural Laceration 10 2 5 51 Gastrointestinal disorders Diarrhea Injury, poisoning and procedural Laceration 10 2 0 31 Nausea complications 0 31 Nausea complications 0 25 Constipation Psychiatric disorders Anxiety 10 0 0 25 Constipation Anxiety 10 0 5 Psychiatric disorders 24 Abdominal pain Insomnia 10 0 5 24 Abdominal pain Insomnia 10 0 0 23 Vomiting Vascular disorders Hypertension 17 8 0 23 Vomiting Hypertension 17 8 1 Vascular disorders 17 Stomatitis 1 17 Stomatitis *One patient death due to histiocytic sarcoma.

0 *One patient death due to histiocytic sarcoma.

11 Dyspepsia 0 11 Dyspepsia Infections and infestations Upper respiratory Infections and infestations Upper respiratory Table 4: Treatment-Emergent* Decrease of Hemoglobin, 0 34 tract infection Table 4: Treatment-Emergent* Decrease of Hemoglobin, 0 34 tract infection Platelets, or Neutrophils in Patients with CLL (N=48) 3 14 Urinary tract infection Platelets, or Neutrophils in Patients with CLL (N=48) 3 14 Urinary tract infection Percent of Patients (N=48) 7 14 Pneumonia Percent of Patients (N=48) 7 14 Pneumonia 5 14 Skin infections All Grades (%) Grade 3 or 4 (%) 5 14 Skin infections All Grades (%) Grade 3 or 4 (%) 1 13 Sinusitis 1 13 Sinusitis Platelets Decreased 71 10 71 10 5 Platelets Decreased 41 General disorders and administrative Fatigue 5 41 General disorders and administrative Fatigue 3 35 site conditions Peripheral edema Neutrophils Decreased 54 27 3 35 site conditions Peripheral edema Neutrophils Decreased 54 27 1 18 Pyrexia 1 18 Pyrexia Hemoglobin Decreased 44 0 3 Hemoglobin Decreased 14 Asthenia 44 0 3 14 Asthenia * Based on laboratory measurements per IWCLL criteria and adverse reactions 0 * Based on laboratory measurements per IWCLL criteria and adverse reactions 30 Skin and subcutaneous tissue disorders Bruising 0 30 Skin and subcutaneous tissue disorders Bruising 3 25 Rash Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These 3 25 Rash (10%) discontinued treatment due to adverse reactions in the trial (N=48). These 0 Five patients 11 Petechiae included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse 0 11 Petechiae included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse 1 37 Musculoskeletal and connective tissue Musculoskeletal pain reactions leading to dose reduction occurred in 13% of patients.

1 37 Musculoskeletal and connective tissue Musculoskeletal pain reactions leading to dose reduction occurred in 13% of patients.

0 14 disorders Muscle spasms Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study including 0 14 disorders Muscle spasms percent of patients had shifts from normal to elevated uric acid levels on study including 0 Thirty-eight4% 11 Arthralgia with values above 10 mg/dL. 0 11 Arthralgia 4% with values above 10 mg/dL. 4 27 Respiratory, thoracic and mediastinal Dyspnea 4 27 Respiratory, thoracic and mediastinal Dyspnea DRUG INTERACTIONS 0 DRUG INTERACTIONS 19 disorders Cough 0 19 disorders Cough is primarily metabolized by cytochrome P450 enzyme 3A. 0 Ibrutinib isIbrutinib 11 Epistaxis primarily metabolized by cytochrome P450 enzyme 3A. 0 11 Epistaxis CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A Metabolism and nutrition disorders Decreased appetite 21 2 CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A Metabolism and nutrition disorders Decreased appetite 21 2 inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib Dehydration 12 4 inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib Dehydration 12 4 dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days Nervous system disorders Dizziness 14 0 dose evaluated with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady Nervous system disorders Dizziness 14 0 with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady Headache 13 0 state exposures seen at the highest indicated dose (560 mg).

Headache 13 0 state exposures seen at the highest indicated dose (560 mg).

IMBRUVICATM (ibrutinib) capsules IMBRUVICATM (ibrutinib) capsules Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For 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., 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 ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors 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. 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 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]. 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 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 inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information].

Prescribing Information].

CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold. plasma concentrations by approximately 10-fold.

Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and 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 St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

(12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions].

Pregnancy: Pregnancy Category D [see Warnings and Precautions].

Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to 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 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. 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 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 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 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 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, 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 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 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. 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 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 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 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. 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 Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. established.

Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall 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 differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. A greater number of effectiveness were observed between these patients and younger patients. A greater number of adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of younger patients). younger patients).

Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in 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 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 renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].

Prescribing Information].

Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of 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 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 (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 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]. 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 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]. taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) See FDA-approved patient labeling (Patient Information) • Hemorrhage: • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools 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 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]. interrupted for medical or dental procedures [see Warnings and Precautions].

• Infections: • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions]. chills) suggestive of infection [see Warnings and Precautions].

• Renal toxicity: • Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions]. [see Warnings and Precautions].

• Second primary malignancies: • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with 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].

IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].

• Embryo-fetal toxicity: • Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. and Precautions].

• Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and • 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, 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 or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information].

Prescribing Information].

• Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon • 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 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 not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information].

Prescribing Information].

• Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions].

• 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. 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 • 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 prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

Interactions].

• Advise patients that they may experience loose stools or diarrhea, and should contact their doctor • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. if their diarrhea persists.

Active ingredient made in China.

Active ingredient made in China.

Distributed and Marketed by: Distributed and Marketed by: Pharmacyclics, Inc. Pharmacyclics, Inc. Sunnyvale, CA USA 94085 Sunnyvale, CA USA 94085 and and Marketed by: Marketed by: Janssen Biotech, Inc. Janssen Biotech, Inc. Horsham, PA USA 19044 Horsham, PA USA 19044 Patent http://www.imbruvica.com Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. ©Pharmacyclics, Inc. 2014 ©Pharmacyclics, Inc. 2014 PRC-00339 PRC-00339

Issued: February 2014 Issued: February 2014

ASCOPost.com | JUNE 25, 2014

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Journal Spotlight Breast Cancer

ASCO Clinical Practice Guideline: Systemic Therapy for Patients With Advanced HER2-Positive Breast Cancer

By Matthew Stenger

A

pproximately 15% of patients with breast cancer have tumors that overexpress the HER2 protein and these patients can benefit from HER2-targeted therapies. The American Society of Clinical Oncology recently released a clinical practice guideline on Sharon H. Giordano, MD Eric P. Winer, MD systemic therapy for patients with advanced HER2-positive breast and/or endocrine therapy?” The guidecancer, published in the Journal of Clinical line recommendations are summarized Oncology.1 The rationale for the guideline below, along with notation of type of is that several new agents have become recommendation, evidence quality, and available for treatment of metastatic strength of recommendation.

HER2-positive breast cancer since the General Recommendations approval of trastuzumab (Herceptin).

According to the guideline, cliUp to half of all patients with HER2positive metastatic breast cancer de- nicians should recommend HER2-­ velop brain metastases over time. Rec- targeted therapy–based combinations ommendations for the management for first-line treatment, except in highly of brain metastases in patients with selected patients with estrogen recepHER2-positive breast cancer are de- tor–positive or progesterone receptor– tailed in another recently released com- positive and HER2-positive disease; in such patients, endocrine therapy alone panion guideline.2 The guideline recommendations were may be used. (Type = evidence based, developed by a multidisciplinary group evidence quality = high, strength of recof experts based on a systematic review ommendation = strong.) of phase III randomized controlled trials For patients with disease progressing and clinical experience. Literature search- during or after first-line HER2-targeted es identified a total of 16 eligible random- therapy, clinicians should recommend ized controlled trials reported between second-line HER2-targeted therapy2009 and 2012, consisting of 9 first-line, based treatment. (Type = evidence 3 second-line, and 4 post–second-line tri- based, evidence quality = high, strength als. Three first-line hormonal therapy plus of recommendation = strong.)

HER2-targeted therapy trials addressed For patients with disease progressing the role of hormonal/endocrine therapy, during or after second-line or greater and two trials addressed the issue of how HER2-targeted treatment, clinicians prior adjuvant HER2-targeted therapy should recommend third-line or greater might influence subsequent treatment HER2-targeted therapy-based treatchoices. Outcomes of interest included ment. (Type = evidence based, evioverall survival, progression-free survival, dence quality = intermediate, strength and adverse events. of recommendation = moderate.)

The ASCO expert panel was cochaired by Sharon H. Giordano, MD, Specific Regimens Clinicians should recommend the of The University of Texas MD Anderson Cancer Center, Houston, and Eric combination of trastuzumab, pertuP. Winer, MD, of Dana-Farber Cancer zumab (Perjeta), and a taxane for firstline treatment, unless the patient has a Institute, Boston. contraindication to taxanes. (Type = Primary Clinical Question evidence based, evidence quality = high, The primary clinical question ad- strength of recommendation = strong.) dressed by the guideline is: “What is the For patients with disease progressing optimal medical therapy for advanced during or after first-line HER2-targeted HER2–positive breast cancer, specifical- therapy, clinicians should recommend ly HER2-targeted therapy, either alone ado-trastuzumab emtansine (Kadcyla) continued on page 64 or in combination with chemotherapy

The ASCO Post | JUNE 25, 2014

PAGE 64

Perspective

A New Era in the Management of Advanced HER2-Positive Breast Cancer

By Karen Lisa Smith, MD, MPH, and Vered Stearns, MD

A

pproximately 20% of all breast cancers are human epidermal growth factor receptor 2 (HER2)-positive. Prior to the era of HER2-targeted therapy, HER2-positive breast cancer was characterized by a poor prognosis.1,2 The development of the first HER2-targeted therapy, trastuzumab (Herceptin), led to dramatically improved outcomes for this population in both the early-stage and metastatic settings.3-7 In recent years, outcomes for women with advanced HER2-posDr. Smith is Assistant Professor of Oncology and Dr. Stearns is Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore.

Clinical Practice Guideline continued from page 63

as second-line treatment. (Type = evidence based, evidence quality = high, strength of recommendation = strong.)

For patients with disease progressing during or after second-line or greater HER2-targeted therapy who have not received ado-trastuzumab emtansine, clinicians should offer ado-trastuzumab emtansine. (Type = evidence based, evidence quality = high, strength of recommendation = strong.)

For patients with disease progressing during or after second-line or greater HER2-targeted treatment who have not received pertuzumab, clinicians may offer pertuzumab. (Type = informal consensus, evidence quality = insufficient, strength of recommendation = weak.)

For patients with disease progressing during or after second-line or greater HER2-targeted treatment who have already received pertuzumab and adotrastuzumab emtansine, clinicians should recommend third-line or greater HER2targeted therapy- based treatment. Op-

itive breast cancer have improved further with the development and approval of three additional HER2-targeted therapies—lapatinib (Tykerb), pertuzumab (Perjeta), and ado-trastuzumab emtansine, formerly known as T-DM1 (Kadcyla).

With the addition of these agents to the therapeutic armamentarium, metastatic HER2-positive breast cancer is no longer characterized by a rapid disease course, but rather by median survival rates in excess of 3 years.8 The approval of these new HER2targeted therapies prompted ASCO to release the first clinical guideline for systemic therapy for advanced HER2-positive breast cancer; the guideline was published in the Jourtions include lapatinib (Tykerb) plus capecitabine, as well as other combinations of chemotherapy and trastuzumab, lapatinib and trastuzumab, or hormonal therapy (in patients with estrogen receptor–positive and/or progesterone receptor–positive disease). There is insufficient evidence to recommend one regimen over another. (Type = informal consensus, evidence quality = insufficient, strength of recommendation = weak.)

Chemotherapy Duration In patients receiving HER2-targeted therapy and chemotherapy combinations, chemotherapy should continue for approximately 4 to 6 months (or longer) and/or to the time of maximal response, depending on toxicity and in the absence of progression. When chemotherapy is stopped, clinicians should continue HER2-targeted therapy; no further change in the regimen is needed until the time of progression or unacceptable toxicities. (Type = evidence based, evidence quality = intermediate, strength of recommendation = moderate.)

ASCO Guideline on Treating HER2-Positive Breast Cancer ■■ HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left-ventricular ejection fraction, who should be evaluated on an individual basis.

■■ Trastuzumab, pertuzumab, and a taxane are recommended for first-line treatment and ado-trastuzumab emtansine for second-line treatment.

■■ For third-line treatment, clinicians should offer other HER2-targeted therapy combinations or ado-trastuzumab emtansine (if not previously administered) and may offer pertuzumab (if not previously administered).

nal of Clinical Oncology9 and is reviewed in this issue of The ASCO Post. Since the brain is a sanctuary site for HER2-positive breast cancer, with up to 50% of patients developing brain metastases,10-12 ASCO also released a companion guideline regarding the management of brain metastases in this population.13

Four Key Questions The ASCO guideline for systemic therapy for advanced HER2-positive breast cancer was developed by a multidisciplinary expert panel using evidence from two systematic reviews incorporating data published prior to 2009 and from a systematic review of phase III trials published in 2009 to 2012 in con-

Patients Who Received Adjuvant Trastuzumab For patients finishing trastuzumabbased adjuvant treatment ≤ 12 months before recurrence, clinicians should follow the second-line HER2-targeted therapy- based treatment recommendations. (Type = evidence based, evidence quality = intermediate, strength of recommendation = moderate.)

For patients finishing trastuzumabbased adjuvant treatment > 12 months before recurrence, clinicians should follow the first-line HER2-targeted therapy–based treatment recommendations. (Type = evidence based, evidence quality = high, strength of recommendation = strong.)

Endocrine Therapy For patients with hormone receptor–positive and HER2-positive disease, clinicians may recommend: • HER2-targeted therapy plus chemotherapy. (Type = evidence based, evidence quality = high, strength of recommendation = strong.)

• Endocrine therapy plus trastuzumab or lapatinib (in selected cases). (Type = evidence based, evidence quality = high, strength of recommendation = moderate.)

• Endocrine therapy alone (in selected cases). (Type = evidence based, evidence quality = intermediate, strength of recommendation = weak.)

For patients who have started with a HER2-positive targeted therapy and chemotherapy combination, clinicians may add endocrine therapy to the

junction with clinical experience.9 The guideline addresses four key clinical questions: (1) In which line(s) of treatment should HER2-targeted therapy be incorporated? (2) Which regimens are recommended for firstline treatment? (3) Which regimens are recommended for later lines of treatment? And (4) What is the recommended treatment approach for hormone receptor–positive, HER2positive metastatic breast cancer?

When to Use With the exception of carefully chosen hormone receptor–positive patients in whom a trial of endocrine therapy alone can be considered, the continued on page 65

HER2-targeted therapy when chemotherapy ends and/or when the cancer progresses. (Type = informal consensus, evidence quality = insufficient, strength of recommendation = weak.)

In special circumstances, such as low disease burden, presence of comorbidities (contradictions to HER2-targeted therapy such as congestive heart failure), and/or presence of a long disease-free interval, clinicians may offer first-line endocrine therapy alone. (Type = informal consensus, evidence quality = intermediate, strength of recommendation = weak.)

Qualifying statement: Although clinicians may discuss using endocrine therapy with or without HER2-targeted therapy, the majority of patients will still receive chemotherapy plus HER2-targeted therapy. n Disclosure: For full disclosures of the guideline authors, visit jco.ascopubs.org.

References 1. Giordano SH, Temin S, Kirshner JJ, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. May 5, 2014 (early release online).

2. Ramakrishna N, Temin S, Chandarlapaty S, et al: Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2–positive breast cancer and brain metastases: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol.

May 5, 2014 (early release online).

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Perspective

HER2-Positive Breast Cancer specify which taxane should be used continued from page 64

expert panel recommends incorporation of HER2-targeted therapy into the treatment of patients with advanced HER2-positive breast cancer in first-line therapy and in second-line and later lines of therapy after progression on prior HER2-targeted therapy.9 The recommendation to incorporate HER2-targeted therapy into first-line treatment is supported by the pivotal trial by Slamon et al demonstrating improved time to progression and overall survival with chemotherapy plus trastuzumab compared to chemotherapy alone.3 More recent data demonstrate benefit of first-line HER2-targeted therapy using dual HER2-targeted therapy and the newer HER2-targeted agents, although these regimens have not been compared to therapeutic approaches that do not incorporate HER2-targeted treatments.14,15 The principle of continuing HER2targeted therapy after progression and using serial lines of therapy against the same molecular target (HER2) is similar to that applied in the management of hormone receptor–positive metastatic breast cancer, for which serial endocrine therapies can be beneficial.16,17 Indeed, the continuation of trastuzumab along with chemotherapy improves progression-free survival compared to chemotherapy alone in this population.18 Data evaluating the newer HER2-targeted therapies in patients who have had disease progression following first-line trastuzumabbased therapy further confirm the benefit of continuing HER2-targeted treatment in later lines of therapy.15,19-21

First-Line Options In the first-line setting, the expert panel recommends the combination of pertuzumab, trastuzumab, and a taxane for patients without a contraindication to taxane therapy. This recommendation is based on results from the CLEOPATRA trial, in which the addition of pertuzumab to trastuzumab and docetaxel was associated with significant improvement in median progression-free survival (12.4 vs 18.7 months) and median overall survival (37.6 months vs not reached).8,14 Solid preclinical and clinical data demonstrating improved outcomes with dual HER2-targeted therapy supported the development of this regimen.2126 Notably, the expert panel does not

in combination with pertuzumab and trastuzumab, and it proposes paclitaxel as a possible alternative to docetaxel.9 We agree that a taxane combined with trastuzumab and pertuzuamb should be considered as first-line therapy for HER2-positive metastatic breast cancer, but caution that data to support the use of paclitaxel in this setting are currently not available.

Extrapolating from literature in the HER2-negative setting, we remind readers that when dosed every 3 weeks, docetaxel is more efficacious than paclitaxel for metastatic breast cancer.27 However, weekly paclitaxel is more efficacious than paclitaxel ev-

no data to support this approach.9 Participants in the CLEOPATRA trial received a median of eight cycles of docetaxel therapy14; thus, we agree that the 4- to 6-month time frame for discontinuation of taxane therapy proposed in the guideline is reasonable to reduce cumulative toxicity.9 For patients who show progression on dual HER2-targeted therapy after the taxane has been discontinued, we feel it is appropriate to consider resuming the taxane or treating according to guidelines for second-line therapy, although data to support either approach are lacking.

While results from CLEOPATRA have defined the current standard of

The fact that a new guideline for the management of advanced HER2-positive breast cancer is required speaks to the rapid progress in this field of late.

—Karen Lisa Smith, MD, MPH, and Vered Stearns, MD

ery 3 weeks,28 and thus, it may be reasonable to combine weekly paclitaxel with trastuzumab and pertuzumab in the first-line setting for HER2-positive advanced breast cancer.

It is hoped that studies such as the PERUSE trial (ClinicalTrials.gov Identifier NCT01572038), evaluating pertuzumab and trastuzumab in combination with a taxane (paclitaxel, docetaxel, or nab-paclitaxel [Abraxane]) will help clarify whether one taxane is more appropriate than another in this setting.

Considering the risk of cumulative toxicity, the expert panel recommends discontinuing the taxane after 4 to 6 months or when maximal clinical response has been achieved. After discontinuation of the taxane, the expert panel recommends maintaining the dual HER2-targeted therapy alone. For hormone receptor–positive patients, endocrine therapy can be added at this time, although there are

care for first-line therapy for HER2positive metastatic breast cancer, several questions remain. For example, the role of ado-trastuzumab emtansine in this setting has not been determined. Only a small proportion of participants in the EMILIA trial, comparing capecitabine and lapatinib to ado-trastuzumab emtansine in patients who previously received taxane and trastuzumab therapy, were treated in the first-line setting. Thus, data supporting ado-trastuzumab emtansine in this setting are currently limited.15 Results from the ongoing MARIANNE trial (ClinicalTrials.gov Identifier NCT01120184), comparing first-line ado-trastuzumab emtansine plus pertuzumab and ado-trastuzumab emtansine plus placebo to trastuzumab plus taxane therapy, have the potential to change first-line therapy for HER2-positive metastatic breast cancer further. If equally efficacious, use of ado-trastuzumab emtansine in

the first-line setting may be preferable to therapy with pertuzumab, trastuzumab, and a taxane, since toxicity with the agent is minimal.15

Further First-Line Considerations Whether there is a subgroup of patients with HER2-positive advanced breast cancer for whom first-line HER2-targeted therapy alone (in the absence of chemotherapy) is appropriate remains to be determined. Data from the neoadjuvant setting demonstrate an overall pathologic complete response rate of 16.8% with pertuzumab and trastuzumab alone; however, the rate was 27% in women with hormone receptor–negative tumors,29 suggesting that some hormone receptor–negative and HER2-positive patients, if properly identified, may be able to avoid the toxicity of chemotherapy without compromising outcomes.

Inoue et al addressed this question in a small trial comparing first-line treatment with concurrent trastuzumab plus chemotherapy to trastuzumab with delayed chemotherapy for metastatic HER2-positive breast cancer, and results favored upfront chemotherapy.30 However, this study was performed with trastuzumab alone and findings may differ with dual or newer HER2-targeted therapies.

At this time, we do not recommend HER2-targeted therapy alone as a standard first-line option, although it is reasonable to consider this approach in asymptomatic patients with low disease burden, especially in the presence of comorbidities or poor performance status.

The guidelines do not address which therapy should be recommended for patients with metastatic disease who received pertuzumab in the adjuvant or neoadjuvant settings. Pertuzumab-based regimens were recently approved in the neoadjuvant setting based on phase II data29,31 and are under evaluation in the adjuvant setting in the AFFINITY trial (ClinicalTrials. gov Identifier NCT01358877).

Recent guidelines from the National Comprehensive Cancer Network (NCCN) incorporate pertuzumabbased regimens as management options in both the adjuvant and neoadjuvant algorithms for HER2-positive early-stage breast cancer,32 and firstline management of these patients continued on page 66

The ASCO Post | JUNE 25, 2014

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Perspective

HER2-Positive Breast Cancer multiple therapeutic options for the therapy and endocrine therapy comcontinued from page 65

should they develop metastatic disease is not defined at this time. The expert panel recommends treating patients who completed adjuvant trastuzumab-based treatment > 12 months prior to development of metastatic disease with docetaxel, pertuzumab, and trastuzumab, since they would have been eligible for the CLEOPATRA trial.9,14 For those who develop metastatic disease < 12 months after completing adjuvant trastuzumabbased therapy, the panel recommends treating as if the patients are in the second-line setting.9 Notably, very few patients in the CLEOPATRA trial received prior adjuvant trastuzumab.14 Until additional data are available, we agree with these recommendations.

Subsequent Options Based on solid efficacy and toxicity data from the EMILIA trial, the guideline recommends ado-trastuzumab emtansine as second-line therapy. In EMILIA, ado-trastuzumab emtansine use was associated with improvements in progression-free survival (9.6 vs 6.4 months) and overall survival (30.9 vs 25.1 months) along with reduced toxicity compared to the combination of lapatinib and capecitabine.15 For third-line and later lines of therapy, the expert panel does not recommend specific regimens, since data regarding the relative merits of one regimen over another in these settings are lacking. The guideline suggests consideration of ado-trastuzumab emtansine or pertuzumab-based regimen in these settings for patients who have not received these therapies in earlier lines of care.9 The recommendation for adotrastuzumab emtansine in this scenario is appropriate given that most participants in the EMILIA trial had received multiple lines of prior therapy.15 Although data to support the use of pertuzumab beyond the first-line setting are currently limited to a small phase II trial of trastuzumb and pertuzumab in patients who received prior trastuzumab,24 we agree that offering pertuzumab-based regimens in later lines of care is reasonable for patients who did not have the opportunity to receive pertuzumab earlier.

For patients who have received ado-trastuzumab emtansine and pertuzumab-based therapy in earlier lines of care, the guideline proposes

third-line and later settings, including dual HER2-targeted therapy with trastuzumab and lapatinib, various combinations of chemotherapy with trastuzumab, the combination of lapatinib and capecitabine, and, for hormone receptor–positive patients, combinations of endocrine therapy with trastuzumab or lapatinib.9,19-21,33,34 Since data to guide clinicians in selecting the optimal regimen in these later settings are not currently available, we suggest making selections based on factors such as prior treatments, extent of disease, performance status, and toxicity.

Hormone Receptor–Positive Disease After suggesting HER2-targeted regimens for each line of care, the expert panel turns to the management of advanced breast cancer that is both hormone receptor– and HER2-positive. Unfortunately, optimal management of these patients remains uncertain, although the panel indicates that it expects most patients to be treated according to the standard recommendations for chemotherapy plus HER2-targeted therapy regardless of hormone receptor status.

The guideline recommends consideration of a trial of endocrine therapy alone for select patients.9 Although not supported by data, the proposed selection criteria for this approach, which include patient-related factors (such as presence of a contraindication to HER2-targeted therapy or comorbidities) and disease-related factors (such as a long time to recurrence and low disease burden), are appropriate.9 Although there may be some HER2-positive patients in whom endocrine therapy alone is reasonable, we encourage caution in applying this approach, since trials evaluating endocrine therapy alone for the treatment of HER2-positive metastatic breast cancer have revealed a short time to progression.33-35 Another option proposed by the ASCO panel for patients who are both hormone receptor– and HER2-positive is the combination of endocrine therapy and HER2-targeted therapy, which can be used during first-line therapy after discontinuation of the taxane or at another time point.9 This is a reasonable recommendation, but we note that, to date, trials evaluating the combination of HER2-targeted

pared to endocrine therapy alone have demonstrated improvement in progression-free survival but not in overall survival, a finding which may be partially explained by crossover of patients from the endocrine therapy alone arms to the combination arms.33-35 The lack of an overall survival benefit in the trials of HER2-targeted therapy and endocrine therapy contrasts with trials evaluating the combination of chemotherapy and HER2-targeted therapy, such as the CLEOPATRA trial, in which a survival benefit was noted for the experimental arm regardless of hormone receptor status.14 However, to the best of our knowledge, upfront treatment using endocrine therapy plus HER2targeted therapy with delayed initiation of chemotherapy has not been compared to upfront chemotherapy plus HER2-targeted therapy in this population.

Such an approach may be desirable for select patients who are both hormone receptor– and HER2-positive, as it can allow patients to delay chemotherapy-associated toxicity. However, validation of criteria to select patients in whom this approach is safe is required. Regardless, the panel suggests that most hormone receptor– and HER2-positive patients should receive endocrine therapy at some point during their treatment course.9 We agree with this recommendation and also encourage considering different clinical trial opportunities for women with HER2-positive advanced breast cancer who are hormone receptor–positive and those who are hormone receptor–negative, since these diseases may be biologically distinct.

Areas of Uncertainty While the ASCO guideline for systemic therapy for advanced HER2positive breast cancer covers management decisions for many common clinical scenarios, areas of uncertainty remain. For example, given the success with today’s HER2-targeted therapies, one occasionally encounters a patient in whom all evidence of disease is eradicated by systemic therapy.

Whether it is of benefit to administer HER2-targeted therapy indefinitely in such patients is unknown. Moreover, given the substantial cost associated with the newer HER2-targeted therapies, we feel incorporation of

economic considerations into future trials and guidelines is appropriate.

The optimal regimens and sequencing in later lines of care for HER2-positive metastatic breast cancer are still not well defined. It is our hope that observational studies, such as the ongoing SystHERS prospective cohort study (ClinicalTrials.gov Identifier NCT01615068), describing treatment patterns and outcomes in this population will better characterize the optimal treatment trajectory for these patients.

Furthermore, the use of HER2targeted therapies requires adequate cardiac function. More studies such as the SAFE-HEaRt trial (ClinicalTrials. gov Identifier NCT01904903), a pilot study assessing the cardiac safety of HER2-targeted therapy in patients with mildly reduced ejection fraction, are needed to define safety parameters for the use of these important agents in women with compromised cardiac function. Finally, many ongoing investigations will help define mechanisms of resistance to HER2-targeted therapy and therapeutic approaches to overcome resistance to HER2-targeted therapy.

In Conclusion The fact that a new guideline for the management of advanced HER2positive breast cancer is required speaks to the rapid progress in this field of late. The three recently approved HER2-targeted therapies, along with trastuzumab, together with promising new HER2-targeted agents, such as neratinib and afatinib (Gilotrif), and agents that may overcome resistance to HER2-targeted therapy, such as phosphatidylinositol 3-kinase inhibitors,36 are bringing us toward a new era in the management of HER2-positive metastatic breast cancer. n Disclosure: Dr. Stearns has received research grants from Abbive, Abraxis, Merck, Medimmune, Novartis, and Pfizer. Dr. Smith reported no potential conflicts of interest.

References 1. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987.

2. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al: High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor continued on page 72

VOTRIENT is indicated for the treatment of advanced renal cell carcinoma (RCC)1

EFFICACY AGAINST PROGRESSION

VOTRIENT demonstrated an overall median progression-free survival (PFS) of

9.2 months vs 4.2 months with placebo (HR 0.46; 95% CI 0.34-0.62; P<0.001)1*

*Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of VOTRIENT in first-line or cytokine-pretreated patients (N=435) with advanced RCC of clear cell or predominantly clear cell histology. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

• Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

• QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

Please see additional Important Safety Information for VOTRIENT on subsequent pages.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

EFFICACY LIGHTS THE WAY

VOTRIENT® (pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1

VOTRIENT: Significant PFS improvement in patients with advanced RCC1 Median PFS in patients with advanced RCC receiving VOTRIENT vs placebo1,2 12 10

VOTRIENT Placebo

11.1

MONTHS

9.2

MONTHS

7.4

Months

8 6 4

MONTHS

4.2

2.8

MONTHS

4.2

MONTHS

MONTHS

2 0

HR 0.46; 95% CI 0.34-0.62 (P<0.001) All patients

HR 0.40; 95% CI 0.27-0.60 (P<0.001) First-line patients

HR 0.54; 95% CI 0.35-0.84 (P<0.001) Cytokine-pretreated patients

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC of clear cell or predominantly clear cell histology were randomized (2:1) to receive either VOTRIENT 800 mg (n=290) once daily or placebo (n=145). The study included first-line patients receiving VOTRIENT (n=155) or placebo (n=78) as well as cytokine-pretreated patients receiving VOTRIENT (n=135) or placebo (n=67).1

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure.

• Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials.

In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months.

• Arterial Thromboembolic Events: Arterial thromboembolic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months.

• Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have occurred, including venous thrombosis and fatal pulmonary

emboli. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms.

• Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan.

VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued.

Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated.

• Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms.

• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence

of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension.

• Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence.

• Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended.

• Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions.

• Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed.

The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In advanced RCC, initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced RCC trial, 42% of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose reduced • No dose adjustment is required in patients with mild hepatic impairment • In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment and at Weeks 3, 5, 7, and 9.

Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications based on drug interactions, please see Sections 2.2 and 7 of accompanying Brief Summary of Prescribing Information

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials.

Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting Please see additional Important Safety Information for VOTRIENT on adjacent pages.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

VOTRIENT (pazopanib) has a Category 1 recommendation as a first-line therapy in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for relapsed or Stage IV unresectable RCC of predominant clear cell histology.3 NCCN Guidelines® also include therapies other than VOTRIENT (pazopanib) as first-line treatment options.

• Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death.

VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age.

• Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

• Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients.

• Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax.

• Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm.

• Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice.

Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized

by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT.

• Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced.

The most common adverse reactions (≥20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%).

Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%).

References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Sternberg CN, et al. J Clin Oncol.

2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.2.2014. ©National Comprehensive Cancer Network, Inc. 2013. All rights reserved.

Accessed December 9, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Please see additional Important Safety Information for VOTRIENT on adjacent pages.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

www.GSKSource.com

VOTRIENT.com/HCP/aRCC

©2014 GlaxoSmithKline group of companies. All rights reserved. Printed in USA. 3825R0 January 2014

EFFICACY LIGHTS THE WAY

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information.

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided.

Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo.

Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9.

Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information].

Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients who received placebo on the trial had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure.

5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/ intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events.

VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated.

5.8 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances.

Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and

hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)].

5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290)

(N=145)

All All Gradesa Gradesa Grade 3 Grade 4 % % % % Adverse Reactions Diarrhea 52 3 <1 9 Hypertension 40 4 0 10 Hair color changes 38 <1 0 3 Nausea 26 <1 0 9 Anorexia 22 2 0 10 Vomiting 21 2 <1 8 Fatigue 19 2 0 8 Asthenia 14 3 0 8 Abdominal pain 11 2 0 1 Headache 10 0 0 5 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Grade 3 % <1 <1 0 0 <1 2 1 0 0 0

Grade 4 % 0 0 0 0 0 0 1 0 0 0

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below: Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms.

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290) All Gradesa %

Grade 3 %

Placebo (N=145) Grade 4 %

All Gradesa %

Parameters Hematologic Leukopenia 37 0 0 6 Neutropenia 34 1 <1 6 Thrombocytopenia 32 <1 <1 5 Lymphocytopenia 31 4 <1 24 Chemistry ALT increased 53 10 2 22 AST increased 53 7 <1 19 Glucose increased 41 <1 0 33 Total bilirubin increased 36 3 <1 10 Phosphorus decreased 34 4 0 11 Sodium decreased 31 4 1 24 Magnesium decreased 26 <1 1 14 Glucose decreased 17 0 <1 3 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Grade 3 %

Grade 4 %

0 0 0 1

0 0 <1 0

1 <1 1 1 0 4 0 0

0 0 0 <1 0 0 0 0

T:14”

B:14.25”

S:13”

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials.

Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients.

Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to <1% (1/145) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.

CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP).

Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of

dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC).

Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product.

However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away.

• Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications.

• Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure.

• Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding.

• Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis.

• Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs.

• Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances).

• Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting.

• GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula.

• VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery.

• Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment.

• Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection.

• Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

• Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs.

• Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements.

• Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

©2013, GlaxoSmithKline. All rights reserved.

Revised: 11/2013 VTR:11BRS ©2014 GlaxoSmithKline group of companies. All rights reserved.

Printed in USA. 3825R0 January 2014

The ASCO Post | JUNE 25, 2014

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2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27:5700-5706, 2009.

3. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783792, 2001.

4. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:16731684, 2005.

5. Slamon D, Eiermann W, Robert N, et al: Adjuvant trastuzumab in HER2positive breast cancer. N Engl J Med 365:1273-1283, 2011.

6. Perez EA, Romond EH, Suman VJ, et al: Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 29:3366-3373, 2011.

7. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:16591672, 2005.

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

Lancet Oncol 14:461-471, 2013.

9. Giordano SH, Temin S, Kirshner JJ, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2014; doi: 10.1200/JCO.2013.54.0948.

10. Pestalozzi BC, Holmes E, de Azambuja E, et al: CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: A retrospective substudy of the HERA trial (BIG 1-01). Lancet Oncol 14:244-248, 2013.

11. Olson EM, Abdel-Rasoul M, Maly J, et al: Incidence and risk of central nervous system metastases as

site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab. Ann Oncol 24:1526-1533, 2013.

12. Brufsky AM, Mayer M, Rugo HS, et al: Central nervous system metastases in patients with HER2-positive metastatic breast cancer: Incidence, treatment, and survival in patients from registHER. Clin Cancer Res 17:4834-4843, 2011.

13. Ramakrishna N, Temin S, Chandarlapaty S, et al: Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2–positive breast cancer and brain metastases: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2014; doi: 10.1200/JCO.2013.54.0955.

14. Baselga J, Cortes J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.

15. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.

16. Chia S, Gradishar W, Mauriac L, et al: Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptorpositive, advanced breast cancer: results from EFECT. J Clin Oncol 26:1664-1670, 2008.

17. 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 receptorpositive advanced breast cancer. J Clin Oncol 28:4594-4600, 2010.

18. von Minckwitz G, Schwedler K, Schmidt M, et al: Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer 47:2273-2281, 2011.

19. Cameron D, Casey M, Oliva C, et al: Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: Final survival analysis of a phase III randomized trial. Oncologist 15:924934, 2010.

20. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for

HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006.

21. Blackwell KL, Burstein HJ, Storniolo AM, et al: Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28:11241130, 2010.

22. Konecny GE, Pegram MD, Venkatesan N, et al: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumabtreated breast cancer cells. Cancer Res 66:1630-1639, 2006.

23. Blackwell KL, Burstein HJ, Storniolo AM, et al: Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: Final results from the EGF104900 Study. J Clin Oncol 30:25852592, 2012.

24. Baselga J, Gelmon KA, Verma S, et al: Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 28:1138-1144, 2010.

25. Cortes J, Fumoleau P, Bianchi GV, et al: Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: Activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 30:1594-1600, 2012.

26. Scheuer W, Friess T, Burtscher H, et al: Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res 69:9330-9336, 2009.

27. Jones SE, Erban J, Overmoyer B, et al: Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 23:5542-5551, 2005.

28. Seidman AD, Berry D, Cirrincione C, et al: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: Final results of Cancer and

Leukemia Group B protocol 9840. J Clin Oncol 26:1642-1649, 2008.

29. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25-32, 2012.

30. Inoue K, Nakagami K, Mizutani M, et al: Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: The JO17360 Trial Group.

Breast Cancer Res Treat 119:127-136, 2010.

31. Schneeweiss A, Chia S, Hickish T, et al: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278-2284, 2013.

32. National Comprehensive Cancer Network Guidelines: Breast Cancer Version 3.2014, 2014.

33. Kaufman B, Mackey JR, Clemens MR, et al: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: Results from the randomized phase III TAnDEM study. J Clin Oncol 27:5529-5537, 2009.

34. Huober J, Fasching PA, Barsoum M, et al: Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer—results of the eLEcTRA trial. Breast 21:27-33, 2012.

35. Schwartzberg LS, Franco SX, Florance A, et al: Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer.

Oncologist 15:122-129, 2010.

36. Tsang RY, Finn RS: Beyond trastuzumab: Novel therapeutic strategies in HER2-positive metastatic breast cancer.

Br J Cancer 106:6-13, 2012.

ASCOPost.com | JUNE 25, 2014

PAGE 73

Expert’s Corner Breast Cancer

Issues in the Management of the Axilla in Patients With Breast Cancer A Conversation With Hiram S. Cody III, MD

By Ronald Piana small single-digit differences in local recurrence observed between the various strategies of axillary management in contemporary practice will not affect survival.

Sentinel Lymph Node Biopsy

Hiram S. Cody III, MD

F

or the past 40 years the story of breast cancer surgery in general, and for the past 20 years the management of the axilla in particular, has been one of increasing conservatism.

To give our readers insight into the current and future direction of axillary management, The ASCO Post spoke with Hiram S. Cody III, MD, principal investigator of Memorial Sloan Kettering Cancer Center’s Sentinel Lymph Node Biopsy Program. Dr. Cody presented a Meet the Professor session on this issue at the recent Society of Surgical Oncology (SSO) Annual Cancer Symposium in Phoenix.1

Axillary Dissection Have we reached consensus on the survival benefit of axillary dissection?

The survival advantage of axillary dissection, if any, is probably very small. This was first studied 30 years ago by the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial,2 in which women with clinically node-negative primary breast cancer had a mastectomy with or without axillary dissection. Despite axillary recurrence in about 20% of patients treated without axillary dissection (75% of these within 2 years), there was no survival advantage for either arm.

The dominant rationale for axillary dissection in subsequent trials by the NSABP and others was prognostication to guide systemic therapy; local control was regarded as a secondary goal, and any survival benefit was speculative. The historic 2005 Oxford Overview3 showed for the first time that local control and survival were related, but that a survival benefit was not apparent until the absolute rate of local recurrence had been reduced by at least 10%. It seems clear that the

Is sentinel lymph node biopsy as good as axillary dissection?

Overwhelming data show that for node-negative breast cancer patients, sentinel lymph node biopsy is just as effective as axillary dissection in staging accuracy, local control, and survival, but with substantially less morbidity. It’s now clear that many sentinel lymph node–positive patients can also avoid axillary dissection, as evidenced by the ACOSOG Z0011 trial,4 in which patients with positive sentinel nodes were randomly assigned to axillary dissection vs no further axillary treatment.

with neoadjuvant chemotherapy and postoperative radiotherapy—a topic of particular current interest as more clinical trials transition to the neoadjuvant model.

We have a substantial literature showing that the success rate and accuracy of sentinel node biopsy are roughly comparable, whether done before or after systemic adjuvant therapy.

For clinically node-negative patients, sentinel node biopsy after neoadjuvant chemotherapy seems safe, reasonable, and has the added advantage of sparing patients another trip to the OR. What about patients with biopsyproven axillary metastases prior to neoadjuvant chemotherapy?

Neoadjuvant chemotherapy downstages the axilla. Among patients with biopsy-proven axillary node metastases, contemporary treatment regimens

The decision for systemic therapy is increasingly based on the characteristics of the primary tumor, and in the genomic era we are getting so much information—both prognostic and predictive—that the role of axillary node staging for treatment selection will continue to decline.

—Hiram S. Cody III, MD

At 6 years, there were no differences in local control or survival between arms (even though axillary dissection found additional axillary node metastases in 27% of patients, axillary local recurrence was < 1% in each arm).

The Z0011 patients were cN0, had no more than two positive sentinel lymph nodes, and no extranodal extension. All had breast conservation with whole-breast radiotherapy, and no other axillary-specific treatment. Some of the success of Z0011 may be due to the inadvertent axillary radiation inherent in whole-breast radiotherapy.

Neoadjuvant Chemotherapy What about patients outside the Z0011 selection criteria, especially those receiving neoadjuvant chemotherapy?

Going forward, we must ask whether sentinel lymph node–positive patients outside the Z0011 selection criteria can avoid axillary dissection as well. Lively debate still surrounds the integration of sentinel node biopsy

yield axillary complete response rates of 40% or more. Could these patients avoid axillary lymph node dissection?

Just last year, two major prospective trials began to address this question. ACOSOG Z10715 is a prospective observational trial of patients with positive axillary nodes who had neoadjuvant chemotherapy followed by sentinel node biopsy and a “backup” axillary dissection. Sentinel lymph nodes were found in 90% of patients, and if two or more sentinel nodes were removed, the false-negative rate of sentinel node biopsy was 12.8%, slightly higher than the authors’ predefined threshold of 10%. The falsenegative rate was significantly higher if only one sentinel lymph node was removed (30%) or when patients’ sentinel nodes were mapped with a single agent (dye or isotope) vs dual agent (dye plus isotope), 20% vs 10%. The take-home message is that for sentinel node biopsy done after chemotherapy, technique matters: one must map with

dye plus isotope and remove at least two (and preferably more) sentinel nodes.

In the German trial SENTINA,6 patients were stratified by clinical axillary node status. If cN0, they had sentinel lymph node biopsy before chemotherapy; sentinel node–negative patients had no further axillary treatment, and sentinel node–positive patients received chemotherapy followed by repeat sentinel node biopsy and axillary dissection. If cN1-2, they received chemotherapy followed by sentinel node biopsy; those who became cN0 had sentinel node biopsy and axillary node dissection, and those who remained cN1-2 had axillary dissection.

For the cN0 patients with positive sentinel lymph nodes upfront, the performance of the repeat sentinel node biopsy postchemotherapy was poor, with only 60% success and a 50% false-negative rate. For the cN1-2 patients who converted to cN0 postchemotherapy, performance was better (and comparable to ACOSOG Z1071): 80% success and 14% false-negative rate. The take-home message from SENTINA is that sentinel node biopsy works best if done once, after chemotherapy.

One must acknowledge that although these two large prospective trials specifically address the performance characteristics of sentinel node biopsy following neoadjuvant therapy, they do not ask whether local therapy can be modified based on the response to neoadjuvant therapy.

Looking Ahead So where do we go from here?

Two new randomized trials specifically address axillary management following neoadjuvant chemotherapy in patients with proven axillary node metastases. In both trials, patients receive neoadjuvant chemotherapy followed by sentinel lymph node biopsy.

If the sentinel nodes have converted to benign, NSABP B-51/Radiation Therapy Oncology Group (RTOG) 1304 randomly assigns patients to nodal radiotherapy vs no nodal radiotherapy (without further surgery). If the sentinel nodes remain positive, Alliance A11202 randomly assigns patients to axillary dissection vs no axillary dissection (with nodal raditohercontinued on page 74

The ASCO Post | JUNE 25, 2014

PAGE 74

Expert’s Corner Management of the Axilla continued from page 73

apy for all patients). These two trials will give us a more definitive answer as to the longer-term safety of sentinel node biopsy after neoadjuvant chemotherapy and whether we can modify local therapy based on the response to neoadjuvant chemotherapy.

The decision for systemic therapy is increasingly based on the characteristics of the primary tumor, and in the genomic era we are getting so much information—both prognostic and predictive—that the role of axillary node staging for treatment selection

will continue to decline. New trials are certain to compare the outcomes of sentinel node biopsy vs no axillary staging, and the axillary dissection of the future will be an operation done most often to salvage local recurrences rather than prevent them. n

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

References 1. Cody HS: Update on the axilla management in breast cancer—what is next? Meet the Professor session. SSO Annual Cancer Symposium. Presented March 15, 2014.

2. Fisher B, Redmond C, Fisher ER, et al: Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 312:674-681, 1985.

3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005.

4. Giuliano AE, McCall L, Beitsch P, et al: Locoregional recurrence after sentinel lymph node dissection with and without axillary dissection in patients

with sentinel lymph node metastases. The American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 252:426-432, 2010.

5. Boughey JC, Suman VJ, Mittendorf EA, et al: Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: The ACOSOG Z1071 (Alliance) clinical trial.

JAMA 310:1455-1461, 2013.

6. Kuehn T, Bauerfeind I, Fehm T, et al: Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): A prospective, multicentre cohort study. Lancet Oncol 14:609-618, 2013.

Awards

Paying It Forward: Breakthrough Prize Winners and Institutions Commit $3 Million in Support of Next Generation of Scientists

F

ollowing last year’s announcement of the first-ever Breakthrough Prizes, established by a group of Silicon Valley entrepreneurs to celebrate scientists and encourage careers in the field, the winners were frequently asked what they would do with their newfound prize money of $3 million each. Three of the winners — Charles L. Sawyers, MD, of Memorial Sloan Kettering Cancer Center, Cornelia I. Bargmann, PhD, of the Rockefeller University, and Lewis C. Cantley, PhD, of Weill Cornell Medical College — have answered that question by collaborating to “invest” in the next generation of scientists. They have committed a portion of their Breakthrough Prize in Life Sciences award to establish a new annual prize for promising postdoctoral trainees. The award will be sustained by a $3 million endowment, including financial commitments made by each of their respective institutions,

Tri-Institutional Breakout Awards The Tri-Institutional Breakout Awards for Junior Investigators will be given to three to six outstanding postdoctoral trainees every year, with each recipient receiving $25,000. One prize will be awarded to an applicant from each of the three founding institutions, and additional awards will be given to the best candidates, regardless of their institutional af-

filiation. The inaugural winners will be announced by the end of 2014.

“By establishing the Tri-Institutional Breakout Awards we hope to stimulate young scientists at the start of their careers,” said Dr. Sawyers. “I am grateful to the Breakthrough Prize in Life Sciences Foundation for raising the level of recognition for the life sciences community, and I hope that by creating an award for postdoctoral scholars, we can contribute to furthering that vision.”

“We want to recognize and encourage the rising stars in science,” said Dr. Bargmann. “With this prize for exceptional postdocs, we can highlight their talent, passion, and accomplishment and celebrate exciting discoveries in our community.”

“The Tri-Institutional Breakout Awards are a unique and powerful statement of our institutions’ support for early-career investigators,” Dr. Cantley said. “They will encourage our trainees to pursue innovative work and reinforce their commitment to critical basic science research.”

The Breakthrough Prize in Life Sciences — established by Art Levinson, Sergey Brin, Anne Wojcicki, Mark Zuckerberg, Priscilla Chan, and Yuri Milner — “recognizes excellence in research aimed at curing intractable diseases and extending human life.” Eleven inaugural winners each received $3 million to “advance breakthrough

research, celebrate scientists and generate excitement about the pursuit of science as a career.

About the Investigators Dr. Sawyers is a Howard Hughes Medical Institute investigator whose research focuses on cancer drug resistance with an eye toward developing innovative therapies. Dr. Sawyers completed his term as President of

Charles L. Sawyers, MD

esel Professor, Head of the Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior; and codirector of the Shelby White and Leon Levy Center for Mind, Brain and Behavior at The Rockefeller University as well as an Investigator of the Howard Hughes Medical Institute. She is a member of the National Academy of Sciences, the American Philosophical Society, and the American Academy of Arts and

Cornelia I. Bargmann, PhD

the American Association for Cancer Research in April and was recently appointed by President Barack Obama to the National Cancer Advisory Board. He is past President of the American Society of Clinical Investigation and a Member of the National Academy of Sciences and of the Institute of Medicine. He is Chair of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering and holds the Marie-Josée and Henry R. Kravis Chair.

Dr. Bargmann is Torsten N. Wi-

Lewis C. Cantley, PhD

Sciences. IDr. Bargmann currently cochairs the working group at NIH that is planning President Obama’s Brain Initiative.

Dr. Cantley is the Drector of the Sandra and Edward Meyer Cancer Center, the Margaret and Herman Sokol Professor in Oncology Research, and Professor of Cancer Biology in Medicine at Weill Cornell Medical College. He is a Fellow of the American Academy of Arts and Sciences and a member of the National Academy of Sciences. n

In the research of advanced cancers

What if inhibiting the PD-1 checkpoint pathway played an important role in restoring immune response to tumor cells?

In a normal state, the immune system recognizes tumors and can mount an active antitumor response1,2 Antigen-presenting cell

Step 1:

Tumor releases antigen3

Active T cells

Step 2:

Antigen-presenting cells activate T cells that proliferate and migrate to the tumor.

T cells then release apoptosisinducing proteins, which attack the tumor cells3,4

Tumor

One way that tumors can evade normal immune attack is through exploitation of the PD-1 checkpoint pathway via the PD-1 receptor, a key regulator of T-cell activity, by converting active T cells to inactive T cells5-8

PD-L1 ligand

Tumor cell

PD-L2 ligand

PD-1 receptor

Inhibited T cell

Both PD-L1 and PD-L2 ligands on the tumor cells bind to the PD-1 receptor on T cells to exploit the immune checkpoint pathway.

This inhibits activated T cells and suppresses T-cell attack 6-9

PD-1 receptor

Inactive T cells

Bristol-Myers Squibb is researching ways to block the interaction between the PD-1 receptor and PD-L1 and PD-L2 ligands to restore T-cell activation, which may play a role in helping the body fight cancer.8,10 PD-1=programmed death 1; PD-L1=programmed death 1 ligand 1; PD-L2=programmed death 1 ligand 2.

References: 1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 2. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 3. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. 4. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway.

Nat Rev Immunol. 2002;2(10):735-747. 5. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 6. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111(7): 3635-3643. 7. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 8. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 9. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation.

Nat Immunol. 2001;2(3):261-268. 10. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Proc Natl Acad Sci U S A. 2002;99(19):12293-12297.

Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology. Learn more at www.pd1pathway.com.

Š2013 Bristol-Myers Squibb Company. All rights reserved. ONCUS13UB02888-01-01 10/13 Printed in USA.

The ASCO Post | JUNE 25, 2014

PAGE 76

In the Clinic Hematology

Mercaptopurine Oral Suspension for Acute Lymphoblastic Leukemia

By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n April 28, 2014, an oral suspension of mercaptopurine ­(Purixan) was approved for use in patients with acute lymphoblastic leukemia (ALL) as part of a combination regimen.1,2 Mercaptopurine has been available only as a 50 mg tablet since its initial approval in 1953. Treatment of children with a 50mg tablet is complicated by the ranges of age and weight that make body surface area dosing and dose adjustments difficult. Tablets also are not an ideal dosage form for children aged < 6 years.

The current formulation is a 20-mg/ mL oral suspension, which offers the advantage of more accurate delivery of desired doses to children with a wide range of weights using a consistent administration schedule and more flexibility in dose adjustment. The commercially produced suspension is more likely to provide a more consistent dose of mercaptopurine than compounded formulations.

Pivotal Study Approval was based on assessment of the bioequivalence of mercaptopurine from 50 mg Purinethol tablets and mercaptopurine from the oral suspension in a single-dose crossover clinical pharmacology study conducted in 62 healthy adult subjects under fasting conditions. Bioequivalence was demonstrated based on the primary phar-

OF NOTE Mercaptopurine activation occurs via HGPRTase and several enzymes to form 6-thioguanine nucleotides, incorporation of which into nucleic acids (instead of purine bases) results in cell-cycle arrest and cell death.

macokinetic parameters of area under the concentration-time curve (AUC) (0-t) and AUC(0-∞). Maximum con-

centration (Cmax) was not bioequivalent, with mean Cmax being 34% higher with the oral suspension.

Other clinical studies have shown that the absorption of an oral dose of mercaptopurine is incomplete and variable, averaging approximately 50% of the administered dose, and the factors affecting absorption are unknown.

Following a single 50-mg dose of mercaptopurine oral suspension under

gle daily dose. Continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count and platelet count to assure sufficient drug exposure to maintain absolute neutrophil count at a desirable level and to adjust for excessive hematologic toxicity.

Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe toxicity from conventional doses

Mercaptopurine Oral Suspension for ALL ■■ An oral suspension of mercaptopurine (Purixan) was approved for use in patients with acute lymphoblastic leukemia as part of a combination regimen.

■■ The starting dose of mercaptopurine in multiagent combination chemotherapy maintenance regimens in ALL is 1.5 to 2.5 mg/kg (50 to 75 mg/m2) as a single daily dose; continued appropriate dosing requires monitoring of absolute neutrophil count and platelet count.

fasting conditions, median AUC was 136 h*ng/mL (range = 74.2–264.8 h*ng/mL) and Cmax was 95 ng/mL (range = 39.5–204 ng/mL).

How It Works Mercaptopurine activation occurs via hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) and several enzymes to form 6-thioguanine nucleotides, incorporation of which into nucleic acids, instead of purine bases, results in cell-cycle arrest and cell death. Mercaptopurine competes with hypoxanthine and guanine for HGPRTase and is converted to thioinosinic acid. This intracellular nucleotide inhibits several reactions involving inosinic acid, including the conversion of inosinic acid to xanthylic acid and adenylic acid.

Methylation of thioinosinic acid produces 6-methylthioinosinate. Both have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis.

How It Is Given The starting dose of mercaptopurine in multiagent combination chemotherapy maintenance regimens in ALL is 1.5 to 2.5 mg/kg (50 to 75 mg/m2) as a sin-

of mercaptopurine and generally require dose reduction. Testing for TPMT gene polymorphism should be considered in patients who experience severe bone marrow toxicities. Homozygous deficient patients may require a dose reduction of up to 90%. Most patients with heterozygous TPMT deficiency have tolerated recommended mercaptopurine doses, with some requiring dose reduction based on toxicities.

Safety Profile Based on multicenter cooperative group ALL trials, the most common adverse events in > 20% of patients are anemia, neutropenia, lymphopenia, and thrombocytopenia. Adverse events occurring in 5% to 20% of patients include anorexia, nausea, vomiting, diarrhea, malaise, and rash. Rare adverse events occurring in < 5% include urticaria, hyperuricemia, oral lesions, elevated transaminases, hyperbilirubinemia, hyperpigmentation, and pancreatitis. Oral lesions resemble thrush rather than antifolic ulcerations.

Delayed or late toxicities include hepatic fibrosis, hyperbilirubinemia, alopecia, pulmonary fibrosis, oligospermia, and secondary malignancies. Drug fever has been rarely reported with mercaptopurine; every attempt should be made to exclude more common causes

OF NOTE Mercaptopurine carries warnings/ precautions for myelosuppression, hepatotoxicity, immunosuppression, and embryo-fetal toxicity.

of pyrexia, such as sepsis, in patients with acute leukemia.

Mercaptopurine carries warnings/ precautions for myelosuppression, hepatotoxicity, immunosuppression, and embryo-fetal toxicity. Complete blood count should be monitored and the mercaptopurine dose adjusted for severe neutropenia and thrombocytopenia. Patients with repeated severe myelosuppression should be evaluated for TPMT deficiency. Serum transaminase levels, alkaline phosphatase, and bilirubin levels should be monitored weekly at the start of therapy and monthly thereafter.

Due to immunosuppression associated with maintenance chemotherapy for ALL, response to all vaccines may be diminished and there is a risk of infection with live virus vaccines. Immunization guidelines for immunocompromised children should be consulted. n References 1. U.S. Food and Drug Administration: Mercaptopurine. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm395156.htm.

2. PURIXAN™ (mercaptopurine) oral suspension prescribing information, NOVA Laboratories Limited, April 2014. Available at www.accessdata.fda.gov/drugsatfda_ docs/label/2014/205919s000lbl.pdf.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/ medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

ASCOPost.com | JUNE 25, 2014

PAGE 77

Journal Spotlight Gastrointestinal Oncology

Colonoscopy Adenoma Detection Rate Inversely Proportional to Risk of Interval Colorectal Cancer and Colorectal Cancer Mortality

By Matthew Stenger

I

n a study of health-care organization data reported in The New England Journal of Medicine, Douglas A. Corley, MD, PhD, of Kaiser Permanente, and colleagues assessed the relationship between proportion of colonoscopies performed by a gastroenterologist that detect an adenoma and risk of subsequent interval colorectal cancer and colorectal cancer mortality.1 They found that adenoma detection rate is inversely proportional to risk of interval cancer and death from colorectal cancer.

tal adenocarcinoma, discontinuation of membership in the health-care organization, or the end of the follow-up period on December 31, 2010.

Associations between adenoma detection rate and the risk of colorectal cancer diagnosed 6 months to 10 years after colonoscopy and cancer-related death were examined. Cox regression analysis adjusted for patient demographic characteristics, indications for colonoscopy, and coexisting conditions were used to estimate attributable risks for interval

These findings support the validity of the adenoma detection rate as a quality measure of physicians’ performance of colonoscopy in community practice. Studies to determine whether improving the adenoma detection rate leads to improved outcomes are warranted.

—Douglas A. Corley, MD, PhD, and colleagues

Adenoma detection rate has been recommended as a quality benchmark and recently has been proposed as a reportable quality measure by the Centers for Medicare & Medicaid Services. Currently, adenoma detection rates ≥ 15% in women and ≥ 25% in men are recommended as indicators of adequate colonoscopy quality. Data validating these thresholds are lacking.

Study Details The study involved analysis of 314,872 colonoscopies performed by 136 gastroenterologists in an integrated health-care delivery organization (Kaiser Permanente Northern California, total of 17 medical centers). Patients in the organization were enrolled in Medicare, Medicaid, or a commercial insurance plan and were included in the study if they had undergone a colonoscopy between January 1, 1998, and December 31, 2010, were ≥ 50 years old at the time of colonoscopy, and had at least 6 months of subsequent follow-up. Gastroenterologists included in the study had to have completed ≥ 300 colonoscopic examinations and ≥ 75 screening examinations during the study period.

Patients were followed from the date of the colonoscopy to completion of 10 years of follow-up, diagnosis of colorec-

colorectal cancer, advanced-stage interval cancer, and fatal interval cancer.

Colorectal Cancer in Study Population Of all colonoscopies, 58% were for diagnosis, 24% were for surveillance, and 18% were for screening. Exclusion of 8,018 examinations that detected cancer within 6 months of colonoscopy and an additional 41,882 examinations occurring with < 6 months of follow-up left 264,972 colonoscopies among 223,842 patients and totals of 712 interval colorectal adenocarcinomas (8.2% of all colorectal cancers), 255 advanced-stage cancers, and 147 deaths from interval colorectal cancer included in the analysis.

The median interval between index examination and the diagnosis of interval cancer was 39 months. Among the 712 interval cancers detected, the indi-

cation for colonoscopy was diagnosis for 55% of cases, surveillance for 33%, and screening for 13%.

Adenoma Detection Rates and Subsequent Risk The average number of colonoscopies performed by individual physicians was 2,150 (range = 355–6,005). Adenoma detection rates ranged from 7.4% to 52.5% (9.7%–60.5% in male patients and 3.9%– 45.9% in female patients). There was a strong correlation between adenoma detection rates based on screening alone and those based only on diagnostic examination (r = 0.75, P < .001) or only on surveillance (r = 0.72, P < .001).

Adenoma detection rates per lowest (1st) to highest (5th) quintile were 16.56% (range = 7.35%–19.05%), 21.50% (19.06%–23.85%), 25.70% (23.86%– 28.40%), 30.96% (28.41%–33.50%), and 38.86% (33.51%–52.51%).

Unadjusted risks of interval cancer per 10,000 person-years of follow-up according to lowest to highest quintiles of adenoma detection rate were 9.8, 8.6 (hazard ratio [HR] vs 1st quintile = 0.83, 95% confidence interval [CI] = 0.70–1.23), 8.0 (HR = 0.85, 95% CI = 0.68–1.06), 7.0 (HR = 0.70, 95% CI = 0.54–0.91), and 4.8 (HR = 0.52, 95% CI = 0.39–0.69).

On adjusted analysis, compared with patients with physicians in the 1st quintile, risk reductions in the 4th and 5th quintiles were significant for any adenocarcinoma (adjusted hazard ratio [HR] = 0.70, 95% confidence interval [CI] = 0.54–0.91, for 4th quintile; HR = 0.52, 95% CI = 0.39– 0.69, for 5th quintile), advanced-stage colorectal cancer (HR = 0.48, 95% CI = 0.33–0.71; HR = 0.43, 95% CI = 0.29– 0.64), and colorectal cancer death (HR = 0.51, 95% CI 0.33–0.81; HR = 0.38, 95% CI = 0.22–0.65). Each 1.0% increase in the adenoma detection rate was associated with a 3.0% decrease in the risk of cancer (HR = 0.97, 95% CI = 0.96–0.98) and a 5.0% decrease in the risk of fatal interval cancer (HR = 0.95, 95% CI = 0.94–0.97).

Impact of Colorectal Cancer Screening ■■ There was an inverse association between adenoma detection rate and risk of colorectal cancer, advanced-stage colorectal cancer, and colorectal cancer mortality.

■■ The data suggest that increase in adenoma detection rate from the lowest to highest quintiles (< 19% to 34%–53%) in the study could result in prevention of 1 additional cancer over the next 10 years for every 213 colonoscopies performed.

Risk Reduction by Gender and Cancer Location The association between the adenoma detection rate and the risk of interval cancer was observed both in women (HR for 5th vs 1st quintile = 0.43, 95% CI = 0.28–0.66) and men (HR = 0.60, 95% CI = 0.42–0.88), with no significant interaction according to sex (P = .23).

There was an inverse association between adenoma detection rate and subsequent risk of cancer in the proximal colon (HR for 5th vs 1st quintile = 0.49, 95% CI = 0.35–0.69) and distal colon (HR = 0.55, 95% CI = 0.39–0.79) and for early cancer (HR = 0.40, 95% CI = 0.23–0.68) and delayed cancer (HR = 0.61, 95% CI = 0.39–0.96).

As noted by the investigators, the hazard ratio of 0.52 for interval colorectal cancer suggests that physicians who increase their adenoma detection rate from < 19% (lowest quintile) to 34% to 53% (highest quintile) might prevent 1 additional interval cancer over the next 10 years for every 213 colonoscopies performed.

The investigators concluded: [I]n a large community-based US population across multiple medical centers, physicians’ adenoma detection rates were inversely related to the risk of interval colorectal cancer, including advanced-stage cancer and fatal interval colorectal cancer, among patients with up to 10 years of follow-up. This association was approximately linear across quintiles of adenoma detection rates in our population and was observed for male and female patients, cancers in the proximal and distal colon, and early and delayed interval cancers. These findings support the validity of the adenoma detection rate as a quality measure of physicians’ performance of colonoscopy in community practice. Studies to determine whether improving the adenoma detection rate leads to improved outcomes are warranted. n Disclosure: The study was funded by the Kaiser Permanente Community Benefit program and the National Cancer Institute. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Corley DA, Jensen CD, Marks AR, et al: Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med 370:1298-1306, 2014.

See perspective by G.S. Raju, MD, FACG, FASGE, on page 78.

The ASCO Post | JUNE 25, 2014

PAGE 78

Perspective

Colon Cancer Prevention: It’s All About Mindset and Minute Details

By G.S. Raju, MD, FACG, FASGE

I

would like to congratulate Corley and his colleagues for their seminal work on the association between adenoma detection rate and risk of colorectal cancer, advanced colorectal cancer, and colorectal cancer mortality. The impact of their findings—reported in The New England Journal of Medicine1 and reviewed in this issue of The ASCO Post—is far-reaching in society and brings the debate on quality of colonoscopy screening to center field. Each and every player in the field has a stake in this operation. So let us step back and look at what it takes for colonoscopy to prevent colon cancer.

For colonoscopy to be effective in the prevention of colon cancer prevention, one needs to have a searchand-destroy mindset—screen the colon carefully for both the obvious large polypoid lesions as well as the less obvious subtle flat lesions, and cut the precancerous lesions completely and safely. In order to accomplish this task, all players—the patient, the endoscopist, and the primary care provider—need to perform their assigned tasks well, and programs must be set in place to monitor and maximize the chances of optimal outcome.

‘Wash and Rinse’ From the patient’s perspective, it is critical to prepare the colon well to allow the colonoscopist to detect subtle flat lesions. Residual stool after an incomplete colonoscopy preparation frequently noted after a single overnight-dose colon preparation can hide polyps, flat lesions, and cancer.

This could be avoided by splitting the dose of colon preparation: half in the evening before the procedure and the other half on the morning of the Dr. Raju is Professor of Medicine, Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston.

procedure, with the last dose 4 hours before the procedure, results in a clean colon for excellent screening.

This is best described to the patient as a “wash and rinse” cycle in a dishwasher that ensures excellent clean out in the majority of patients. We should aim for an excellent preparation, and this method can produce a Boston Bowel Preparation Scale score of 8 to 9 in over 95% of cases.

Search and Destroy From the colonoscopist’s perspective, it is critical to have a mindset of going on a search mission—taking pains to search for polyps and not going in casually for just another colonoscopy. This can be accomplished by

that the goal is to screen a particular patient’s colon completely—and take whatever time it takes to get the job done.

From the colonoscopist’s perspective, it is also critical to remove the lesions completely and safely. Removal of pedunculated polyps (those that look like mushrooms) is easy—all that is required is a simple snare resection. However, removal of flat lesions by the same snare resection can be risky (may precipitate bleeding and perforation) and is incomplete in up to 15% to 30% of cases. Removal of these flat lesions requires additional skills, such as injection of fluid to lift the lesion from the wall, followed by snare resection; one should

Although patients prefer colonoscopists who offer efficient and on-time service, with free parking and other perks, it is time to educate everyone about the importance of adenoma detection rate and high-quality colonoscopy screening in colon cancer prevention.

—G.S. Raju, MD, FACG, FASGE

adequate training that allows reaching the cecum in over 95% of cases, carefully scanning the entire wall circumferentially for subtle flat lesions, checking the bends and corners as well as folds for hidden lesions, suctioning puddles of fluid as well as clearing froth in search of submerged lesions, and taking the time to examine the entire colon.

Although various society guidelines suggest a minimum of 6 minutes of withdrawal time for adequate examination, one should not forget

be prepared to control bleeding and close a perforation if a complication were to occur when removing flat lesions.

When such skills are not available, patients could be referred to colonoscopy centers of excellence for safe and complete removal of such large flat lesions and avoid unnecessary surgery.

Because large lesions are at high risk of progression to malignancy, close follow-up to document complete eradication of the neoplasm at 6 to 12 months after resection is critical.

Choose Well From the referring physician’s perspective, it is important to safeguard the interests of their patients. Unlike many screening programs involved in cancer prevention (skin, breast, prostate, etc), colon cancer prevention is labor intensive and costly for the patient and family; the patient needs to take time off from work to prepare for the procedure; and family members need to take time off from work to escort the patient back from the procedure. Finally, incomplete screening of the colon is a waste of time and a loss of the opportunity to prevent cancer.

So, how does one choose a colonoscopist to screen the patients?

Corley and colleagues’ work offers some insights on how to choose the colonoscopist. Those that screen well and showcase a high adenoma detection rate are likely to have less interval colorectal cancers in their patients.

The three major GI societies identified adenoma detection rate as an important quality metric and recommended it as a physician quality reporting system metric to the Centers for Medicare & Medicaid Services. It is time to request adenoma detection rates from your local colonoscopists and use the data to refer to those with an excellent track record. Although patients prefer colonoscopists who offer efficient and on-time service, with free parking and other perks, it is time to educate everyone about the importance of adenoma detection rate and high-quality colonoscopy screening in colon cancer prevention. n

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

Reference 1. Corley DA, Jensen CD, Marks AR, et al: Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med 370:1298-1306, 2014.

NOW ENROLLING – A RANDOMIZED PHASE III STUDY

A phase III study of the CDK4/6 inhibitor LEE011 in combination with letrozole for the treatment of postmenopausal women with advanced breast cancer Screening assessments

Postmenopausal women with HR+/HER2– advanced breast cancer No prior systemic anticancer therapy for advanced disease

Randomization (1:1)

ECOG performance status 0 or 1 Additional inclusion/exclusion criteria apply.

Letrozole 2.5 mg QD + LEE011 600 mg QD

For more information • Contact your local Novartis medical representative • Call Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (US only)

Letrozole 2.5 mg QD + placebo QD

Primary end point: Progression-free survival Key secondary end point: Overall survival

Abbreviations: CDK4/6, cyclin-dependent kinase 4/6; ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; QD, once daily.

• Visit www.clinicaltrials.gov (NCT01958021)

LEE011 is an investigational drug. Efficacy and safety have not been established. There is no guarantee that LEE011 will become commercially available.

MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.

Novartis Pharma AG CH-4002 Basel, Switzerland

© Novartis 2014

March 2014

G-PIP-1084431

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936-1080

The ASCO Post | JUNE 25, 2014

PAGE 80

Announcements

Maurie Markman, MD, Named President of Medicine & Science Unit, Cancer Treatment Centers of America

C

ancer Treatment Centers of America (CTCA) recently announced the appointment of Maurie Markman, MD, as President of the

Maurie Markman, MD

company’s Medicine & Science unit.

He will be responsible for advancing the organization’s overall commitment to clinical excellence, innova-

tion, safety, and patient satisfaction.

Dr. Markman served most recently as Senior Vice President of Clinical Affairs & National Director of Medical Oncology at CTCA. “We are delighted to have Dr. Markman assume the leadership of this vitally important group within Cancer Treatment Centers of America,” said CTCA President and CEO Gerard van Grinsven. His expertise in the field of medical oncology and clinical research, combined with his pioneering work in the emerging field of advanced genomic testing, will ensure we continue to deliver the very best clinical care to our patients.”

In his new role, Dr. Markman will assume oversight of the CTCA

national clinical team, with a focus on the application of all clinical and translational research to patient care. An expert in research on gynecologic malignancies, new drug development, and novel management strategies, Dr. Markman served in a variety of clinical leadership and academic positions at prior to joining CTCA in 2010, including The Cleveland Clinic, the University of Texas-MD Anderson Cancer Center, The Ohio State University, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, and the University of California San Diego School of Medicine.

A graduate of the University of Southern California, Dr. Markman received

his medical degree from New York University (NYU) School of Medicine, as well as a Master of Science in Health Policy and Management from the NYU Graduate School of Public Administration. After completing his internship and residency in internal medicine at Bellevue Hospital - New York University Medical Center, he served as a Clinical Associate of the National Cancer Institute’s Immunology Branch, then as an Assistant Professor of Oncology and Medicine at The Johns Hopkins Hospital.

“Dr. Markman, “and look forward to lending my expertise to the continued advancement of the exceptional quality of care we deliver to our patients.” n

Marie-Josée and Henry R. Kravis Foundation Provides $100 Million Gift to Support Precision Oncology Work at Memorial Sloan Kettering Cancer Center

M

emorial Sloan Kettering Cancer Center has launched an initiative to improve cancer care and research through genomic analysis. The new program will reshape clinical trials and speed the translation of novel molecular discoveries into routine clinical practice. The Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO) is named in honor of Marie-Josée and Henry R. Kravis, whose gift of $100 million will make it possible to further the promise of precision oncology and support the development of new, individualized cancer therapies and diagnostic tools.

“Progress in our understanding of the biology of cancer has completely shifted the way we think about and treat cancer,” says Craig Thompson, MD, President and CEO, Memorial Sloan Kettering Cancer Center.

Craig Thompson, MD

“We’re moving away from the concept of treating cancer as many different

types of the same disease and toward treating each person’s cancer as its own unique disease. Now, thanks to the inspiring generosity of the Marie-Josée and Henry R. Kravis Foundation, we will be able to expand and intensify this effort, ushering in what will truly be a new era of precision medicine.”

“Memorial Sloan Kettering has already proven itself to be a leader in understanding cancer at the genetic level and in putting that knowledge to work for patients,” says Mr. Kravis. “The new Center for Molecular Oncology (CMO) will take these efforts to an entirely new level, and I look forward with great anticipation to the discoveries that lie ahead.”

integrated clinical and scientific teams coupled with our ever-increasing genetic sequencing capabilities will allow us to build upon the molecular insights we’ve gleaned over the past decade to accelerate the development of more effective and less toxic cancer therapies.”

Next-Generation Sequencing

Basket Studies and Exceptional Responders

Archived tumor specimens and tissues obtained in clinical trials will be comprehensively profiled by nextgeneration sequencing and other molecular technologies. The molecular information of each tumor will then be correlated with clinical outcomes to better understand the significance of genetic alterations in tumors and the opportunities they offer for treating cancers more precisely.

David Solit, MD, the inaugural Director of the CMO, said, “The vision for the CMO is nothing less than to revolutionize the treatment of cancer. Our

Jose Baselga, MD

David Solit, MD

A cornerstone of the CMO will be to enroll patients in phase I clinical trials called basket studies, in which therapies are offered to patients whose tumors test positive for certain mutations regardless of cancer type. “The location of a tumor, such as breast or lung cancer, is becoming less important than the genomic information of the tumor, and basket studies include many more people than a diseasespecific trial. A therapy designed for a specific mutation could benefit everyone whose tumor has that mutation.

It really is a game changer,” said Jose Baselga, MD, Physician-in-Chief, of Memorial Sloan Kettering Cancer Center.

The CMO will also focus on retrospectively analyzing tumors of exceptional responders, defined as patients who have a sustained response to treatment in a clinical trial in which almost all other participants do not.

Michael Berger, PhD, Associate Director of the CMO, developed the Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) test, a new technology platform that can reliably and accurately screen for mutations in 341 cancer-associated genes. Memorial Sloan Kettering plans to use the IMPACT test to help screen more than 10,000 patients each year for genetic mutations that predict for sensitivity to novel cancer therapies.

This effort will also help identify new drug targets that will serve as the basis for future clinical studies. n

ASCOPost.com | JUNE 25, 2014

PAGE 81

Announcements

David Craig, PharmD, Named to FDA Advisory Committee

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offitt Cancer Center recently announced that Clinical Pharmacist David Craig, PharmD, has been appointed to the U.S. Food and Drug Administration’s Anesthetic and Analgesic Drug Products Advisory Committee. Dr. Craig specializes in pain medicine and palliative care. The Anesthetic and Analgesic Drug Products Advisory Committee reviews and evaluates the safety and effectiveness of products used for anesthesiology as well as for treatment for pain after surgery.

“Through my involvement on this committee, I hope to improve the safety and efficacy of all pharmacological analgesic treatment strategies,” said

Dr. Craig. The committee consists of 13 members, who are knowledgeable in the fields of anesthesiology, surgery, epidemiology, and other related specialties.

Safe Tools to Manage Pain “My interest in pain management began when I was a pharmacist resident at Duke University Hospital and continued at Moffitt. I was intrigued when I first discovered that often simple clinical strategies can have such a significant impact on something patients cared so much about—their pain control. I am honored that as a member of the Anesthetic and Analge-

David Craig, PharmD

sic Drug Products Advisory Committee, I will guide policy that will impact patients directly and provide them with safe tools to manage their pain,” said Dr. Craig.

Dr. Craig has worked at Moffitt for over 10 years. During that time he

became a member of the American Pain Society and served on the Board of Directors for 3 years and recently completed a 2-year term as Secretary of the society. In addition, he recently completed the Mayday Pain and Society Fellowship, which educates physicians, nurses, pharmacists, social workers, scientists, and legal scholars in the pain management community to more effectively communicate their work and raise awareness about and improve the treatment of acute and chronic pain. His appointment to the Anesthetic and Analgesic Drug Products Advisory Committee will run through 2018. n

Federal Pain Research Database Launched

T

he Interagency Pain Research Portfolio (IPRP), a database that provides information about pain research and training activities supported by the federal government, has been launched by six federal agencies.

“This database will provide the public and the research community with an important tool to learn more about the breadth and details of pain research supported across the federal government. They can search for individual research projects or sets of projects grouped by themes uniquely relevant to pain,” said Linda Porter, PhD, Policy Advisor for Pain at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH). “It also can be helpful in identifying potential collaborators by searching for topic areas of interest or for investigators.”

Users of the database can search over 1,200 research projects in a multi-tiered system. In Tier 1, grants are organized as basic, translational (research that can be applied to diseases), or clinical

research projects. In Tier 2, grants are sorted among 29 scientific topic areas related to pain, such as biobehavioral and psychosocial mechanisms, chronic overlapping conditions, and neurobiological mechanisms.

The database was developed by NIH staff and members of the Interagency Pain Research Coordinating Committee (IPRCC). The IPRCC is a federal advisory committee formed to increase understanding of pain and improve

This database will provide the public and the research community with an important tool to learn more about the breadth and details of pain research supported across the federal government.

—Linda Porter, PhD

The Tier 2 categories are also organized into nine research themes: pain mechanisms, basic to clinical, disparities, training and education, tools and instruments, risk factors and causes, surveillance and human trials, overlapping conditions, and use of services, treatments, and interventions.

treatment strategies by expanding pain research efforts and encouraging collaboration across the government.

Four of the agencies that played a role in developing the IPRP are part of the U.S. Department of Health and Human Services. In addition to NIH, they are the Agency for Healthcare Research

and Quality, the Centers for Disease Control and Prevention, and the Food and Drug Administration. The other two agencies are the Department of Veterans Affairs and the Department of Defense.

“The database reveals a diverse research portfolio in which contributions from federal agencies and departments reflect their unique missions and the populations that they serve. For the first time, this information has been collected into a single database that can be mined to ensure that federal research efforts are not redundant and to identify opportunities to collaborate and share resources across agencies,” said Dr. Porter. “In addition, it will help the federal entities that support pain research to identify gaps in research areas and trends in topic areas over time.”

To access the IPRP database, visit: http://paindatabase.nih.gov For information about the IPRCC, visit: http://iprcc.nih.gov n

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | JUNE 25, 2014

PAGE 82

Issues in Oncology Health-Care Policy

Cancer Care Under the Affordable Care Act

By Ronald Piana

T

he problematic rollout of the Affordable Care Act’s website, HealthCare.gov, made good political theater, but while much of the heated discussion centered on the plan’s need to enroll “young invincibles,” America’s cancer care system and the older patients it serves were also affected by parts of the bill implemented in January 2014. Notably, insurance companies can no longer deny coverage for preexisting conditions, such as cancer, or put lifetime dollar limits on policies, once a financial trapdoor for cancer patients.

Beyond these valuable new provisions, one of the aims of the Affordable Care Act is to incrementally move the country toward universal health-care coverage. The scope is formidable: Prior to implementation of the Affordable Care Act, more than 47 million Americans—about 18% of the population— were uninsured. To begin the process, two major provisions went into effect this year: the creation of health insurance marketplaces, where low and moderate income families receive premium

Beverly Moy, MD, MPH

tax credits for coverage, and expanded Medicaid coverage to all individuals not eligible for Medicare under age 65 with incomes up to 138% of the federal poverty level (although, at this time, 24 states have chosen not to move forward with the Medicaid expansion).

In a Journal of Clinical Oncology article published the year after the Affordable Care Act was signed into law, the authors wrote, “The elimination of cancer disparities is critically important for lessening the burden of cancer. The [Affordable Care Act] provides both the opportunities and challenges for addressing cancer care disparity and access to care.”1 The ASCO Post asked the article’s lead author, Beverly Moy, MD, MPH, Clinical Director of the Breast Oncology Program at Massachusetts General Hospital, Boston, to comment on the effects of the Affordable Care Act’s 2014 rollout. “I would say that the [Affordable Care Act] has had less effect

in Massachusetts compared with other areas of the country since we have had health-care reform since 2006. A recent study published in the Annals of Internal Medicine showed that death rates in Massachusetts are lower compared with comparable areas of the country since near-universal health-care coverage began in 2006.2 Improvements in mortality were greatest in counties where incomes were lower and pre-reform uninsured rates were higher,” said Dr. Moy. Dr. Moy remarked that while the benefits seen in the study may not be generalizable to other states, these data suggest that improving access to health care leads to better clinical outcomes.

“Moving beyond demanding access to health insurance for all Americans, we should also carefully scrutinize the medical benefits offered under Medicaid in order to ensure the best cancer care possible,” said Dr. Moy.

“The Medicaid population is heterogeneous, consisting of long-time enrollees and those who join the program as a safety net after being diagnosed with a life-threatening disease, such as cancer. For various reasons, the safety-net group, comprised mostly of individuals who may have been previously uninsured or underinsured, is more likely to have worse cancer outcomes than longtime Medicaid enrollees. These findings demonstrate the benefit of being on Medicaid rather than uninsured, relative to cancer outcomes,” said Dr. Koroukian.

When States Opt Out The Congressional Budget Office estimates that the federal government will bear nearly 93% of the costs of the Medicaid expansion over its first 9

Expanding Medicaid On June 28, 2012, the Supreme Court issued a ruling upholding the constitutionality of the Affordable Care Act; however, the high court also ruled that individual states have the right to choose whether to adopt the Act’s Medicaid expansion, which some governors have opted out of, claiming that it would place an undue financial burden on their states. More than 15 million uninsured adults could become newly eligible for Medicaid across all states.

The sheer number of potential enrollees makes for gargantuan challenges, but for populations of uninsured, low-income people with cancer, the Medicaid expansion program offers an opportunity for new access to cancer care. Nevertheless, studies have found disparities in outcomes among Medicaid cancer patients and inadequacies in the program’s process of care.3 Some experts have even posited that uninsured cancer patients fair no worse than their counterparts enrolled in Medicaid.

According to health policy expert, Siran M. Koroukian, PhD, Associate Professor in the Department of Epidemiology and Biostatistics at Case Western Reserve University, Cleveland, most studies that compare cancer outcomes between Medicaid patients and the uninsured rely on data that reflect insurance status at a given point in time, such as time of diagnosis, without accounting for the patient’s history of enrollment in relation to the diagnosis of cancer.

Martin J. Heslin, MD

years, from 2014 to 2022. The federal government will also pick up 100% of the cost of covering people made newly eligible for Medicaid from 2014 to 2017 and no less than 90% on a permanent basis. Currently, 27 states, including the District of Columbia, are implementing Medicaid expansion; 5 states are in open debate about the issue, and 19 states are not moving forward with Medicaid expansion.

To shed light on the issues facing states that decline the Affordable Care Act’s offer of Medicaid expansion, The ASCO Post spoke with Martin J. Heslin, MD, MSHA, Chief of Surgical Oncology and Associate Director for Clinical Programs at the University of Alabama at Birmingham (UAB) Comprehensive Cancer Center. Dr. Heslin said that Medicaid has been an issue in Alabama for a long time due to four issues: (1) Alabama is the only state where the hospital portion of the State Medicaid portion is funded 100% by the hospitals themselves, (2) Medicaid only reimburses 67% of costs, (3) the disproportionate share payments, which compensate hospitals that treat low-income patients, will be significantly reduced, and (4) Medicaid is moving

to a managed care program, and cost savings will only be through improved population health management.

To deal with their impending fiscal travails, UAB and a number of statewide stakeholders are working to form a Regional Care Organization whose goal is to manage the risks of a Medicaid population. “This is obviously a large shift from a volume- to a value-based care program. Currently we provide stateof-the-art cancer care regardless of the patient’s ability to pay, even though we lose money through our current Medicaid program,” said Dr. Heslin.

The other critical issue in Alabama is the Affordable Care Act’s high-deductible plans. Data suggest that Alabama residents have lower-than-national-average monthly premiums, but one of the highest average deductibles in the nation.

“The concern is that patients might not seek care in a timely fashion or that they might be financially compromised with a very high deductible for lifesaving cancer care. Similarly, some families might not be able to pay very high deductibles, which will increase the institution’s bad debt. Like other institutions, UAB has revised its charity program to manage families that cannot pay the large deductible. Ultimately, the goal at UAB is to provide quality costeffective care regardless of one’s payer status,” said Dr. Heslin.

Inner-City Cancer Patients John V. Cox, DO, MBA, FASCO, is part of a 10-doctor team at Texas Oncology Methodist Dallas Cancer Cen-

John V. Cox, DO, MBA, FASCO

ter, that serves a safety-net hospital in urban Dallas. Asked about access issues under the Affordable Care Act, Dr. Cox responded, “We recognize it is early and we are monitoring multiple issues, but as of now I’m not aware of any identifiable access problems. The issue we’re most concerned about is the [Affordable Care Act’s] 90-day grace period rule for patients on premium payments, continued on page 84

The ASCO Post | JUNE 25, 2014

PAGE 84

Issues in Oncology Affordable Care Act continued from page 82

which puts us at risk for providing expensive services we might not be reimbursed for. Most of the [Affordable Care Act] exchange plans in our area are providing real-time data on the payment status of the patients we care for. To my knowledge, that system is working adequately.”

Dr. Cox’s patient population is largely blue-collar working poor with difficult financial challenges. “When you have a malignancy, you’re going to face the financial responsibility for the ­[Affordable Care Act’s] $6,300 deductible pretty quickly, which can create a barrier to the working poor. We have certain payment plans to offer, but given the expensive therapies we deliver, I fear the high deductible is going to create access problems down the line.”

On a positive note, Dr. Cox believes that all the political ballyhoo over the health insurance exchanges has informed and encouraged many Medicaid-eligible Texans to visit HealthCare.gov and evaluate their own coverage opportunities. “Texas has very stringent Medicaid guidelines, but we’re seeing an uptick in enrollment and we’re hopeful that it will make a significant dent in the uninsured in our state,” said Dr. Cox. Asked about Medicaid’s historically low reimbursement rates to providers, Dr. Cox observed, “The real tension in our practice is seeing patients who fall between the cracks of Medicaid’s reimbursement guidelines. We fight to provide quality care for uninsured patients, and oftentimes we lose money in the process. Texas is among the states with the poorest Medicaid reimbursement rates in the country. We’re certainly not looking to become a primary Medicaid provider, but hands down it is better than treating cancer patients who are uninsured. Dealing with the uninsured consumes a huge

amount of practice resources and time.”

Dr. Cox acknowledged that Medicaid creates barriers to care. “Medicaid poses access issues because a lot of our specialty colleagues in the area don’t accept patients from the program. But having Medicaid is far better than being uninsured,” said Dr. Cox, adding, “There are multiple provisions in the [Affordable Care Act] that serve our cancer patient populations. Speaking as a doctor who treats a lot of working poor patients, anything that gets them health coverage is good.”

Cancer Prevention According to Johnie Rose, MD, PhD, Assistant Professor and Preventive Medicine Residency Program Director at Case Western Reserve

fordable Care Act] by 2017, more people will be in a position to access these newly covered services,” said Dr. Rose.

He continued, “The [Affordable Care Act] also takes some steps to reduce risk factors for many cancers through enhanced support of workplace wellness programs, grants for various wellness demonstration projects, grants for community health programs, requirements for nutritional labeling of menu items at chain restaurants, and other provisions.”

Top Cancer Centers There is substantial pressure under the Affordable Care Act for exchange plans to limit the growth of health costs.

Recently, several articles in the lay press have pointed out that many of the na-

Patients want to be insured. The Affordable Care Act provides a pathway to health-care coverage, and we’re in a better place because of it.

—Michael N. Neuss, MD

University, a significant benefit of the Affordable Care Act is improved access to numerous evidence-based preventive services.

“Under the [Affordable Care Act], most insured individuals will receive first-dollar coverage of U.S. Preventive Services Task Force–recommended clinical preventive services including screening and intervention for obesity, tobacco use, and alcohol abuse and screening for colorectal cancer, breast cancer, and cervical cancer. Importantly, with 26 million Americans expected to gain insurance as a result of [the Af-

tion’s leading academic cancer centers are not included in certain plans covered by the Affordable Care Act’s insurance exchanges. Some experts are concerned that cost-reduction provisions in the law might compromise access to premier cancer centers. In reaction, the Obama administration has released a statement saying that insurers in states served by federal health exchanges will receive closer scrutiny to ensure compliance with the law.

According to Michael N. Neuss, MD, Chief Medical Officer, VanderbiltIngram Cancer Center, Nashville, “I

have never been aware of a patient who needed treatment who was denied that care for payment reasons. Hospitals and pharmaceutical companies have been excellent and generous partners to physicians who have donated their expertise, effort, and time for patients who were unable to pay. This collaborative tradition is as old as our profession.”

Dr. Neuss noted that in a few instances, established patients have purchased Affordable Care Act plans that were not included in Vanderbilt and the Vanderbilt-Ingram Cancer Center coverage. “Several patients have had to change providers who are outside of our system. Unfortunately, two patients had to stop participation in clinical trials because they weren’t open in the facilities participating in their plan,” said Dr. Neuss.

He continued, “For all the business language of panels, coverage plans, open enrollment periods, and preexisting conditions, the bottom line is clear: Patients want to be insured. The Affordable Care Act provides a pathway to health-care coverage, and we’re in a better place because of it.” n

Disclosure: Drs. Moy, Koroukian, Heslin, Rose, and Neuss reported no potential conflicts of interest.

References 1. Moy B, Polite BN, Halpern MT, et al: American Society of Clinical Oncology policy statement: Opportunities in the patient protection and affordable care act to reduce cancer care disparities. J Clin Oncol 29:3816-3824, 2011.

2. Sommers BD, Long SK, Baicker A, et al: Changes in mortality after Massachusetts health care reform: A quasi-experimental study. Ann Intern Med 160:585-593, 2014.

3. Koroukian SM, Bakaki PM, Raghavan D: Survival disparities by Medicaid status: An analysis of 8 cancers. Cancer 118:42714279, 2012.

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The ASCO Post | JUNE 25, 2014

PAGE 86

JCO Spotlight Genomics

Physician Attitudes About Multiplex Tumor Genomic Testing: Variation in Projected Use and Confidence

By Matthew Stenger

I

t is a widely expressed belief that predictive multiplex somatic genomic testing represents the ability to transform cancer care by identifying targetable alterations in multiple cancer genes. Do oncologists share this belief ? How do they intend to use such tests in practice?

In a study reported in the Journal of Clinical Oncology, Stacy W. Gray, MD, AM, of Dana-Farber Cancer Institute, Boston, and colleagues surveyed physicians at a tertiary-care National Cancer Institute–designated comprehen-

alterations of uncertain significance (tier 3 results—ie, all other genetic variants) was prohibited.

Physician Survey The survey contained questions on use of genetic testing before the introduction of Profile (baseline testing), anticipated impact of testing, and sociodemographic and practice characteristics. Physicians were asked to estimate the proportion of patients who they would test, how often they would disclose results to patients, and

Given that many physicians reported low genomic confidence, evidencebased guidelines and enhanced physician genomic education efforts may be needed to ensure that genomically guided cancer care is adequately delivered.

—Stacy W. Gray, MD, AM, and colleagues

sive cancer center about their current use of somatic testing, attitudes about multiplex testing, and confidence in their knowledge of genomics as well as their ability to use and explain genomic information in practice.1 They found considerable variation in intentions to incorporate such testing into clinical practice and frequent reporting of low “genomic confidence.”

Profile Study In the study, all faculty members who provide clinical care to adult patients with cancer at Dana-Farber Cancer Institute/Brigham and Women’s Hospital were recruited between September 2011 and January 2012 to participate in the survey prior to the initiation of enterprise-wide multiplex testing as part of the Profile study. In the first part of the study, all patients with cancer were offered OncoMap, a test for 471 alterations in 41 cancer-related genes.

Test results were tiered based on clinical utility. Tier 1 results (genomic variants proven to be clinically relevant) and tier 2 results (potentially actionable genomic variants) could be returned to the patient’s provider with patient consent; disclosure of

how often they would use results in making treatment recommendations.

They were also asked about the terms that they would use to describe multiplex testing to patients and about how much they agreed or disagreed with the decision to prohibit disclosure of tier 3 alterations.

A “genomic confidence” scale was constructed by combining three questions on physician confidence in their knowledge about genomics, ability to explain genomic concepts to patients, and ability to make treatment recommendations based on genomic information.

Baseline Data Of 276 physicians contacted, 13 were ineligible and 160 (61%) completed the survey. Of respondents,

57% were medical oncologists, 29% surgeons, and 14% radiation oncologists, 37% were female, and 83% were research principal investigators.

Prior to the introduction of the Profile program, physicians ordered tumor genomic testing for an average of 24% of patients (range, 0%–100%), with testing for KRAS (25%), EGFR (24%), BRAF (24%), C-KIT (13%), BRC-ABL (13%), and JAK2 (9%) being most common.

Many physicians were “not very confident” or “not confident at all” in their knowledge of genomics (22%), ability to explain genomic concepts to patients (14%), or ability to make treatment recommendations based on genomic data (26%). The largest group of respondents rated themselves as “somewhat confident” in these three areas (approximately 50% in each category), whereas approximately 25% to 35% rated themselves as “very confident.” The average score on the genomic confidence scale indicated an average response of “somewhat confident.”

In analysis adjusting for potential confounders, high genomic confidence was associated with being a medical oncologist, being a researcher, and high baseline genomic test use.

Predicted Use of Testing Overall, 18% of physicians stated they would test ≤ 10% of patients, whereas 25% said they would test 91% to 100%. Approximately 85%, 55%, and 42% of physicians felt that tier 1, tier 2, and tier 3 genomic alterations, respectively, should be discussed with patients, with approximately 15%, 25%, and 30%, respectively, indicating “do not know.” Approximately 70%, 50%, and 40% felt that tier 1, tier 2, and tier 3 wild-type results should be discussed with patients, with approximately 10%, 20%, and 25% indicating “do not know.”

Oncologists on Genomic Testing ■■ Physicians varied widely in estimates of the proportions of patients in whom they would use multiplex tumor genomic testing.

■■ Physician genomic confidence also varied widely.

■■ Higher genomic confidence was associated with greater likelihood of using testing, using test results to inform treatment recommendations, and disagreeing with a policy prohibiting disclosure of genomic information of uncertain significance.

Terms to describe testing to patients most frequently cited by physicians included tumor testing (77%), molecular testing (72%), tumor profiling (66%), genetic testing (62%), and biomarker testing (41%). On open-ended questioning, other terms physicians indicated they would use included tumor fingerprinting, treatment target testing, molecular biology testing, scanning for actionable mutations, and personalized therapy testing.

A majority of physicians indicated that OncoMap testing would “somewhat” or “greatly” increase patient treatment options (73%), prognostic information (62%), patient satisfaction (80%), time required to discuss treatment options with patients (73%), research opportunities (> 90%), and professional satisfaction (80%); 22% felt that OncoMap testing would increase their clinical uncertainty.

Predictors of Attitudes Toward Testing Logistic regression modeling controlling for potential confounders was used to assess the effects of years since medical school, sex, type of physician (medical oncologist or radiation oncologist vs surgical specialist as reference category), researcher (vs nonresearcher) status, number of new patients each month, percentage of patients tested at baseline (prior to Profile), percentage of patents recommended for phase 1 of Profile, and confidence in genomics on the likelihood of wanting to test a majority of patients, disclosing tier 1 and tier 2 results, using tier 1 and tier 2 results to inform treatment recommendations, and agreeing with the policy prohibiting return of tier 3 results.

The analysis showed that higher genomic confidence was significantly associated with wanting to test a majority of patients (adjusted odds ratio [OR] = 6.09, P < .001), likelihood of disclosing tier 1 results (OR = 2.14, P < .05), likelihood of using tier 1 (OR = 2.46, P < .05) and tier 2 results (OR = 2.89, P < .05) to inform treatment recommendations, and disagreement with the policy of prohibiting disclosure of tier 3 results (OR = 0.38, P < .05). continued on page 88

ASCOPost.com | JUNE 25, 2014

PAGE 87

Perspective

Genomic Confidence and Competence

By Patrick M. Boland, MD, and Michael J. Hall, MD, MS

A

s reported in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post, Stacy W. Gray, MD, AM, a medical oncologist at Dana-Farber Cancer Institute, Boston, and colleagues presented one of the first studies evaluating how academic oncologists perceive the incorporation of a novel multiplex somatic genomic testing platform, OncoMap, into clinical practice as part of the Profile study.1 A total of 160 academic oncologists at Dana-Farber and Brigham and Women’s Hospital completed the survey (an impressive 61% response rate), with the largest group being medical (43%) vs surgical or radiation oncologists. This was a group of physicians with substantial clinical and research experience: Over 70% had practiced oncology for at least 10 years, and 83% had served as a principal investigator for a clinical trial or laboratory research.

The study’s objectives were to describe current use of somatic testing by the participating physicians, to assess their intentions toward incorporation of OncoMap into clinical practice, and to examine how their intentions toward use of the OncoMap test would be impacted by their perceived ability to incorporate genomic medicine into their clinical practice.

A novel measure, genomic confidence, was developed by the investigative team as a composite measure of perceived clinical acumen in genomics, including knowledge of, ability to communicate about, and ability to practice genomic medicine.

tients. Genomic confidence, however, was variable among participants, with a substantial minority reporting feeling “not very” or “not at all” confident in their knowledge (22%), communication skills (14%), and ability to use genomic data to guide treatment (26%).

High genomic confidence was associated with being a researcher or a medical oncologist, and greater use of genomic tests at baseline. In a multivariate model, genomic confidence

Variation in ‘Genomic Confidence’

Current Practice

The investigators found that somatic tests were commonly being ordered (for approximately one of every four patients), and that physicians held largely positive attitudes toward the potential impact of ­OncoMap on their practice and paDr. Boland is Assistant Professor of Oncology, Department of Medicine, GI Center, Roswell Park Cancer Institute, Buffalo, NY. Dr. Hall is Assistant Professor of Medicine, Department of Clinical Genetics, Director of Gastrointestinal Risk Assessment, Fox Chase Cancer Center, Philadelphia.

tient outcomes. However, it is currently unclear how oncologists plan to use the information generated by multiplex somatic genomic tests in practice, especially results that may suggest a potential role for experimental therapy or off-label use of an approved agent. While these novel tests may be viewed as the future of personalized medicine, inappropriate testing and subsequent decisionmaking could in the short term result in increased costs without benefit,

As more data are generated on the potential utility of multiplex testing in improving patient access to targeted novel therapeutics and in cancer-related outcomes, ground-breaking research such as that conducted by Gray et al to examine physician practice patterns becomes increasingly important.

—Patrick M. Boland, MD, and Michael J. Hall, MD, MS

was a significant predictor of intention to use clinically relevant (tier 1) and potentially actionable (tier 2) mutations to guide treatment and of disagreement with the institutional policy prohibiting disclosure of uncertain variants (tier 3).

Next-generation sequencing technologies allow multiplex genomic testing to be performed on a paraffin-embedded tumor specimen in a clinically relevant time period of 1 to 2 weeks. Coupled with the ongoing robust development of novel targeted cancer therapeutics, the number of putatively clinically actionable alterations detected by these tests will continue to rise.

These advances have the potential to fuel more widespread use of costly multiplex somatic genomic tests by the oncology community, despite uncertain benefits in improving pa-

use of unproven or potentially harmful therapies, and ultimately greater clinical uncertainty.

Interpretation Initiated in 2011, the survey developed by Gray et al was conducted at a time when few oncologists would have been expected to have been exposed to multiplex somatic tests in the clinic, which may have limited their perspective when responding to hypothetical questions about making treatment decisions based on test results. In addition, because the survey was conducted prior to the roll-out of OncoMap, physicians’ intentions were themselves hypothetical in nature.

Nonetheless, it is interesting to note that physicians’ intentions to discuss results with patients and to use results in therapeutic decisions had no relation to their phase I trial referral rate, an association one might have expected to see. We are also not

informed of what providers actually did with the results of OncoMap and whether their behaviors changed over time during the study—specifically, which results were disclosed to patients and whether testing affected treatment decisions or outcomes.

Additionally, the measurement of genomic confidence was not accompanied by an objective assessment of knowledge. Thus, it remains difficult to understand whether genomic confidence is reflective of true genomic competence, and whether genomic incompetence could lead to inappropriate application of results and overuse of tests by inexperienced and/or ill-informed providers.

Finally, over half of participants surveyed were not medical oncologists, and many of these participants had never ordered a genomic test.

Thus, the immediate relevance of intentions toward somatic genomic testing to guide targeted cancer therapeutics in this population is questionable.

Conclusions As more data are generated on the potential utility of multiplex testing in improving patient access to targeted novel therapeutics and in cancerrelated outcomes, ground-breaking research such as that conducted by Gray et al to examine physician practice patterns becomes increasingly important. Follow-up studies examining how providers incorporate the results of multiplex testing into decision-making and clinical practice will be highly informative.

Further, efforts on the part of professional societies like ASCO to develop guidelines on the use of multiplex genomic panels accompanied by educational efforts to address knowledge deficiencies related to this technology will also be critical to build provider confidence in adopting new technologies in clinical practice and to mitigate risks of inappropriate use. n

Disclosure: Drs. Boland and Hall reported no potential conflicts of interest.

Reference 1. Gray SW, Hicks-Courant K, Cronin A, et al: Physicians’ attitudes about multiplex tumor genomic testing. J Clin Oncol 32:1317-1323, 2014.

The ASCO Post | JUNE 25, 2014

PAGE 88

JCO Spotlight Genomic Testing continued from page 86

Physicians with higher baseline genomic testing were significantly more likely to favor disclosing tier 2 results (OR = 1.02, P < .05). Medical oncologists were significantly less likely to favor disclosing tier 2 results (OR = 0.24, P < .05) and to believe

that tier 2 results would help inform treatment recommendations (OR = 0.16, P < .05) compared with surgical specialists. No other significant associations were found.

The investigators concluded: Physicians at a tertiary-care National Cancer Institute–designated comprehensive cancer center varied

considerably in how they planned to incorporate predictive multiplex somatic genomic tests into practice and in their attitudes about the disclosure of genomic information of uncertain significance. Given that many physicians reported low genomic confidence, evidence-based guidelines and enhanced physician genomic educa-

TELL YOUR ADVANCED PRACTICE COLLEAGUES TO

SAVE THE DATE

tion efforts may be needed to ensure that genomically guided cancer care is adequately delivered. n Disclosure: The study was supported by the Dana-Farber Cancer Institute and a grant from the American Cancer Society. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. Gray SW, Hicks-Courant K, Cronin A, et al: Physicians’ attitudes about multiplex tumor genomic testing. J Clin Oncol 32:1317-1323, 2014.

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2014–2015 Oncology Meetings June MASCC/ISOO International Symposium on Supportive Care in Cancer June 26-28 • Miami, Florida For more information: www.mascc.org/symposium

NCCN Policy Summit: The Impact of Health Care Reform on Academic Oncology Practice July 10 • Arlington, Virginia For more information: www.nccn.org/professionals/ meetings/oncology_policy_program/ impact_health_care_reform.aspx

European Conference of Oncology Pharmacy 2 June 26-28 • Krakow, Poland For more information: http://ecop2014.wordpress.com

Breast Cancer: New Horizons, Current Controversies July 10-12 • Boston, Massachusetts For more information: www.hms-cme.net/341279/

6th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone Disease June 28-July 2 • Oxford, United Kingdom For more information: www.oxfordbonepharm.org/

The 12th Annual Scientific Meeting of Japanese Society of Medical Oncology July 17-19 • Fukuoka, Japan For more information: www.congre.co.jp/jsmo2014/en/

16th International Symposium on Pediatric Neuro-Oncology June 28-July 2 • Singapore For more information: www.ispno2014.com

2014 Pan Pacific Lymphoma Conference July 21-25 • Kohala Coast, Hawaii For more information: www.unmc.edu/cce/ panpacificlymphoma.htm

July

8th Int’l Conference on Teenage and Young Adult Cancer Medicine July 7-8 • London, United Kingdom For more information: www.teenagecancertrust.org/whatwe-do/international-conference/

August

Best of ASCO® Seattle August 22-23 • Seattle, Washington For more information: boa.asco.org 6th Mayo Clinic Angiogenesis Symposium August 22-24 • Rochester, Minnesota For more information: www.mayo.edu/cme/ hematology-and-oncology-2014r606

Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org ASH Meeting on Lymphoma Biology August 10-13 • Colorado Springs, Colorado For more information: www.hematology.org/LymphomaBiology/ Hematology and Medical Oncology Best Practices August 14-21 • Arlington, Virginia For more information: smhs.gwu.edu/ cehp/activities/courses/hemonc Best of ASCO® Chicago August 15-16 • Chicago, Illinois For more information: boa.asco.org 16th Annual Scientific Meeting: AGITG Trials in Action August 20-22 • Brisbane, Australia For more information: www.agitg.asnevents.com.au

Best of ASCO in Japan July 5-6 • Kobe, Japan For more information: www.jsmo.or.jp/en/ 23rd Biennial Congress of the European Association for Cancer Research July 5-8 • Munich, Germany For more information: http://eacr23.eacr.org

2014-2015

5th World Congress of International Federation of Head and Neck Oncologic Societies Annual Meeting of American Head and Neck Society July 26-30 • New York, New York For more information: www.ahns.info/meetings/index.php AACR/ASCO Methods in Clinical Cancer Research Workshop July 26-August 1 • Vail, Colorado For more information: www.aacr.org

6th Latin American Conference on Lung Cancer August 21-23 • Lima, Peru For more information: www.lalca2014.org ISEH Society for Hematology and Stem Cells 43rd Annual Scientific Meeting August 21-24 • Montreal, Canada For more information: www.iseh.org

September Association of Pediatric Hematology/Oncology Nurses 38th Annual Conference September 4-6 • Portland, Oregon For more information: www.aphon.org Breast Cancer Symposium September 4-6 • San Francisco, California For more information: breastcasym.org 2014 APAO Annual Conference September 10-14, 2014 • Austin, Texas Sheraton Austin at the Capitol For more information: www.apao.cc/node/9 American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: www.aonnonline.org NCCN 9th Annual Congress: Hematologic Malignancies™ September 19-20 • New York, New York For more information: www.nccn.org/professionals/ meetings/hematological/ continued on page 90

July 21-25, 2014

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The Kohala Coast, Hawaii

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The ASCO Post | JUNE 25, 2014

PAGE 90

2014–2015 Oncology Meetings

2014-2015

continued from page 89

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 European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress 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

October ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.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

18th SIS World Congress on Breast Healthcare October 16-19 • Orlando, Florida For more information: www2.kenes.com/sis/Pages/Home.aspx 2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org 16th World Congress of Psycho-Oncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com 14th Annual Conference of SIOG October 23-25 • Lisbon, Portugal For more information: www.siog.org ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org 11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

11th Meeting of the European Association of NeuroOncology (EANO) October 9-12 • Turin, Italy For more information: www.eano.eu/mee_welcome.php 2nd Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: cme.baptisthealth.net/ breastcancer/pages/index.aspx

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: www.cutaneousmalignancies.com

20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/ home/programs/physicians

19th Annual Meeting of the Society for Neuro-Oncology November 13-16 • Miami Beach, Florida For more information: www.soc-neuro-onc.org/

2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.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 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

European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl 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 UICC World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org ASH Annual Meeting and Exposition December 6-9 • San Francisco, California For more information: hematology.org

In postmenopausal women with advanced HR+, HER2-negative breast cancer,

After letrozole or anastrozole fails,

Discover a treatment worth a DOUBLE take Abbreviation: HR+, hormone receptor-positive.

DOUBLE INHIBITION In advanced disease, targeting one pathway may not be enough AFINITOR® (everolimus) Tablets plus exemestane is the only regimen to deliver dual inhibition of the ER and PI3K/Akt/mTOR signaling pathways, providing synergistic inhibition of tumor survival signaling.1-3 Aromatase inhibition

Typical ER Pathway Blockade

Estrogen

In HR+ breast cancer, NSAI treatments (eg, letrozole or anastrozole) inhibit the production of estrogen, thereby reducing ER signaling, a key driver of tumor growth and survival in breast cancer.4,5

ER

Nucleus Cell Proliferation and Survival Aromatase inhibition

Key Mechanism of Progression

Estrogen

P ER

In the advanced setting, multiple signaling pathways and hyperactivation of the PI3K/Akt/mTOR pathway can give tumor cells alternate pathways for progression.4,6-8

mTOR

P ER

Nucleus Cell Proliferation and Survival

Cell Proliferation and Survival

AFINITOR + exemestane

Double Inhibition

Estrogen

AFINITOR

ER

mTOR

Cell Proliferation and Survival

Cell Proliferation and Survival

Nucleus

In patients who have progressed on an NSAI, AFINITOR, in combination with exemestane, offers a unique treatment strategy to address disease progression through dual inhibition of the ER and PI3K/Akt/mTOR signaling pathways.4,5

Only AFINITOR plus exemestane offers dual inhibition of the ER and mTOR pathways1 AFINITOR is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated

• For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances.

If toxicity recurs at grade 3, consider discontinuation of AFINITOR • For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • The development of pneumonitis has been reported even at a reduced dose Abbreviations: BOLERO-2, Breast Cancer Trials of Oral Everolimus-2; ER, estrogen receptor; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; NSAI, nonsteroidal aromatase inhibitor; P, phosphorylation; PFS, progression-free survival.

DOUBLE MEDIAN PFS AFINITOR plus exemestane more than doubled median PFS over exemestane alone1

55%

Combination Therapy Gives You More: Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

reduction in risk of progression or death1

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

PFS curves began to diverge at

6 weeks

(the first tumor assessment)1,3

PFS Probability (%)

80

Median PFS

7.8 months

60

40

[95% CI, 6.9-8.5] Median PFS

3.2 months

[95% CI, 2.8-4.1]

20

0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

Time (months) AFINITOR plus exemestane (n/N=310/485)

Exemestane plus placebo (n/N=200/239)

Exemestane plus placebo (n/N=200/239)

62% reduction in risk of progression or death1

Independent central assessment confirmed benefit1 Median PFS was 11.0 months with AFINITOR plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6] (HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

Overall survival (OS) results were not mature at the time of the interim analysis, and no statistically significant treatment-related difference in OS was noted (HR=0.77 [95% CI, 0.57-1.04]).1 Important Safety Information (cont) Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens) • Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR

• Be vigilant for signs and symptoms of infection and institute appropriate

treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.

Important Safety Information .

AFINITOR®® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated • For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR • For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens) • Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 78% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients • In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed

Novartis Novartis Pharmaceuticals Pharmaceuticals Corporation Corporation East East Hanover, Hanover, New New Jersey Jersey 07936-1080 07936-1080

Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Impaired Wound Healing: • Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma • These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the perisurgical period Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared with 2% in patients <65 years of age • Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age • Careful monitoring and appropriate dose adjustments for adverse reactions are recommended Laboratory Tests and Monitoring: • Elevations of serum creatinine and proteinuria have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine) should be evaluated prior to treatment and periodically thereafter, particularly in patients who have additional risk factors that may further impair renal function • Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported. Blood glucose and lipids should be evaluated prior to treatment and periodically thereafter. More frequent monitoring is recommended when AFINITOR is coadministered with other drugs that may induce hyperglycemia. Management with appropriate medical therapy is recommended. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR • Reductions in hemoglobin, lymphocytes, neutrophils, and platelets have been reported.

Monitoring of complete blood count is recommended prior to treatment and periodically thereafter Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4/PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) • Avoid coadministration with strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less

© © 2014 2014 Novartis Novartis

Hepatic Impairment: • Exposure to everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%) • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST, 69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT, 51%), and hypertriglyceridemia (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%) Please see Brief Summary of Prescribing Information on adjacent pages.

To learn more, please visit www.AFINITOR.com.

References: References: 1.

1. AFINITOR AFINITOR [prescribing [prescribing information]. information]. East East Hanover, Hanover, NJ: NJ: Novartis Novartis Pharmaceuticals Pharmaceuticals Corp; Corp; 2014.

2014. 2.

2. Fedele Fedele P,P, Calvani Calvani N, N, Marino Marino A, A, et et al. al. Targeted Targeted agents agents to to reverse reverse resistance resistance to to endocrine endocrine therapy therapy in in metastatic metastatic breast breast cancer: cancer: where where are are we we now now and and where where are are we we going? going?

Crit Crit Rev Rev Oncol Oncol Hematol.

Hematol. 2012;84:243-251.

2012;84:243-251. 3.

3. Data Data on on fifile. le. AFINITOR AFINITOR CRAD001Y2301 CRAD001Y2301 Clinical Clinical Study Study Report.

Report. Novartis Novartis Pharmaceuticals Pharmaceuticals Corp; Corp; March March 2012.

2012. 4.

4. Johnston Johnston SRD. SRD. Enhancing Enhancing the the effi efficacy cacy of of hormonal hormonal agents agents with with selected selected targeted targeted agents. agents. Clin Clin Breast Breast Cancer.

Cancer. 2009;9(suppl 2009;9(suppl 1):S28-S36.

1):S28-S36. 5.

5. Miller Miller TW, TW, Hennessy Hennessy BI, BI, González-Angulo González-Angulo AM, AM, et et al. al.

Hyperactivation Hyperactivation of of phosphatidylinositol-3 phosphatidylinositol-3 kinase kinase promotes promotes escape escape from from hormone hormone dependence dependence in in estrogen estrogen receptor-positive receptor-positive human human breast breast cancer. cancer. JJ Clin Clin Invest.

Invest. 2010;120(7):2406-2413.

2010;120(7):2406-2413. 6.

6. Di Di Cosimo Cosimo S, S, Baselga Baselga J. J. Management Management of of breast breast cancer cancer with with targeted targeted agents: agents: importance importance of of heterogeneity. heterogeneity. Nat Nat Rev Rev Clin Clin Oncol.

Oncol. 2010;7(3):139-147.

2010;7(3):139-147. 7.

7. Shou Shou J, J, Massarweh Massarweh S, S, Osborne Osborne CK, CK, et et al. al. Mechanisms Mechanisms of of tamoxifen tamoxifen resistance: resistance: increased increased estrogen estrogen receptor-HER2/neu receptor-HER2/neu cross-talk cross-talk in in ER/HER2-positive ER/HER2-positive breast breast cancer. cancer. JJ Natl Natl Cancer Cancer Inst.

Inst. 2004;96(12):926-935.

2004;96(12):926-935. 8.

8. De De Laurentiis Laurentiis M, M, Arpino Arpino G, G, Massarelli Massarelli G, G, et et al. al. AA meta-analysis meta-analysis on on the the interaction interaction between between HER-2 HER-2 expression expression and and response response to to endocrine endocrine treatment treatment in in advanced advanced breast breast cancer. cancer. Clin Clin Cancer Cancer Res. Res. 2005;11(13):4741-4748.

2005;11(13):4741-4748.

4/14 4/14

AFB-1086973 AFB-1086973

AFINITOR AFINITOR®® (everolimus) (everolimus) tablets tablets for for oral oral administration administration Initial Initial U.S. U.S. Approval: Approval: 2009 2009 Brief Brief Summary Summary of of Prescribing Prescribing Information.

Information. See See full full prescribing prescribing information information for for complete complete product product information. information.

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

44 CONTRAINDICATIONS CONTRAINDICATIONS AFINITOR AFINITOR is is contraindicated contraindicated in in patients patients with with hypersensitivity hypersensitivity to to the the active active substance, substance, to to other other rapamycin rapamycin derivaderivatives, tives, or or to to any any of of the the excipients. excipients. Hypersensitivity Hypersensitivity reactions reactions manifested manifested by by symptoms symptoms including, including, but but not not limited limited to, to, anaphylaxis, anaphylaxis, dyspnea, dyspnea, flushing, flushing, chest chest pain, pain, or or angioedema angioedema (e.g., (e.g., swelling swelling of of the the airways airways or or tongue, tongue, with with or or withwithout out respiratory respiratory impairment) impairment) have have been been observed observed with with everolimus everolimus and and other other rapamycin rapamycin derivatives. derivatives.

55 WARNINGS WARNINGS AND AND PRECAUTIONS PRECAUTIONS Non-infectious Non-infectious Pneumonitis Pneumonitis Non-infectious Non-infectious pneumonitis pneumonitis is is aa class class effect effect of of rapamycin rapamycin derivatives, derivatives, including including AFINITOR. AFINITOR. Non-infectious Non-infectious pneupneumonitis monitis was was reported reported in in up up to to 19% 19% of of patients patients treated treated with with AFINITOR AFINITOR in in clinical clinical trials. trials. The The incidence incidence of of Common Common Terminology Terminology Criteria Criteria (CTC) (CTC) Grade Grade 33 and and 44 non-infectious non-infectious pneumonitis pneumonitis was was up up to to 4.0% 4.0% and and up up to to 0.2%, 0.2%, respecrespectively tively [see [see Adverse Adverse Reactions Reactions (6.1, (6.1, 6.2, 6.2, 6.3, 6.3, 6.4, 6.4, 6.5) 6.5) in in the the full full prescribing prescribing information] information].. Fatal Fatal outcomes outcomes have have been been observed. observed.

Consider Consider aa diagnosis diagnosis of of non-infectious non-infectious pneumonitis pneumonitis in in patients patients presenting presenting with with non-specific non-specific respiratory respiratory signs signs and and symptoms symptoms such such as as hypoxia, hypoxia, pleural pleural effusion, effusion, cough, cough, or or dyspnea, dyspnea, and and in in whom whom infectious, infectious, neoplastic, neoplastic, and and other other causes causes have have been been excluded excluded by by means means of of appropriate appropriate investigations. investigations. Advise Advise patients patients to to report report promptly promptly any any new new or or worsening worsening respiratory respiratory symptoms. symptoms.

Patients Patients who who develop develop radiological radiological changes changes suggestive suggestive of of non-infectious non-infectious pneumonitis pneumonitis and and have have few few or or no no sympsymptoms toms may may continue continue AFINITOR AFINITOR therapy therapy without without dose dose alteration. alteration. Imaging Imaging appears appears to to overestimate overestimate the the incidence incidence of of clinical clinical pneumonitis. pneumonitis.

IfIf symptoms symptoms are are moderate, moderate, consider consider interrupting interrupting therapy therapy until until symptoms symptoms improve. improve. The The use use of of corticosteroids corticosteroids may may be be indicated. indicated. AFINITOR AFINITOR may may be be reintroduced reintroduced at at aa daily daily dose dose approximately approximately 50% 50% lower lower than than the the dose dose previprevi[see Table Table 11 in in Dosage Dosage and and Administration Administration (2.2) (2.2) in in the the full full prescribing prescribing information] information].. ously ously administered administered [see For For cases cases of of Grade Grade 33 non-infectious non-infectious pneumonitis pneumonitis interrupt interrupt AFINITOR AFINITOR until until resolution resolution to to less less than than or or equal equal to to Grade Grade 1.

1. AFINITOR AFINITOR may may be be re-introduced re-introduced at at aa daily daily dose dose approximately approximately 50% 50% lower lower than than the the dose dose previously previously administered administered depending depending on on the the individual individual clinical clinical circumstances circumstances [see [see Dosage Dosage and and Administration Administration (2.2) (2.2) in in the the full full toxicity recurs recurs at at Grade Grade 3, 3, consider consider discontinuation discontinuation of of AFINITOR. AFINITOR. For For cases cases of of Grade Grade 44 prescribing prescribing information] information].. IfIf toxicity non-infectious non-infectious pneumonitis, pneumonitis, discontinue discontinue AFINITOR. AFINITOR. Corticosteroids Corticosteroids may may be be indicated indicated until until clinical clinical symptoms symptoms resolve. resolve. The The development development of of pneumonitis pneumonitis has has been been reported reported even even at at aa reduced reduced dose. dose.

Infections Infections AFINITOR AFINITOR has has immunosuppressive immunosuppressive properties properties and and may may predispose predispose patients patients to to bacterial, bacterial, fungal, fungal, viral, viral, or or protozoal protozoal [see Adverse Adverse Reactions Reactions (6.1, (6.1, 6.2, 6.2, 6.3, 6.3, 6.4, 6.4, 6.5) 6.5) in in infections, infections, including including infections infections with with opportunistic opportunistic pathogens pathogens [see the the full full prescribing prescribing information] information].. Localized Localized and and systemic systemic infections, infections, including including pneumonia, pneumonia, mycobacterial mycobacterial infecinfections, tions, other other bacterial bacterial infections, infections, invasive invasive fungal fungal infections, infections, such such as as aspergillosis aspergillosis or or candidiasis, candidiasis, and and viral viral infecinfections tions including including reactivation reactivation of of hepatitis hepatitis BB virus virus have have occurred occurred in in patients patients taking taking AFINITOR. AFINITOR. Some Some of of these these infections infections have have been been severe severe (e.g., (e.g., leading leading to to sepsis, sepsis, respiratory respiratory or or hepatic hepatic failure) failure) or or fatal. fatal. Physicians Physicians and and patients patients should should be be aware aware of of the the increased increased risk risk of of infection infection with with AFINITOR. AFINITOR. Complete Complete treatment treatment of of pre-existing pre-existing invasive invasive fungal fungal infections infections prior prior to to starting starting treatment treatment with with AFINITOR. AFINITOR. While While taking taking AFINITOR, AFINITOR, be be vigilant vigilant for for signs signs and and symptoms symptoms of of infection; infection; ifif aa diagnosis diagnosis of of an an infection infection is is made, made, institute institute appropriate appropriate treatment treatment promptly promptly and and conconsider sider interruption interruption or or discontinuation discontinuation of of AFINITOR. AFINITOR. IfIf aa diagnosis diagnosis of of invasive invasive systemic systemic fungal fungal infection infection is is made, made, discontinue discontinue AFINITOR AFINITOR and and treat treat with with appropriate appropriate antifungal antifungal therapy. therapy.

T:14”

B:14.25”

S:13”

Oral Oral Ulceration Ulceration Mouth Mouth ulcers, ulcers, stomatitis, stomatitis, and and oral oral mucositis mucositis have have occurred occurred in in patients patients treated treated with with AFINITOR AFINITOR at at an an incidence incidence ranging ranging from from 44%-78% 44%-78% across across the the clinical clinical trial trial experience. experience. Grade Grade 33 or or 44 stomatitis stomatitis was was reported reported in in 4%-9% 4%-9% of of [see Adverse Adverse Reactions Reactions (6.1, (6.1, 6.2, 6.2, 6.3, 6.3, 6.4, 6.4, 6.5) 6.5) in in the the full full prescribing prescribing information] information].. In In such such cases, cases, topical topical patients patients [see treatments treatments are are recommended, recommended, but but alcohol-, alcohol-, hydrogen hydrogen peroxide-, peroxide-, iodine-, iodine-, or or thyme-containing thyme-containing mouthwashes mouthwashes should should be be avoided avoided as as they they may may exacerbate exacerbate the the condition. condition. Antifungal Antifungal agents agents should should not not be be used used unless unless fungal fungal infection infection has has been been diagnosed diagnosed [see [see Drug Drug Interactions] Interactions]..

Renal Renal Failure Failure Cases Cases of of renal renal failure failure (including (including acute acute renal renal failure), failure), some some with with aa fatal fatal outcome, outcome, have have been been observed observed in in patients patients [see Laboratory Laboratory Tests Tests and and Monitoring] Monitoring].. treated treated with with AFINITOR AFINITOR [see Impaired Impaired Wound Wound Healing Healing Everolimus Everolimus delays delays wound wound healing healing and and increases increases the the occurrence occurrence of of wound-related wound-related complications complications like like wound wound dehisdehiscence, cence, wound wound infection, infection, incisional incisional hernia, hernia, lymphocele, lymphocele, and and seroma. seroma. These These wound-related wound-related complications complications may may require require surgical surgical intervention. intervention. Exercise Exercise caution caution with with the the use use of of AFINITOR AFINITOR in in the the peri-surgical peri-surgical period. period.

Geriatric Geriatric Patients Patients In In the the randomized randomized advanced advanced hormone hormone receptor-positive, receptor-positive, HER2-negative HER2-negative breast breast cancer cancer study, study, the the incidence incidence of of deaths deaths due due to to any any cause cause within within 28 28 days days of of the the last last AFINITOR AFINITOR dose dose was was 6% 6% in in patients patients ≥≥ 65 65 years years of of age age comcompared pared to to 2% 2% in in patients patients << 65 65 years years of of age. age. Adverse Adverse reactions reactions leading leading to to permanent permanent treatment treatment discontinuation discontinuation occurred occurred in in 33% 33% of of patients patients ≥≥ 65 65 years years of of age age compared compared to to 17% 17% in in patients patients << 65 65 years years of of age. age. Careful Careful monitoring monitoring [see Dosage Dosage and and Administration Administration (2.2) (2.2) and and appropriate appropriate dose dose adjustments adjustments for for adverse adverse reactions reactions are are recommended recommended [see in in the the full full prescribing prescribing information information and and Use Use in in Specific Specific Populations] Populations]..

Laboratory Laboratory Tests Tests and and Monitoring Monitoring Renal Renal Function Function Elevations Elevations of of serum serum creatinine creatinine and and proteinuria proteinuria have have been been reported reported in in patients patients taking taking AFINITOR AFINITOR [see [see Adverse Adverse Reactions Reactions (6.1, (6.1, 6.2, 6.2, 6.3, 6.3, 6.4, 6.4, 6.5) 6.5) in in the the full full prescribing prescribing information] information].. Monitoring Monitoring of of renal renal function, function, including including measurement measurement of of blood blood urea urea nitrogen nitrogen (BUN), (BUN), urinary urinary protein, protein, or or serum serum creatinine, creatinine, is is recommended recommended prior prior to to the the start start of of AFINITOR AFINITOR therapy therapy and and periodically periodically thereafter. thereafter. Renal Renal function function of of patients patients should should be be monitored monitored particularly particularly where where patients patients have have additional additional risk risk factors factors that that may may further further impair impair renal renal function. function.

Blood Blood Glucose Glucose and and Lipids Lipids Hyperglycemia, Hyperglycemia, hyperlipidemia, hyperlipidemia, and and hypertriglyceridemia hypertriglyceridemia have have been been reported reported in in patients patients taking taking AFINITOR AFINITOR [see [see Monitoring of of fasting fasting serum serum glugluAdverse Adverse Reactions Reactions (6.1, (6.1, 6.2, 6.2, 6.3, 6.3, 6.4, 6.4, 6.5) 6.5) in in the the full full prescribing prescribing information] information].. Monitoring cose cose and and lipid lipid profile profile is is recommended recommended prior prior to to the the start start of of AFINITOR AFINITOR therapy therapy and and periodically periodically thereafter thereafter as as well well as as management management with with appropriate appropriate medical medical therapy. therapy. More More frequent frequent monitoring monitoring is is recommended recommended when when AFINITOR AFINITOR is is co-administered co-administered with with other other drugs drugs that that may may induce induce hyperglycemia. hyperglycemia. When When possible, possible, optimal optimal glucose glucose and and lipid lipid concontrol trol should should be be achieved achieved before before starting starting aa patient patient on on AFINITOR. AFINITOR. Hematologic Hematologic Parameters Parameters Decreased Decreased hemoglobin, hemoglobin, lymphocytes, lymphocytes, neutrophils, neutrophils, and and platelets platelets have have been been reported reported in in patients patients taking taking AFINITOR AFINITOR [see [see Adverse Adverse Reactions Reactions (6.1, (6.1, 6.2, 6.2, 6.3, 6.3, 6.4, 6.4, 6.5) 6.5) in in the the full full prescribing prescribing information] information].. Monitoring Monitoring of of complete complete blood blood count count is is recommended recommended prior prior to to the the start start of of AFINITOR AFINITOR therapy therapy and and periodically periodically thereafter. thereafter.

Drug-drug Drug-drug Interactions Interactions Due Due to to significant significant increases increases in in exposure exposure of of everolimus, everolimus, co-administration co-administration with with strong strong CYP3A4/PgP CYP3A4/PgP inhibitors inhibitors [see Dosage Dosage and and Administration Administration (2.2, (2.2, 2.5) 2.5) in in the the full full prescribing prescribing information information and and Drug Drug should should be be avoided avoided [see Interactions] Interactions]..

AA reduction reduction of of the the AFINITOR AFINITOR dose dose is is recommended recommended when when co-administered co-administered with with aa moderate moderate CYP3A4/PgP CYP3A4/PgP inhibitor inhibitor [see [see Dosage Dosage and and Administration Administration (2.2, (2.2, 2.5) 2.5) in in the the full full prescribing prescribing information information and and Drug Drug Interactions] Interactions]..

An An increase increase in in the the AFINITOR AFINITOR dose dose is is recommended recommended when when co-administered co-administered with with aa strong strong CYP3A4/PgP CYP3A4/PgP inducer inducer [see [see Dosage Dosage and and Administration Administration (2.2, (2.2, 2.5) 2.5) in in the the full full prescribing prescribing information information and and Drug Drug Interactions] Interactions]..

Hepatic Hepatic Impairment Impairment Exposure Exposure to to everolimus everolimus was was increased increased in in patients patients with with hepatic hepatic impairment impairment [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in in the the full full prescribing prescribing information] information]..

For For advanced advanced HR+ HR+ BC, BC, advanced advanced PNET, PNET, advanced advanced RCC, RCC, and and renal renal angiomyolipoma angiomyolipoma with with TSC TSC patients patients with with severe severe hepatic hepatic impairment impairment (Child-Pugh (Child-Pugh class class C), C), AFINITOR AFINITOR may may be be used used at at aa reduced reduced dose dose ifif the the desired desired benefit benefit outoutweighs weighs the the risk. risk. For For patients patients with with mild mild (Child-Pugh (Child-Pugh class class A) A) or or moderate moderate (Child-Pugh (Child-Pugh class class B) B) hepatic hepatic impairment, impairment, [see Dosage Dosage and and Administration Administration (2.2) (2.2) and and Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in in the the aa dose dose reduction reduction is is recommended recommended [see full full prescribing prescribing information] information]..

For For patients patients with with SEGA SEGA and and mild mild or or moderate moderate hepatic hepatic impairment, impairment, adjust adjust the the dose dose of of AFINITOR AFINITOR Tablets Tablets or or AFINITOR AFINITOR DISPERZ DISPERZ based based on on therapeutic therapeutic drug drug monitoring. monitoring. For For patients patients with with SEGA SEGA and and severe severe hepatic hepatic impairment, impairment, reduce reduce the the starting starting dose dose of of AFINITOR AFINITOR Tablets Tablets or or AFINITOR AFINITOR DISPERZ DISPERZ by by approximately approximately 50% 50% and and adjust adjust subsequent subsequent doses doses based based [see Dosage Dosage and and Administration Administration (2.4, (2.4, 2.5) 2.5) in in the the full full prescribing prescribing information] information].. on on therapeutic therapeutic drug drug monitoring monitoring [see Vaccinations Vaccinations During During AFINITOR AFINITOR treatment, treatment, avoid avoid the the use use of of live live vaccines vaccines and and avoid avoid close close contact contact with with individuals individuals who who have have received received live live vaccines vaccines (e.g., (e.g., intranasal intranasal influenza, influenza, measles, measles, mumps, mumps, rubella, rubella, oral oral polio, polio, BCG, BCG, yellow yellow fever, fever, varicella, varicella, and and TY21a TY21a typhoid typhoid vaccines). vaccines).

Embryo-fetal Embryo-fetal Toxicity Toxicity Based Based on on the the mechanism mechanism of of action, action, AFINITOR AFINITOR can can cause cause fetal fetal harm. harm. Everolimus Everolimus caused caused embryo-fetal embryo-fetal toxicities toxicities in in animals animals at at maternal maternal exposures exposures that that were were lower lower than than human human exposures. exposures. IfIf this this drug drug is is used used during during pregnancy pregnancy or or ifif the the patient patient becomes becomes pregnant pregnant while while taking taking this this drug, drug, the the patient patient should should be be apprised apprised of of the the potential potential hazard hazard to to aa fetus fetus [see [see Use Use in in Specific Specific Populations] Populations]..

Advise Advise female female patients patients of of reproductive reproductive potential potential to to avoid avoid becoming becoming pregnant pregnant and and to to use use highly highly effective effective contracontra[see Use Use in in Specific Specific Populations] Populations].. ception ception while while using using AFINITOR AFINITOR and and for for up up to to 88 weeks weeks after after ending ending treatment treatment [see 66 ADVERSE ADVERSE REACTIONS REACTIONS The The efficacy efficacy and and safety safety of of AFINITOR AFINITOR (10 (10 mg/day) mg/day) plus plus exemestane exemestane (25 (25 mg/day) mg/day) (n=485) (n=485) versus versus placebo placebo plus plus exemestane exemestane (25 (25 mg/day) mg/day) (n=239) (n=239) was was evaluated evaluated in in aa randomized, randomized, controlled controlled trial trial in in patients patients with with advanced advanced or or metastatic metastatic hormone hormone receptor-positive, receptor-positive, HER2-negative HER2-negative breast breast cancer. cancer. The The median median age age of of patients patients was was 61 61 years years (range (range 28-93 28-93 years), years), and and 75% 75% were were Caucasian.

Caucasian. Safety Safety results results are are based based on on aa median median follow-up follow-up of of approximately approximately 13 13 months. months.

The The most most common common adverse adverse reactions reactions (incidence (incidence ≥≥ 30%) 30%) were were stomatitis, stomatitis, infections, infections, rash, rash, fatigue, fatigue, diarrhea, diarrhea, and and decreased decreased appetite. appetite. The The most most common common Grade Grade 3/4 3/4 adverse adverse reactions reactions (incidence (incidence ≥≥ 2%) 2%) were were stomatitis, stomatitis, infections, infections, hyperglycemia, hyperglycemia, fatigue, fatigue, dyspnea, dyspnea, pneumonitis, pneumonitis, and and diarrhea. diarrhea. The The most most common common laboratory laboratory abnormalities abnormalities (inci(incidence dence ≥≥ 50%) 50%) were were hypercholesterolemia, hypercholesterolemia, hyperglycemia, hyperglycemia, increased increased aspartate aspartate transaminase transaminase (AST), (AST), anemia, anemia, leukopenia, leukopenia, thrombocytopenia, thrombocytopenia, lymphopenia, lymphopenia, increased increased alanine alanine transaminase transaminase (ALT), (ALT), and and hypertriglyceridemia. hypertriglyceridemia.

The The most most common common Grade Grade 3/4 3/4 laboratory laboratory abnormalities abnormalities (incidence (incidence ≥≥ 3%) 3%) were were lymphopenia, lymphopenia, hyperglycemia, hyperglycemia, aneanemia, mia, decreased decreased potassium, potassium, increased increased AST, AST, increased increased ALT, ALT, and and thrombocytopenia. thrombocytopenia.

Fatal Fatal adverse adverse reactions reactions occurred occurred more more frequently frequently in in patients patients who who received received AFINITOR AFINITOR plus plus exemestane exemestane (2%) (2%) comcompared pared to to patients patients on on the the placebo placebo plus plus exemestane exemestane arm arm (0.4%).

(0.4%). The The rates rates of of treatment-emergent treatment-emergent adverse adverse events events resulting resulting in in permanent permanent discontinuation discontinuation were were 24% 24% and and 5% 5% for for the the AFINITOR AFINITOR plus plus exemestane exemestane and and placebo placebo plus plus exemestane exemestane treatment treatment groups, groups, respectively. respectively. Dose Dose adjustments adjustments (interruptions (interruptions or or reductions) reductions) were were more more frequent frequent among among patients patients in in the the AFINITOR AFINITOR plus plus exemestane exemestane arm arm than than in in the the placebo placebo plus plus exemestane exemestane arm arm (63% (63% versus versus 14%).

14%).

Table Table 22 compares compares the the incidence incidence of of treatment-emergent treatment-emergent adverse adverse reactions reactions reported reported with with an an incidence incidence of of ≥10% ≥10% for for patients patients receiving receiving AFINITOR AFINITOR 10 10 mg mg daily daily versus versus placebo. placebo.

Table 2: 2: Adverse Adverse Reactions Reactions Reported Reported ≥≥ 10% 10% of of Patients Patients with with Advanced Advanced HR+ HR+ BC* BC* Table AFINITOR (10 (10 mg/day) mg/day) AFINITOR exemestaneaa ++ exemestane N=482 N=482 All All grades grades Grade Grade 33 Grade Grade 44 % % % % % % Any adverse adverse reaction reaction 100 41 Any 100 41 Gastrointestinal disorders disorders Gastrointestinal 67 67 88 Stomatitisbb Stomatitis Diarrhea Diarrhea 33 33 22 Nausea Nausea 29 29 0.2 0.2 Vomiting Vomiting 17 17 0.8 0.8 Constipation Constipation 14 14 0.4 0.4 Dry Dry mouth mouth 11 11 00 General General disorders disorders and and administration administration site site conditions conditions Fatigue Fatigue 36 36 44 Edema Edema peripheral peripheral 19 19 11 Pyrexia Pyrexia 15 15 0.2 0.2 Asthenia Asthenia 13 13 22 Infections Infections and and infestations infestations 50 50 44 Infections Infectionscc Investigations Investigations Weight Weight decreased decreased 25 25 11 Metabolism Metabolism and and nutrition nutrition disorders disorders Decreased Decreased appetite appetite 30 30 11 Hyperglycemia Hyperglycemia 14 14 55 Musculoskeletal Musculoskeletal and and connective connective tissue tissue disorders disorders Arthralgia Arthralgia 20 20 0.8 0.8 Back Back pain pain 14 14 0.2 0.2 Pain Pain in in extremity extremity 99 0.4 0.4 Nervous Nervous system system disorders disorders Dysgeusia Dysgeusia 22 22 0.2 0.2 Headache Headache 21 21 0.4 0.4 Psychiatric Psychiatric disorders disorders Insomnia Insomnia 13 13 0.2 0.2 Respiratory, Respiratory, thoracic thoracic and and mediastinal mediastinal disorders disorders Cough Cough 24 24 0.6 0.6 Dyspnea Dyspnea 21 21 44 Epistaxis Epistaxis 17 17 00 Pneumonitis Pneumonitisdd 19 19 44 Skin Skin and and subcutaneous subcutaneous tissue tissue disorders disorders Rash Rash 39 39 11 Pruritus Pruritus 13 13 0.2 0.2 Alopecia Alopecia 10 10 00 Vascular Vascular disorders disorders Hot Hot flush flush 66 00 Median duration duration of of treatment treatmentee Median

Placebo Placebo ++ exemestane exemestaneaa N=238 N=238 All All grades grades Grade Grade 33 Grade Grade 44 % % % % % %

99

90 90

22 22

55

00 0.2 0.2 0.2 0.2 0.2 0.2 00 00

11 11 18 18 28 28 12 12 13 13 77

0.8 0.8 0.8 0.8 11 0.8 0.8 0.4 0.4 00

00 00 00 00 00 00

0.4 0.4 00 00 0.2 0.2

27 27 66 77 44

11 0.4 0.4 0.4 0.4 00

00 00 00 00

11

25 25

22

00

00

66

00

00

00 0.4 0.4

12 12 22

0.4 0.4 0.4 0.4

00 00

00 00 00

17 17 10 10 11 11

00 0.8 0.8 22

00 00 00

00 00

66 14 14

00 00

00 00

00

88

00

00

00 0.2 0.2 00 0.2 0.2

12 12 11 11 11 0.4 0.4

00 0.8 0.8 00 00

00 0.4 0.4 00 00

00 00 00

66 55 55

00 00 00

00 00 00

00

14 14

00

00

23.9 23.9 weeks weeks

13.4 13.4 weeks weeks

Grading Grading according according to to CTCAE CTCAE Version Version 3.0 3.0 *160 *160 patients patients (33.2%) (33.2%) were were exposed exposed to to AFINITOR AFINITOR therapy therapy for for aa period period of of ≥≥ 32 32 weeks) weeks) aa Exemestane Exemestane (25 (25 mg/day) mg/day) bb Includes Includes stomatitis, stomatitis, mouth mouth ulceration, ulceration, aphthous aphthous stomatitis, stomatitis, glossodynia, glossodynia, gingival gingival pain, pain, glossitis glossitis and and lip lip ulceration ulceration cc Includes Includes all all preferred preferred terms terms within within the the ‘infections ‘infections and and infestations’ infestations’ system system organ organ class, class, the the most most common common being being nasopharyngitis nasopharyngitis (10%), (10%), urinary urinary tract tract infection infection (10%), (10%), upper upper respiratory respiratory tract tract infection infection (5%), (5%), pneumonia pneumonia (4%), (4%), bronchibronchitis tis (4%), (4%), cystitis cystitis (3%), (3%), sinusitis sinusitis (3%), (3%), and and also also including including candidiasis candidiasis (<1%), (<1%), and and sepsis sepsis (<1%), (<1%), and and hepatitis hepatitis CC (<1%). (<1%). dd Includes Includes pneumonitis, pneumonitis, interstitial interstitial lung lung disease, disease, lung lung infiltration, infiltration, and and pulmonary pulmonary fibrosis fibrosis ee Exposure Exposure to to AFINITOR AFINITOR or or placebo placebo Key Key observed observed laboratory laboratory abnormalities abnormalities are are presented presented in in Table Table 3.

3.

Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory parameter

Hematologyb Hemoglobin decreased WBC decreased Platelets decreased Lymphocytes decreased Neutrophils decreased Clinical chemistry Glucose increased Cholesterol increased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Triglycerides increased Albumin decreased Potassium decreased Creatinine increased

AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % 68 58 54 54 31

6 1 3 11 2

0.6 0 0.2 0.6 0

40 28 5 37 11

0.8 5 0 5 0.8

0.4 0.8 0.4 0.8 0.8

69 70 69 51 50 33 29 24

9 0.6 4 4 0.8 0.8 4 2

0.4 0.2 0.2 0.2 0 0 0.2 0.2

44 38 45 29 26 16 7 13

0.8 0.8 3 5 0 0.8 1 0

0.4 0.8 0.4 0 0 0 0 0

Grading according to CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively.

• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively.

Concomitant strong inhibitors of CYP3A4/PgP should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions].

Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions].

Agents That May Decrease Everolimus Blood Concentrations CYP3A4/PgP Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone.

Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information].

Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a nonCYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf).

Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D Risk Summary Based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman.

Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, apprise the patient of the potential hazard to the fetus [see Warnings and Precautions].

Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development.

These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Pediatric use of AFINITOR Tablets and AFINITOR DISPERZ is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets and AFINITOR DISPERZ have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA.

The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in disease-related symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown.

Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least 1 serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information].

Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information]. The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information].

Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITORtreated patients were ≥ 65 years of age, while 15% were 75 years and over. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age.

Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions].

In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 years and over.

Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information].

No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information].

Females and Males of Reproductive Potential Contraception Females AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations].

Infertility Females Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR [see Adverse Reactions (6.2, 6.4, 6.5) and Nonclinical Toxicology in the full prescribing information].

Males AFINITOR treatment may impair fertility in male patients based on animal findings [see Nonclinical Toxicology in the full prescribing information].

Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information].

For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50%. For patients with SEGA who have mild (ChildPugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Revised Feb 2014 © Novartis T2014-16/T2014-17 February 2014/February 2014

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Opinion Lung Cancer Screening continued from page 1

T:14”

S:13”

B:14.25”

Then note that 40 different organizations—including the American College of Radiology, Radiological Society of North America, American Thoracic Society, Lung Cancer Alliance, Prevent Cancer Foundation, National Comprehensive Cancer Network, and many others—committed to working together to implement screening with systematic approaches.

This commitment included not only the routine integration of tobacco control but also informed decisionmaking and embedded quality control measures. Other major associations like the American Lung Association and American Cancer Society, and now even the American Medical Association, all support screening.

All of the above would seem like a very favorable dynamic for implementing a new clinical service. And yet, on April 30, a Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) panel voted against coverage for annual low-dose CT scans to screen adults at high risk for lung cancer.

Why the Negative Vote?

Where did the wheels fall off?

Could it be that the MEDCAC Committee was dismissive of the statements by representatives of the American Association of Physicists in Medicine and others on the radiation harms issue? Was the initiative voted on so skeptically by the committee because the seven articles discussed by the USPSTF on perceived harms revealed no significant harms despite the insistence of some on the committee—in the absence of objective data—that there still must have been significant psychological harms in this elderly, heavily smoked exposed cohort? Was

it a committee member’s concerns about the unremitting pain associated with chest tube placement—an understandable issue, although in experienced screening centers, chest tubes are not used in the screening process?

Was it the opinion voiced by another panel member that the USPSTF made a mistake in approving lung cancer screening as a B level, when tobacco control would be a better investment?

During testimony that day, everyone endorsed inclusion of robust tobacco cessation measures with screening in an NLST-like population, but not smok-

the many interested parties who visited with MEDCAC that day was essentially either ignored or discounted by the ­Committee.

Next Steps So what happens next? The CMS staff has several months to assess the data. They do this with the knowledge that under provisions of the Affordable Care Act, low-dose CT services are now being rolled out nationally to all individuals in the country who have private insurance and fulfill the eligibility profile of the USPSTF recommendation.

To respect the lives of people who will soon be developing lung cancer and to respect the investment of U.S. citizens who funded the massive National Lung Screening Trial, this is the time to move forward with this promising innovation.

—James L. Mulshine, MD

ing cessation alone. Smoking cessation alone cannot be expected to benefit the majority of lung cancer cases that currently arise in the lungs of people who have already stopped smoking.

Another committee member presented an operative mortality rate for screenidentified lung cancer that was a multiple of the frequency reported by Dr. Douglas Wood, the lead surgeon from the American Thoracic Society. Still another committee member suggested a second NLST trial be performed in the Medicare population to validate the NLST results prior to recommending for Centers for Medicare & Medicaid (CMS) reimbursement of low-dose CT screening.

In my opinion, the expert testimony of

Consider the optics of moving into an election year and CMS accepting the advice of their review committee. If they do so, they will be creating a profoundly disturbing health-care disparity in a disease that is already associated with marked disparities arising from the targeted marketing of tobacco products.

Tobacco products are disproportionately used by people with less college education and fewer financial resources, so this is not an encouraging situation for health-care equity in this nation.

In considering this topic, it is critical to understand that CMS is now reimbursing a low-dose CT scan at less than $180 per scan. As Dr. Ella Kazerooni outlined to the MEDCAC panel, the

American College of Radiology is disseminating a plan of lung cancer screening evaluation that pivots forward best practices derived from their extensive work with mammographic screening.

CMS has existing robust provisions for monitoring clinical services using their standard approaches with reimbursement auditing. An informed estimate from an expert actuarial group projects new lung cancer screening costs to be under a billion dollars, which represents an incremental cost increase for each Medicare beneficiary of about an additional dollar per person per month. As presented at the MEDCAC meeting, for less than $12 per year per Medicare beneficiary, the lives of many thousands of potential lung cancer victims can be saved. Further, as more 55-year-old individuals at high risk for lung cancer are covered by commercial plans, then fewer people will be coming into Medicare coverage with advancedstage lung cancer.

Closing Thoughts If all of the supportive stakeholder groups work together, responsibly, to ensure that lung cancer screening is delivered in an accessible and highquality fashion with routine integration of appropriate tobacco cessation measures, we can collectively achieve a significant public health benefit. To respect the lives of people who will soon be developing lung cancer and to respect the investment of U.S. citizens who funded the massive National Lung Screening Trial, this is the time to move forward with this promising innovation. n Disclosure: Dr. Mulshine is on the Board of Trustees for the Lung Cancer Alliance and Prevent Cancer Foundation, and on the Scientific Advisory Board to I-ELCAP (InternationalEarly Lung Cancer Action Project).

For Your NPs and PAs A CE/CME/CEU Conference for Advanced Practitioners in Oncology

October 30th – November 2nd Loews Royal Pacific Hotel at Universal Orlando, FL apsho.org/jadprolive

The ASCO Post | JUNE 25, 2014

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In the News Breast Cancer

New Option for Preserving Fertility in Women Being Treated With Chemotherapy for Early-Stage Breast Cancer

By Charlotte Bath

O

ne of the most reported studies emanating from the 2014 ASCO Annual Meeting involves the use of the luteinizing hormone–releasing hormone (LHRH) agonist goserelin (Zoladex) to reduce the risk of ovarian failure among women being treated with chemotherapy for early-stage breast cancer, and to increase the likelihood of a successful pregnancy afterward (see page 22).1 Network and cable television, national and regional newspapers, and international news services covered the study and what it might mean to women concerned about preserving fertility after being treated for cancer.

In an interview with The ASCO Post, the study’s lead author, Halle Moore, MD, said that she welcomed the media coverage because “the more the public is aware of fertility preservation options for patients receiving chemotherapy, the more likely it is that those patients will ask their doctors about [such measures].” Dr. Moore is a Staff Physician and Chair of the Survivorship Program

at the Cleveland Clinic. The study was funded by the National Institutes of Health, and Dr. Moore was hopeful that the extensive media coverage might also help the public see “where our dollars are going” and understand the importance of federally funded research.

arm,” Dr. Moore reported at an ASCO press briefing on patient care and quality of life. “In the stratified analysis, this represented a 70% reduction in ovarian failure with a P value of .04. Using

The more the public is aware of fertility preservation options for patients receiving chemotherapy, the more likely it is that those patients will ask their doctors about [such measures].

What the Study Showed The phase III Prevention of Early Menopause Study (POEMS)/Southwest Oncology Group (SWOG) S0230 recruited 257 premenopausal women, aged 18 to 49, with stage I to IIIA estrogen receptor–negative and progesterone receptor–negative breast cancer, and 218 patients were evaluable. The primary endpoint of the study was the rate of ovarian failure at 2 years, defined as having no menstrual periods for the prior 6 months and postmenopausal levels of folliclestimulating hormone (FSH).

“By this definition, the ovarian failure rate was 22% in the standard chemotherapy arm and 8% in the goserelin

Expect Questions From Patients

W

ith the extensive media coverage of a study indicating that injections with the luteinizing hormone–releasing hormone (LHRH) agonist goserelin (Zoladex) may offer a new option for preserving fertility among women treated for breast cancer, physicians can expect questions from interested patients. Presented at the 2014 ASCO Annual Meeting in Chicago, the study found that goserelin can reduce the risk of ovarian failure and increase the possibility of successful pregnancies among premenopausal women being treated with chemotherapy for early-stage breast cancer.

Patients who have read or heard about the study need to know that this new option “is really only for newly diagnosed patients,” the study’s lead author, Halle Moore, MD, told The ASCO Post. Dr. Moore is a Staff Physician and Chair of the Survivorship Program at the Cleveland Clinic. The first injection of goserelin needs to be administered at least 1 week before chemotherapy starts, with additional doses administered once a month over the duration of the chemotherapy regimen.

Addressing Survivorship “This is not for people who are interested in fertility years after their treatment. This is really addressing survivorship at the time of initial diagnosis, which I think is something we need to be doing increasingly,” Dr. Moore remarked.

Goserelin is approved by the Food and Drug Administration for advanced breast cancer, but not for use in women with early-stage breast cancer. Because preserving fertility among women with early-stage breast cancer is not an approved use, patients considering this option should be advised to check their insurance coverage.

The study included only women with estrogen receptor/progesterone receptor–negative breast cancer. Dr. Moore cautioned that more research is needed to understand any role goserelin may have in preserving fertility among women treated for other types of cancer. n

the study by making them wait too long before starting their chemotherapy. We didn’t want to do anything that would delay their chemotherapy in any significant way. So we compromised at

—Halle Moore, MD

a less stringent ovarian failure definition of either postmenopausal FSH or absent menstrual periods for the prior 6 months, 45% of patients in the standard arm vs 20% in the goserelin arm experienced ovarian failure. This difference was highly significant with an adjusted P value of .006,” she added.

Among women receiving chemotherapy alone, 11% reported becoming pregnant, with 7% actually delivering a total of 12 babies, and two other women still pregnant at the time of data submission. Among women who also received goserelin, 21% became pregnant, with 15% actually delivering a total of 18 babies, and three other women still pregnant at the time of data submission. “The greater-thantwofold differencea in becoming pregnant and having a successful outcome was associated with P values between .03 and .05,” Dr. Moore noted.

The pregnancy results applied only to the 5-year study period, and “not all patients on study were actually interested in becoming pregnant,” Dr. Moore pointed out in the interview with The ASCO Post. “The rates might be higher in a highly motivated group or in a younger patient population.”

Goserelin Injections Goserelin injections were started at least 1 week before chemotherapy and continued once a month for the duration of the chemotherapy. The monthly goserelin dose was 3.6 mg.

“It takes about 10 days to fully suppress ovarian function with this medication,” Dr. Moore noted. “But we also didn’t want to limit patients’ interest in

starting at least 1 week prior to the first chemotherapy dose. One week actually appeared to work very well.”

The chemotherapy regimens used for early-stage breast cancer typically extend over a period of 3 to 6 months, Dr. Moore explained, “and the most common regimen that we use in the United States in this population is about a 4-month regimen, which would be about four injections of goserelin for the average patient.”

Goserelin is currently approved by the U.S. Food and Drug Administration for advanced breast cancer, but not for early-stage disease.

Not Mutually Exclusive Goserelin injections and cryopreservation of embryos, the most established fertility-preservation methods for women undergoing chemotherapy, are not mutually exclusive options. While goserelin must be started at least 1 week before chemotherapy, the entire process of cryopreservation takes between 2 and 6 weeks.2 The process includes stimulating the ovaries to mature multiple eggs, removing the mature eggs, and then fertilizing them in the lab with sperm from a partner or donor to create embryos through in vitro fertilization, before freezing them for future use.

“With some other cancers, you may not have the luxury of time to pursue those treatments,” Dr. Moore said. “We were looking at operable breast cancer.

So even though assisted reproduction might delay treatment by a month or two or even more, if somebody has had their surgery and the cancer is out, that might be okay in breast cancer, whereas

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In the News

if you have an aggressive lymphoma, you really may not have the opportunity to take the time to do this.”

Interrupting Endocrine Therapy The International Breast Cancer Study Group, one of the key participants in the POEMS/SWOG S0230 trial, “is planning a study addressing a somewhat different question. It is called the Positive Study, and it is going to look at women with hormone receptor–positive breast cancer and whether it is safe to interrupt endocrine therapy to have a pregnancy,” Dr. Moore noted. “It would be contraindicated to attempt a pregnancy while on tamoxifen, so the study is looking at stopping the tamoxifen in women with hopes of becoming pregnant, and then resuming after the pregnancy, with a plan to be off of the endocrine therapy for no more than 2 years.”

Recommendations to continue

tamoxifen for 5 to 10 years present particular challenges for a woman who is diagnosed with breast cancer in her late 20s and hasn’t had children yet. After chemotherapy and 5 years of tamoxifen, the woman would be in her early 30s, and “she still may have an opportunity to have children. It might be difficult, but it is still an option,” Dr. Moore said. “If you add another 5 years of hormonal therapy, that makes it even more difficult. So I think it is a very important question to address for these patients.”

Currently, “if someone really wants to have a child, we recommend that the tamoxifen be stopped first. You could conceive on it, but it should be stopped immediately if that were to happen. So we recommend using barrier contraceptives while on tamoxifen.”

Surprising Survival Improvement After adjusting for disease stage, women who received goserelin in the

POEMS/S0230 study had a 50% reduction in morality 4 years after starting chemotherapy compared with those who received chemotherapy alone, a result considered somewhat surprising. One possible explanation, Dr. Moore said, is the observation that many breast cancers, including triplenegative breast cancers, have LHRH receptors, and preclinical studies suggest that LHRH agonists and antagonists increase cell death.

Another possible explanation was offered by a study presented during the ASCO Annual Meeting Breast Cancer– HER2/ER poster session. In that study, Recchia et al found that administering an LHRH agonist to premenopausal women with high-risk early breast cancer after surgery but before chemotherapy resulted in a reduction in vascular endothelial growth factor (VEGF) and regulatory T cells, which are considered fundamental for the development of breast cancer. n

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

References 1. Moore HCF, Unger JM, Phillips K-A, et al: Phase III trial (Prevention of Early Menopause Study [POEMS]SWOG S0230) of LHRH analog during chemotherapy to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: An international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance) ASCO Annual Meeting. Abstract LBA505. Presented May 31, 2014.

2. LIVESTRONG Foundation: Fertility preservation options for women. Available at www.livestrong.org. Accessed June 11, 2014.

3. Recchia F, Candeloro G, Cesta A: Total estrogen blockade and chemotherapy in high-risk premenopausal early breast cancer: Long-term follow-up of a phase II study. ASCO Annual Meeting. Abstract 537. Presented June 2, 2014.

Coming Soon on ASCOPost.com

The ASCO Post’s Special Series

Peer-to-Peer Viewpoints on ASCO’s Annual Meeting The ASCO Post presents important discussions LIVE from ASCO’s Annual Meeting.

Visit ASCOPost.com to learn more and view the following videos: Faculty and Guests James O. Armitage, MD, with Richard Fisher, MD, Michael Pfreundschuh, MD, and Clifford Hudis, MD, FACP ■ Derek Raghavan, MD, PhD, with Daniel Petrylak, Maha Hussein, MD, and Siu Yao, MD ■ Nancy Davidson, MD, with Lisa Carey, MD ■ James Mulshine, MD, with Fred Hirsch, MD, Natasha Leighl, MD, Mark Kris, MD, and Carolyn Aldige ■ Jame Abraham, MD, with Halle Moore, MD ■ Halle C. F. Moore, MD ■

Congratulations to the 2014 Grant and Award Recipients!

Visit www.ConquerCancerFoundation.org for a full list of recipients.

ASCOPost.com | JUNE 25, 2014

PAGE 101

ASCO State Affiliates Focus on the Washington State Medical Oncology Society

By Jo Cavallo

Political Activity

Vicky E. Jones, MD

T

he Washington State Medical Oncology Society (WSMOS) was formed in 1993 in response to the health-care reform legislation then being proposed by President Bill Clinton.

“The law never passed, but it spurred the development of our Society, so some good came out of the law’s defeat,” said Vicky E. Jones, MD, President of WSMOS. Twenty-one years later, with passage of the Patient Protection and Affordable Care Act, Washington State has led the way in successfully enrolling residents in health-care plans through the state’s insurance exchanges. WSMOS helped in that effort by providing members with educational sessions on the enrollment process of the state’s insurance exchanges.

With over 300 members, including medical, surgical, and radiation oncologists as well as physician assistants, nurse practitioners, pharmacists, and clinic administrators, WSMOS is among ASCO’s largest state affiliates.

WSMOS is the largest organization in the state representing oncologists, and its members provide care for the majority of patients with cancer in ­Washington.

The ASCO Post talked with Dr. Jones about the Society’s current legislative activity, its unique challenges, and its goals for the future.

Mutually Positive Relationship Why was it important for WSMOS to become an ASCO State Affiliate?

We have more than just a local vision and it is important to be part of a national structure for oncologists. Being an ASCO State Affiliate allows us to tap into ASCO’s myriad areas of expertise and also allows us to offer our expertise on a national level, so it is a positive relationship for both organizations.

WSMOS is among the most politically active state affiliates. Please talk about your legislative and advocacy accomplishments.

We have a long and proud history of legislative successes in helping improve the quality of cancer care in our state. Among our major accomplishments was getting the business and occupation tax that had been imposed on prescription drugs, including chemotherapy agents, repealed. The tax wasn’t uniformly imposed across all healthcare facilities and mainly affected chemotherapies administered in private clinics and practices, which made it challenging for small clinics and community practices to stay solvent. Members of WSMOS testified before the Senate Committee on Ways and Means, and the law was changed to also exempt private clinics and physicians from the business and occupation tax.

We were instrumental in designing a response to a new state law regulating the handling of hazardous drugs, including chemotherapy drugs such as cisplatin, fluorouracil, methotrexate, etoposide, temozolomide, and dacarbazine in workplace settings. In 2011, Washington became the first state in the nation to adopt specific workplace safety rules to protect health-care workers against exposure to these drugs, which go into effect in 2015.

The law’s provision calls for a written inventory of hazardous drugs in the workplace, a hazard assessment, and policies and procedures such as engineering controls, safe handling practices, personal protective equipment (eg,

chemotherapy gloves), spill control, and waste handling. But it is unclear how the rule will be implemented, and we are now actively involved with the State Department of Labor and Industry to formulate the details of how the law will be put into effect.

We are also currently working on refinements to Senate Bill 6016, which would address concerns about the 90day grace period for people enrolling in our health-care exchanges and protect physicians against financial liability during the second and third months of the grace period. We have been reaching out to our members to make them aware of this bill and asking them to contact their senators responsible for this legislation about modifying that provision. I think sometimes legislators don’t understand the impact these rules have on oncologists and patient care.

Unique Challenges What are some of your greatest ­challenges?

Our state’s geographic diversity is one challenge. Washington State encompasses over 71,000 square miles, and is separated by mountains and large

Fast Facts ■■ The Washington State Medical Oncology Society (WSMOS) was founded in 1993.

■■ The current President is Vicky E. Jones, MD. ■■ The Society has 315 members, including oncologists, hematologists, and other cancer specialists working in community practices, hospitals, and other health-care facilities.

■■ The purpose of the Society is to promote the highest professional standards of oncology practice in the state of Washington; to study, research, and exchange information, experiences, and ideals leading to improvement in the practice of oncology; and to represent the practice of oncology and hematology in the state of Washington.

■■ WSMOS holds two general membership meetings each year—one in the spring and one in the fall—and hosts a regional Medicare Administrator Contractor caucus each summer to discuss the latest Medicare rulings and their effects on oncology care. The Society also cohosts meetings featuring highlights from the ASCO Annual Meeting as well the Seattle Blood Club, which focuses on hematology topics.

rural and urban areas, making it difficult to provide outreach to members and address their unique concerns. WSMOS has to be mindful of all members’ concerns, including their geographic locations and how they affect the type of practice they have, whether it is hospital- or private practice–based.

Another great challenge for our members is transitioning from a state that was heavily community practice–based to one where the vast majority of the practices are now connected to a hospital partner. The issues facing the majority of our members are different now and we have had to adjust to the new challenges.

Future Goals What are your future goals?

Our main goal is to maintain highquality oncology care in the state of Washington, regardless of the practice setting or geographic location. One way we have been instrumental in ensuring high-quality care for our patients is the close working relationship we have established over the years with Noridian Healthcare Solutions and our other Medicare Administrative Contactors.

For example, in 2012, we worked with the Oregon Society of Medical Oncology and the Idaho Society of Clinical Oncology as well as Noridian to address the Medicare Recovery Audit Contractor audit of same-day use of pegfilgrastim (Neulasta) following chemotherapy. As a result, an article providing support for the administration of pegfilgrastim on the same day as chemotherapy was posted on the Noridian website. In addition, ASCO sent a letter to the Centers for Medicare & Medicaid Services requesting that these audits be halted. We will continue to work with Noridian and our other local carriers to help them better understand the needs of our members and our patients and to identify areas of concern surrounding Medicare audits. n Disclosure: Dr. Jones reported no potential conflicts of interest.

The ASCO Post | JUNE 25, 2014

PAGE 102

In the Literature

Emerging Clinical Data on Cancer Management COLORECTAL CANCER Colorectal Cancer Screening Recommended Past Age 75 for Previously Unscreened Patients Colorectal cancer screening is costeffective and “should be considered well beyond age 75 years” for individuals not previously screened, according to a computer simulation study published in the Annals of Internal Medicine.

The researchers noted that while the U.S. Preventive Services Task Force recommends against routine screening for colorectal cancer in adequately screened persons older than 75 years, the recommendation does not address the appropriateness of screening in elderly persons without previous screening, and this “has led many members of the medical community to believe that no one older than 75 years should be screened for [colorectal cancer]. However, because unscreened elderly persons are at greater risk for [colorectal cancer] than adequately screened elderly persons, screening them is likely to be effective and cost-effective up to a more advanced age.”

Once individuals reach their late 80s or early 90s, however, “screening is not likely to be cost-effective, even in those without previous screening,” the researchers added, because of risks of death from competing disease and from screening-induced harms, such as colonoscopy-related complications and overdiagnosis and overtreatment.

Simulation Model Researchers used the Microsimulation Analysis Colon (MISCAN-Colon) model to quantify the effectiveness and costs of screening and determine at what ages colorectal cancer screening should be considered in unscreened elderly persons. The model was developed at Erasmus University Medical Center, Rotterdam, the Netherlands, and the study was conducted by researchers there and at Memorial Sloan Kettering Cancer Center, New York. The study was funded by the National Cancer Institute grant as part of the Cancer Intervention and Surveillance Modelling Network.

“For each age between 76 and 90 years, we simulated a cohort of 10 million elderly persons without previous screening with no, moderate, and severe comorbid conditions (a total of 45 cohorts),” the authors explained.

“Compared with cohorts of adequately screened elderly persons, the risk for [colorectal cancer] in these cohorts was substantially greater.”

For example, among simulated patients aged 80 years who had negative screening colonoscopies at ages 50, 60, and 70 years, colorectal cancer was prevalent in 0.3% and adenomas in 14.1%, but in simulated patients aged 80 years without previous screening, colorectal cancer was prevalent in 2.6% and adenomas in 44.9%. Within each cohort, researchers simulated a one-time screening with colonoscopy, sigmoidoscopy, and fecal immunochemical test and assessed costeffectiveness for each method.

The researchers concluded that

“[colorectal cancer] screening should be considered well beyond age 75 years” for elderly persons in the United States without previous screening—a group, the researchers noted, that represents 23% of all U.S. persons older than 75 years. “In unscreened elderly persons with no comorbid conditions, [colorectal cancer] screening should be considered up to age 86 years (up to age 83 years for those with moderate comorbid conditions and up to age 80 years for those with severe comorbid conditions).” The cost-effectiveness of screening with sigmoidoscopy and [fecal immunochemical testing] depended on age and comorbid conditions, but “colonoscopy is indicated at most ages.”

Important Implications The model used in the study “takes into account a wide range of relevant variables to estimate the quality-adjusted life-years gained or lost with screening,” according to an accompanying editorial. “Thus, the model is sensitive both to the benefits of screening when life expectancy is long and deaths from cancer are prevented and to the harms of screening when life expectancy is short and screening leads to detection and treatment that do not prolong life.”

The study “has important implications,” the editorialists added. “Colonoscopy should be considered in every American aged 75 years (and in many who are older) who has not had colorectal cancer screening, and those who do not have a fatal illness will likely benefit from screening.” van Hees F, et al: Ann Intern Med 160:750-759, 2014.

Clark AV, Landefeld CS: Ann Intern Med 160:804-805, 2014.

BREAST CANCER Long-Term Follow-up Confirms Low Incidence of Cardiac Events Associated With Trastuzumab

©Danny Shanahan/The New Yorker Collection/www.cartoonbank.com

At a median follow-up of 8 years, patients receiving trastuzumab (Herceptin) sequentially after chemotherapy and radiotherapy in the Herceptin Adjuvant (HERA) trial had a low incidence of cardiac events and these were reversible in the vast majority of patients. This long-term assessment confirms and extends previous reports of cardiac safety.

The three-arm HERA trial compared 2 years or 1 year of trastuzumab with

observation in 5,102 patients with human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer. “This is the first time that results of the 2-year trastuzumab arm have been reported, and the follow-up time has doubled,” researchers reported in the Journal of Clinical Oncology.

Eligible patients had a left-ventricular ejection fraction of at least 55% following neoadjuvant chemotherapy with or without radiotherapy and cardiac function was closely monitored. Cardiac adverse events leading to discontinuation of trastuzumab occurred in 9.4% of the 1,673 patients receiving 2 years of trastuzumab and 5.2% of the 1,682 patients receiving 1 year of trastuzumab.

Cardiac death, severe congestive heart failure, and confirmed significant left-ventricular ejection fraction decrease remained low in both treatment and the observation arms. “The incidence of severe [congestive heart failure] (0.8%, 0.8%, and 0.0%, respectively) and confirmed significant [leftventricular ejection fraction] decrease (7.2%, 4.1%, and 0.9%, respectively) was significantly higher in the 2-year and 1-year trastuzumab arms compared with the observation arm. Severe [congestive heart failure] was the same for 2-year and 1-year trastuzumab,” the investigators stated. More than 80% of patients with confirmed left-ventricular ejection fraction decrease receiving trastuzumab for 1 or 2 years reached acute recovery, defined as two or more sequential left-ventricular ejection fraction assessments of > 50%.

“Importantly, our data are consistent with the reassuring cardiac safety data reported in the other pivotal adjuvant trastuzumab trials testing the 1-year trastuzumab duration,” the authors noted. This includes the NSABP B-31 trial, which reported a 4.0% incidence of cardiac events in the trastuzumab arm vs 1.3% in the control arm, with most of those experiencing a cardiac event recovering within 6 months.

“Despite this low incidence of cardiac toxicity in our trial, patients treated with adjuvant trastuzumab should have a cardiac assessment before and during its administration to ensure the early detection of cardiac events and prompt treatment,” the authors advised. n de Azambuja E, at al: J Clin Oncol.

June 9, 2014 (early release online).

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

ASCOPost.com | JUNE 25, 2014

PAGE 103

Lab Notes

Ongoing Molecular Research in the Science of Oncology TARGETED THERAPY Aflibercept More Active Than Bevacizumab in Patient-Derived Colorectal Cancer Xenografts Some evidence suggests that dual targeting of vascular endothelial growth factor (VEGF) and placental growth factor (which binds to VEGFR-1) might provide more effective antiangiogenic therapy. In a study reported in Molecular Cancer Therapeutics, Chiron and colleagues compared the antitumor effects of ziv-aflibercept (Zaltrap), which binds VEGF-A, VEGF-B, and placental growth factor, with those of the anti–VEGF-A antibody bevacizumab (Avastin) in patient-derived xenograft colorectal cancer models.

Tumors (47 adenocarcinomas) were freshly excised from primary (n = 9) or metastatic sites (n = 39) of 48 patients and engrafted and passaged subcutaneously into female NMRI nu/nu mice, which received biweekly aflibercept or bevacizumab. Complete tumor stasis was observed with aflibercept in 31 (65%) of 48 models (including 15 of 31 with KRAS-activating mutations) and with bevacizumab in 2 (4%) of 48.

Tumor cells were the major source of VEGF, whereas placental growth factor was primarily produced by tumor stroma. According to the investigators, the markedly higher human vs mouse VEGF-A levels observed in the tumors makes it unlikely that the results reflect an inability of bevacizumab to bind mouse VEGF-A. The investigators concluded, “Neu-

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tralizing of [placental growth factor] and VEGFR-1 activation may be a factor [in this setting] and should be investigated in future studies. In these [colorectal cancer patient–derived xenograft] models, aflibercept demon-

strated greater antitumor activity than bevacizumab…. [Since] many of the xenograft tumors were derived from [metastatic colorectal cancer] tumors, there is the suggestion that aflibercept may have activity in retarding the pro-

gression of later-stage disease.” n Chiron M, et al: Mol Cancer Ther.

March 31, 2014 (early release online).

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

Reserve Your Seat Today at NCCN.org/hem

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NCCN 9th Annual Congress:

Hematologic Malignancies

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Additio nal available discounts Member for NCCN Institutio ns

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Highlights include*: • AML: Current Management

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Molecular Monitoring in CML

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Chimeric Antigen Receptor (CAR) Modified T Cells for ALL

Molecular Prognostication in CLL from FISH to Next Generation Sequencing: Implications for Clinical Management

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Current Management of Adult ALL

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Myeloid Growth Factors Revisited

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Diffuse Large B Cell Lymphoma: Treatment Beyond R-CHOP

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Optimal Management of CML without Breaking the Bank

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Evolving Therapy of Mantle Cell Lymphoma

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Role of Molecular Advances in the Classification and Prognosis of MDS

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Follicular Lymphoma and the Role of Maintenance

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Targeted Therapy in Indolent Lymphoma

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Is There a Role for Upfront Transplant in the Current Management of Symptomatic Multiple Myeloma?

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The Continuum of MGUS and Smoldering Myeloma

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Updates on the Prevention and Treatment of Cancer-Related Infections

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This activity will be approved for AMA PRA Category 1 Credit(s)™ for physicians and will also be accredited for nurses, pharmacists, and other health care professionals. Please refer to the complete accreditation details for more information.

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The ASCO Post | JUNE 25, 2014

PAGE 104

In Memoriam

Leading Cancer Researcher and Public Health-Care Expert, Eddie Reed, MD, Dies

By Ronald Piana

I

n a 2010 interview, Eddie Reed, MD, a pioneer in the molecular pharmacology of DNA-damaging anticancer agents and the clinical development of paclitaxel for ovarian cancer, was asked what lay ahead.

Before answering, Dr. Reed first acknowledged the esteemed mentors who gave

Eddie Reed, MD

him their most precious commodity: time.

“I’ve been very fortunate to have had mentors who spent a lot of their valuable time and resources giving me help that I would not have otherwise received.”

He then elucidated the exciting work in molecular pharmacology that he and his group were planning for the future.

Dr. Eddie Reed died on May 28, 2014, at the age of 60.

Humblest of Beginnings Dr. Reed was born to Floyd and Gennora Reed on December 17, 1953, in rural Arkansas, one of 16 children in one of the state’s last sharecropper families. The barriers they faced as a family and what it took to overcome those barriers would inform a central core of Dr. Reed’s career. An outstanding student throughout his early school years, he attended Mildred Jackson School and graduated at the top of his class from Hughes High School in Hughes, Arkansas.

Dr. Reed was accepted to the private, “historically black” Philander Smith College in Little Rock, Arkansas. After obtaining his undergraduate degree from Philander Smith College, Dr. Reed pursued a medical degree at Yale University School of Medicine, in New Haven, Connecticut, graduating in 1979. He completed his internship and residency at Stanford Univer-

sity in Palo Alto, California, in 1981, and was then accepted for a fellowship at the National Cancer Institute (NCI).

Beginning of a Great Career Dr. Reed’s time at the NCI further consolidated his goals as a cancer researcher, working alongside some of the brightest researchers in the country. From 1985 to 2001, he served in a variety of increasingly responsible roles at the NCI, culminating with his appointment as Chief of the Pharmacology Branch and Chief of the Ovarian Cancer and Metastatic Prostate Cancer Clinic in the Division of Clinical Science, becoming the first African American branch chief to serve at the Institute.

Of the many colleagues and mentors who helped nourish Dr. Reed’s career, he singled out Bruce Chabner, MD, who was NCI’s Director of the Division of Cancer Treatment from 1981 to 1995. “More than any other single person, Bruce Chabner has played a central role in my professional development. I know of many others for whom the same statement would be true,” wrote Dr. Reed in a tribute to Dr. Chabner.

Increasingly, Dr. Reed became internationally recognized as a rigorous and innovative researcher. Much of his clinical investigation centered on DNA damage and repair in cancer cells. Dr. Reed was also a renowned authority on the use of the anticancer agents paclitaxel and cisplatin. From 2001 to 2005, Dr. Reed served as Director of the Mary Babb Randolph Cancer Center at West Virginia University, Morgantown, and held academic appointments in the University’s Departments of Internal Medicine, Microbiology, Immunology, Cell Biology, and Basic Pharmaceutical Sciences.

Scientist Humanitarian Along with clinical research, Dr. Reed was deeply involved in many public health cancer prevention, screening, and control programs. In 2005, Dr. Reed was recruited to serve as the Director of the Division of Cancer Prevention and Control, Centers for Disease Control and Prevention

(CDC), in Atlanta. At the CDC, Dr. Reed managed the scientific and programmatic activities in cancer surveillance, cancer epidemiology, public health science, public health policy, and the early detection and prevention programs in cancer.

In 2008, Dr. Reed joined the USA Mitchell Cancer Institute in Mobile, Alabama, where he served as Clinical Director while continuing his research that concentrated on molecular pharmacology and clinical development of novel platinum compounds, with a chief focus on ovarian cancer and metastatic prostate cancer.

While at the Mitchell Cancer Institute, Dr. Reed also worked closely with Alabama’s cancer screening and control programs.

A Larger Stage In 2013, the National Institute on Minority Health and Health Disparities (NIMHD) of the National Institutes of Health announced, “Eddie Reed, MD, an award-winning physician and internationally recognized cancer researcher, will serve as the Clinical Director for the NIMHD Intramural Research Program.”

Dr. Reed’s friend and longtime colleague during his years at the NCI, James Mulshine, MD, wrote a letter of support to the NIMHD in which he stated, “Dr. Reed’s independence and productivity as a scientist was validated in 1991 with the awarding of NIH tenure. As a result of the respect he is afforded in the academic world, he went on to senior research appointments at two universities and the CDC. Through a series of studies and high-impact publications, Dr. Reed elucidated key aspects of how to coordinate chemistry effects and drug responsiveness. His work is highly original and rigorous and has greatly impacted the understanding of drug resistance across the field of clinical pharmacology.”

A Legacy Remembered Dr. Reed was a very active member of the American Association for Cancer Research (AACR). In addition to serving as a member of the AACR Board of Direc-

In Memoriam



Eddie Reed, MD

December 17, 1953 – May 28, 2014



tors from 2008 to 2011, he was elected as Chair of the AACR Minorities in Cancer Research Council, serving a term from 2009 to 2010.

He also served on the National Advisory Council on Minority Health and Health Disparities and on the Institute of Medicine’s National Cancer Policy Forum. He twice received the U.S. Public Health Service Commendation Medal.

Dr. Reed was author or coauthor of more than 275 peer-reviewed research and clinical publications, and is named inventor on eight patents.

Lovell Jones, PhD, former Director of the Center for Research on Minority Health at The University of Texas MD Anderson Cancer Center, Houston, offered this thought about Dr. Reed, his friend and colleague: “Long before, the idea of public health disparities became recognized as a major factor in making us an unhealthy society, the idea of broadly addressing health became a part of Eddie’s career trajectory. When he became head of the Division of Cancer Prevention and Control at CDC, it was all part of a plan—a plan cut short by his death. That is why his loss is not just the loss of one human being, but a critical loss in our efforts to address one of this nation’s most serious problems, health inequities.”

In honor of Dr. Reed’s dedication and advocacy for underserved cancer populations, his friends and colleagues established the Dr. Eddie Reed Fellowship Program in Global Oncology. It will bring cancer care trainees from Africa to Massachusetts General Hospital and its collaborators at Harvard University and other American academic centers.

Dr. Eddie Reed left this world far too soon; much of his planned work was unfinished. He will be remembered as a brilliant researcher and a courtly person with unshakable convictions about the true meaning and dedication of being a doctor. His legacy is well worth remembering. n

ASCOPost.com | JUNE 25, 2014

PAGE 105

Perspective

Sharing 50 Years of Christmas: A Quality Metric?

By Chandrakanth Are, MBBS, MBA, FRCS, FACS

A

very pleasant 68-year-old woman was referred to my clinic with biopsy-proven liver metastasis from primary colon cancer. She was initially diagnosed with colon cancer, which was resected, and she then received chemotherapy. A suspicious liver lesion was biopsied in the adjuvant setting, which confirmed the presence of metastatic disease. After she completed the chemotherapy, she was referred to my clinic.

Staging workup revealed disease isolated to the liver that was resectable with a good future liver remnant. She noted a history of smoking for about 50 years. Cardiopulmonary performance status assessments were completed, and she was considered fit for the proposed surgery.

Case Progression The patient was always accompanied by her daughter, who is a nurse by profession. The patient’s husband had recently passed away, and she now relies on her daughter, who lives close by. The patient led an active lifestyle and was independent in her activities of daily living.

After going over the prognosis and various treatment options, along with their risks/benefits and other pros/ cons, the patient and her daughter wanted to proceed with operative intervention. It was explained to the patient and her daughter that although hepatic resections are safe procedures, her smoking history could likely increase her mortality and morbidity. Nevertheless, the patient and her daughter opted to proceed with resection.

The patient underwent an uneventful right hepatectomy. Her postoperative period was marked by pulmonary problems that were not unexpected given her long-term smoking history. Although these problems were reversible and easily treatable, after a few days the patient and her daughter wanted to withDr. Are is Associate Professor of Surgical Oncology, Vice Chair of Education, and Residency Program Director in General Surgery at University of Nebraska Medical Center, Omaha.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO. Some details have been changed to protect patient privacy.

draw all active interventions. After several discussions, their wishes were respected, and the patient was transitioned to comfort care measures. She passed away peacefully, surrounded by her family members.

Health-Care Redesign Delivering effective, safe, and compassionate care has always been the guiding principle for physicians.

Several factors in recent times have placed a renewed emphasis on delivering high-quality patient care. The two reports published by the Institute of Medicine in 1999 (To Err is Human: Building a Safer Health System) and

now become part and parcel of a physician’s daily practice.

Any and every attempt to improve the quality of patient care should be embraced openly. Our primary constituents are our patients, and anything we can do to improve their care and quality of life should be welcome.

The various agencies should be given credit for their efforts in developing objective metrics to assess the quality of health-care delivery for nearly 300 million people. Similarly, the providers and hospitals should be applauded for their efforts in incorporating these new practices and measurement tools into their practice, which

While [health-care quality] metrics are essential and valuable, the rigid application of these without significant built-in flexibility can have unintended consequences.

—Chandrakanth Are, MBBS, MBA, FRCS, FACS

2001 (Crossing the Quality Chasm: A New Health System for the 21st Century) have been instrumental in zeroing in on the quality of health-care delivery in the United States.

As a result of these reports, pressures from the elected officials, obligations to the public, and a need to improve patient care, a fundamental redesign of health-care delivery got underway. Quality was perched right at the top of this redesign pyramid.

Many new measures and metrics were created by various agencies such as the Center for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality. Some of these measures and metrics included the Surgical Care Improvement Project, Patient Safety Indicators, Hospital Acquired Conditions, and Hospital Consumer Assessment of Healthcare Providers and Systems.

Clear-cut metrics such as mortality, morbidity, length of stay, and readmissions are closely monitored, and hospitals and providers fall somewhere along this quality spectrum based on their performance. Performance on these quality metrics has been incorporated into the reimbursement paradigm. These quality metrics have

is not easy, considering the significant variations in health-care delivery in the United States.

Limitations of Metrics Objective metrics play a key role in assessing performance in any field, and health care is no different in that aspect. While objective metrics enable assessment and measurement, subjective variations need to be borne in mind. This is where the health-care field is unique. Subjective variations are so enormous in health care that sometimes no amount of objective or statistical adjustment can justify the occurrence of some events.

There are situations where despite the satisfaction of all quality metrics, the outcome is either unacceptable or undesirable. For example, even with the use of appropriate pharmacologic/mechanical methods of prophylaxis and ambulation, a patient may still develop deep venous thrombosis. In other cases, despite the failure to fulfill quality metrics, patients may have a satisfactory outcome. These are patients who do not develop any clinical evidence of deep venous thrombosis even without prophylaxis.

Misleading Assessment In our patient with liver metastases, we satisfied all the required quality metrics. She received appropriate preoperative assessment of her performance status, and correct investigations were performed to assess her liver function. Her operative procedure was uneventful with minimal blood loss and acceptable operative time. She received appropriate postoperative care between the ward and intensive care unit. Her pulmonary problems were addressed appropriately until the family wanted us to withhold care.

We held several discussions with the patient and family members and respected their wishes. The family members were very grateful for the compassionate care the patient received and for our abiding by their wishes. The family was completely at peace with the decision they made, as this is what the patient had wanted.

It appears that we did everything appropriately. But for that person sitting by a computer remotely and assessing our quality of care objectively, this mortality will be seen in a negative light. This can negatively influence the Physician Performance Feedback Report and also the hospital mortality statistics when compared to others.

Mortality is a “yes” or “no” metric, with little to explain it subjectively in such situations. Anyone who has ever laid a hand on a patient is fully aware that these types of situations are not uncommon.

Need for Flexibility As we continue on this quality journey, everyone involved in the improvement of health-care quality needs to be constantly aware of the considerable influence of subjective variations. As the spokespersons for our patients, we need to strongly advocate and embrace measures and metrics that improve the quality of patient care. While metrics are essential and valuable, the rigid application of these without significant built-in flexibility can have unintended ­consequences.

Prolonging the life of our patient may have led to her survival, which would make us look good on an objective scale. But try telling this to the families of patients burdened by the emotional and psychological weight of continued on page 106

T:10.25"

The ASCO Post | JUNE 25, 2014

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Perspective

S:9.5"

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.

Quality Metrics continued from page 105

making the decision to withdraw care.

Try explaining this to a patient who has lost all the will to live. That would not qualify as compassionate care, which, as we all know, is not associated with a measurable metric.

The patient’s daughter noted that her parents were married for 49 years and had never spent a Christmas apart. The patient’s husband had

passed away a few months earlier, and the family had to make the decision to withdraw care for the patient in December. As the patient passed away a few days before Christmas, in peace and comfort, surrounded by her family, the daughter commented that her parents had spent 49 Christmases together, and now they would spend the 50th together as well.

Try capturing that aspect of medicine and finding a quality metric for it. 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).]

Passing the Gavel at the 2014 ASCO Annual Meeting: ASCO Immediate Past President Clifford A. Hudis, MD, FACP, and President P ­ eter Yu, MD, during the Annual Business Meeting at the American Society of Clinical Oncology Annual Meeting in Chicago, June 2, 2014. Photo by © ASCO/Phil McCarten 2014.

The ASCO Post 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

Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

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).]

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1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

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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 Preferred terma (n = 304) 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.

S:12.5"

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%

T:13"

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).]

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Confronting a common threat across approved indications Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Rhinitis — Dry skin — Back pain — Headache — Proteinuria — Rectal hemorrhage — Exfoliative dermatitis — Hypertension — Taste alteration — Lacrimation disorder Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

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Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%).

Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,* the incidences of Avastinrelated adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC *Avastin is not approved for use in combination with irinotecan or any other combination regimens.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Reference: 1. Avastin Prescribing Information.

Genentech, Inc. March 2013.

www.avastin-hcp.com