Clinical Oncology News Digital Edition - September 2012

A

nn

iv

40

er

19

sa th r –2 y Ye 01 2 a

72

r

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • September 2012 • Vol. 7, No. 9

INSIDE SOLID TUMORS Blocking angiogenesis in ovarian cancer . . . . ...... 6 FDA approves ziv-aflibercept . . . . . . . . ...... 8 Maintenance therapies fail in ovarian cancer . . . . . . . . . . . . . . . . . . . . ...... 19 Colorectal screening requires a decade to see benefit . . . . . . . . . . . . . . ..... 21 HEMATOLOGIC DISEASE FDA approves vincristine injection ...... 6 Pixantrone for non-Hodgkin’s lymphoma . . . . . . . . . . . . . . ..... 28 CURRENT PRACTICE The limited effect of clinical trials on realworld practice . . . . . . . . ...... 4 Clinical Conundrums . . . . . . . . . . ..... 22 Expert editorial roundtable: sentinel lymph node biopsy in melanoma . . . . . . . . . . . . . . . .... 24 EDUCATIONAL REVIEW Evolving Treatment Paradigms in Non-Small Cell Lung Cancer See insert between pages 16 and 17.

Vismodegib Controls Basal Cell Carcinoma

Prostate Cancer: Low-Cost Interventions

First approved agent that targets hedgehog signaling pathway

At AACR, early research highlights vitamin D, metformin and obesity

Chicago—An inhibitor of the hedgehog signaling pathway has demonstrated such remarkable activity in the control of advanced basal cell carcinoma (BCC) that the FDA has licensed it despite the fact that it is only now entering Phase II trials.

The ability of vismodegib (Erivedge, Genentech) to control BCC reinforces a large body of evidence that genetic alterations in hedgehog signaling drive the proliferation of cancerous basal cells.

Vismodegib also is drawing attention see VISMODEGIB, B page 8

Maintenance Pemetrexed Improves Survival

C

hicago—Prostate cancer continues to be a hot spot in cancer research, with investigators pursuing many paths to reduce the damage caused by this common disease. At the American Association for Cancer Research’s 2012 annual meeting, several presentations highlighted the progress and challenges of prostate cancer research.

Vitamin D Supplementation One of the trials in the first wave of vitamin D clinical studies was led by Reinhold Vieth, PhD, a pro- Anatomy of fessor at the University of Toronto. The results showed human prostate in that higher oral vitamin D levels are linked to lower x-ray view and high levels of a protein associated with cancer proliferation, power microscopic view of the glandular portion. and also with higher levels of microRNAs, which inhib- September is National Prostate it cancer cell proliferation.

Cancer Awareness Month.

In the Phase II, double-blind trial, the investigators randomized 21 men with Gleason score 6 or 7 prostate cancer to vitamin D 400 IU per day. They randomized another 22 to 10,000 IU per day and another 23 to 40,000 IU per day. The subjects took the vitamin D in the interval between being scheduled for radical prostatectomy and having the procedure, a period of four to eight weeks. see PROSTATE, E page 14

Short induction may have limited first-line platinum effect in NSCLC

Vogl, NY...

Chicago—Results from the PARAMOUNT trial show that maintenance pemetrexed therapy immediately following induction pemetrexed-cisplatin increases median overall survival (OS) by roughly three months in patients with advanced nonsquamous nonsmall cell lung cancer (NSCLC) compared with best supportive care (BSC). “[This study] may support a change in the paradigm of treatment in this setting,” said Luiz Paz-Ares, MD, PhD, the chair of oncology at Seville University see PEMETREXED, D page 7

TDM-1 Is a Good Drug, But Better Than WHAT? Drug firms choose inferior comparators to make their new drugs look good

A

merican Society of Clinical Oncology (ASCO) 2012 saw the plenary presentation of the EMILIA trial comparing a new targeted therapy consisting of a HER2 antibody (trastuzumab; Herceptin, Genentech) conjugated to a

Steven Vogl, MD

very toxic chemotherapy drug (a maytansine analog called DM-1) with an “approved” (by the FDA) chemotherapy regimen of lapatinib and capecitabine.

The results appeared quite favorable for see TDM-1, 1 page 11

EXPERT COMMENTARIES FROM SITEMAN CANCER CENTER

Cross-resistance in metastatic castrationresistant prostate cancer . . . . . . . . . . . . . . . . . .... 17 Bruce J. Roth, MD

Carfilzomib for relapsed and refractory multiple myeloma ................ 20 Ravi Vij, MD

NOW

APPROVED in five indications!

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936-1080

©2012 Novartis

7/12

AFI-1046308

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer Michael A. Carducci, MD AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Hematologic Malignancies

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

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

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Maura N. Dickler, MD

Harry Erba, MD, PhD

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

University of Michigan Ann Arbor, MI

Gastrointestinal Cancer Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

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

Gastrointestinal Cancer and Sarcoma

Sara S. Kim, PharmD

University of California, San Diego, CA

The Mount Sinai Medical Center New York, NY

Infection Control

Bioethics

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

Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

Oncology Nursing Betty Ferrell, RN, PhD City of Hope National Medical Center Duarte, CA

Michele Neskey, MMSc, PA-C University of Texas, MD Anderson Cancer Center Houston, TX

Shaji Kumar, MD Mayo Clinic Rochester, MN

Paul J. Ford, PhD Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Pharmacy Cindy O’Bryant, PharmD Richard Stone, MD

University of Colorado Cancer Center Denver, CO

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Rhonda M. Gold, RN, MSN The Pritchard Group Rockville, MD

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

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

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

Charles F. von Gunten, MD

Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Mission Statement

T

he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

Genitourinary y Cancer Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Steven Vogl, MD Medical Oncologist New York, NY

Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Lung, g, and Head and Neck Cancers Edward S. Kim, MD University of Texas, MD Anderson Cancer Center Houston, TX

Lung g Cancer,, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

Editorial Philosophy The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published.

Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

3

4

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

The Real-World Effect of Evidence-Based Clinical Trials There has been considerable discussion in both the medical literature and the lay press regarding the potential of comparative effectiveness research to inform and subsequently help modify clinical practice.

Several worthy goals have been put forward, including improved health of the population by enhancing use of the most effective strategies in a given clinical setting; reducing or eliminating the use of clearly ineffective or excessively costly medical interventions; and increasing the overall value associated with the medical care being delivered.

However, the concept of comparative effectiveness research has—at its core— the realization that a specific randomized clinical trial, no matter how wellconducted, is unlikely to represent “real world” medical care. For example, to optimize the utility of a particular antineoplastic agent within a given Phase III trial, investigators will purposefully reduce the heterogeneity of the patient population being examined (e.g., comorbidities, prior therapy).

Although this may be a sound strategy within the confines of a clinical study, the relevance of the subsequent outcome to the far larger population is highly questionable. Comparative effectiveness research seeks to challenge the paradigm of deciding care based on generalizations drawn from often remarkably

Comments or feedback on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor Gabriel Miller at

gmiller@mcmahonmed.com

®

McMahon Publishing is a 40-year-old, family-owned medical publishing and medical education company.

McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp.

Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2012 McMahon Publishing, New York, NY. All rights reserved.

POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

irrelevant research. For example, basing the management of patients aged at least 70 years on trials that include few such elderly patients.

There should be legitimate enthusi-

elderly breast cancer patients (age >70 years) who received adjuvant radiation after the publication of the cooperative group trial (75% vs. 79%; relative risk of undergoing radiation post- vs. prestudy publication, 0.97).

Furthermore, this modest reduction among the most elderly breast cancer patients was no different from a decrease in the use of adjunctive radiation seen in a younger elderly group, suggesting

EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

‘Just how effective will evidence-based oncology trials designed to examine common clinical scenarios or comparative effectiveness studies employing large public or private databases be in actually influencing the medical care provided to cancer patients?’ asm for a research strategy that examines optimal medical management in the often rarefied environment of a well-controlled clinical trial. But it remains uncertain just how useful these studies will be in routine management, even if they are specifically designed to affect populations seen in the “real world” of cancer management.

To explore this issue, investigators examined the impact of a previously published National Cancer Institute-sponsored cooperative group Phase III randomized trial that had specifically studied the question of adjuvant radiotherapy in elderly patients with breast cancer.1 The study found “minimal benefits” associated with the routine use of adjuvant radiotherapy following definitive surgery in this particular patient population. Several national “treatment guidelines” for the management of breast cancer were changed to reflect the findings.

Yet, in a 2012 analysis of SEER (Surveillance, Epidemiology, and End Results) and Medicare databases from 2001 to 2007, investigators found a very limited change in the proportion of

the observed reduction has little—if anything—to do with the published results of a major clinical trial.

A final figure reveals the lack of effect of these specific study results. The reduction in the percentage of breast cancer patients over the age of 70 did not differ between women with an anticipated life expectancy of less than five years versus at least 10 years (3.7% vs. 3% decline, respectively) from before versus after the publication of this study. If this trial had a genuine effect on medical practice, patients with more modest life expectancy would have had the greatest reduction in the use of adjuvant therapy. However, this was not observed.

The bottom line here is that this study appears to have had at best minimal or— more realistically—no effect on the use of adjuvant radiation therapy in elderly women with breast cancer.

The question to be asked: Just how effective will evidence-based oncology trials designed to examine common clinical scenarios (e.g., management of the elderly breast cancer patient)

or comparative effectiveness studies employing large public or private databases to focus on “real-world” settings actually be in influencing the medical care provided to cancer patients?

And how will incentives (strongly preferred) or penalties be used to optimize the chances that patients receive the care seen to most favorably affect outcome, both survival and quality of life?

It is absolutely essential to state clearly that this discussion does not imply that all cancer patients must be treated identically, or that “guideline” medicine should replace patient choice or physician judgment. However, it is equally important to acknowledge that for “patient choice” and “physician judgment” to be effective, they must be informed by the best possible current clinical trial and retrospective population-based data.

EDITORIAL STAFF

SALES STAFF

Brandy Wilson, Circulation Coordinator

Kevin Horty, Group Publication Editor khorty@mcmahonmed.com

Julianna Dawson, Publication Director jdawson@mcmahonmed.com

Gabriel Miller, Managing Editor gmiller@mcmahonmed.com

Marlena McMahon, Associate Publication Director marlena@mcmahonmed.com

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

ART AND PRODUCTION STAFF

James Prudden, Group Editorial Director

Michele McMahon Velle, Creative Director, MAX Graphics

References 1. Soulos PR, Yu JB, Roberts KB, et al. Assessing the impact of a cooperative group trial on breast cancer care in the Medicare population. J Clin Oncol. 2012;30:1601-1607, PMID: 22393088.

Mark Neufeld, Associate Director, Project Management

MCMAHON PUBLISHING Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner

David Bronstein, Editorial Director Robin B. Weisberg, Manager, Editorial Services Elizabeth Zhong, Associate Copy Chief

Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics Dan Radebaugh, Director of Production and Technical Operations

Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

Continuing Bevacizumab With Second-line Therapy In platinum-resistant ovarian cancer, continued anti-angiogenesis doubled PFS Chicago—Adding the anti-angiogenesis agent bevacizumab to second-line chemotherapy in platinum-resistant ovarian cancer doubled the time to progression, according to the large multicenter, Phase III trial AURELIA. The advantage of bevacizumab (Avastin, Genentech) was seen as both highly statistically significant and clinically meaningful.

“Bevacizumab combined with chemotherapy should be considered a new standard option in platinum-resistant ovarian cancer,” senior author Eric Pujade-Lauraine, MD, of the Hôpital Hotel-Dieu in Paris, said at the 2012 annual meeting of the American Society of Clinical Oncology (abstract LBA5002).

Although several studies have previously established bevacizumab as an effective therapy in front-line

AT A GLANCE AURELIA Bevacizumab doubled time to progression in platinumresistant ovarian cancer There was no significant difference in grade 3 or higher adverse events between treatment groups It was the first trial to show benefits of targeted therapy in this hard-to-treat group Benefit of targeted therapy on mortality is not clear and some argue unlikely for this disease

ovarian cancer treatment, this is the first multicenter study to show benefit in patients with advanced disease in whom the first-line chemotherapy is no longer working, according to Dr. Pujade-Lauraine.

In AURELIA, 361 patients with ovarian cancer who had progressed within six months after at least four cycles of platinum-based therapy were randomized to receive second-line chemotherapy with or without bevacizumab. Several singleagent, second-line chemotherapies were permitted according to the discretion of the treating physician, including pegylated liposomal doxorubicin, topotecan and paclitaxel. Bevacizumab was administered in every-two-week injections of 10 mg/kg or every-three-week injections of 15 mg/kg depending on chemotherapy.

Progression-free survival, the primary end point, was 6.7 months in the group that received bevacizumab and 3.4 months in the group that did not, producing a 0.48 hazard ratio in favor of bevacizumab (P ( =0.001, Table). There were no significant differences between study arms in grade 3 or higher adverse events.

The authors called this an important positive trial for a group with “a high unmet need” for better therapeutic options.

Michael V. Seiden, MD, PhD, the president and CEO of Fox Chase Cancer Center in Philadelphia, agreed that there is a large unmet need in this group of patients and characterized bevacizumab “as arguably the most active single agent in advanced ovarian cancer,” but he was far more cautious about whether this is an important evolution in therapy. Noting that the criterion for a change in the standard of care is a mortality benefit, Dr. Seiden doubted that this protocol—like others not directly targeting the loss of tumor suppressor genes—would ever show a positive survival benefit. This, he said, is the

Image courtesy of Genentech

6

The advantage of bevacizumab was seen as both highly statistically significant and clinically meaningful.

Table. AURELIA: Bevacizumab Plus Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer Chemotherapy (N=182)

Bevacizumab + Chemotherapy (N=179)

Median PFS, mo (95% CI)

3.4 (2.2–3.7)

6.7 (5.7–7.9)

ORR, % (95% CI)

12.6 (8.0–18.4)

30.9 (24.1–38.3)

CI,, confidence interval;; ORR,, objective j response p rate;; PFS,, p progression-free g survival

mechanism that must be targeted.

“To make it worse and perhaps even distinct compared with many other malignancies, [ovarian cancer] is a tumor with loss of multiple tumor suppressors,” said Dr. Seiden, adding that it is unlikely that any therapy targeting a mechanism of proliferation will alter the natural history of ovarian cancer. “I think you could actually defend” the concept of stopping

all clinical trials of molecularly targeted agents in advanced ovarian cancer, he suggested.

twice despite standard treatments. Of these patients, 15.4% had either a complete remission or a complete remission with incomplete blood count recovery, and the median duration of remission was 28 days.

In a safety study, 76% of patients had a serious adverse event, including

low white blood cell counts with fever, respiratory distress and cardiac arrest.

The drug will come with a boxed warning outlining that the new formulation has different dosage recommendations than vincristine sulfate injection alone, and that it must be administered intravenously.

—Ted Bosworth Dr. Pujade-Lauraine has been a consultant to Roche as well as received honoraria and research funding from the company.

Dr. Seiden reported no relevant relationships.

HEMATOLOGIC MALIGNANCIES

Vincristine Injection Approved

T

he FDA has approved vincristine sulfate liposome injection (Marqibo, Talon) for patients with Philadelphia chromosome–negative (Ph–) acute lymphoblastic leukemia (ALL).

The drug is approved for patients who have relapsed or progressed following two or more treatment regimens.

The new formulation encapsulates vincristine sulfate in liposomes. According to Talon Therapeutics, the liposome

encasement allows for higher drug concentrations—as high as two to three times during individual doses and 10 times cumulatively—with a more predictable release.

The drug was approved under the FDA’s accelerated approval program based on a clinical trial of 65 adult patients with leukemia that had relapsed at least

—Gabriel Miller

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

PEMETREXED continued from page 1

Hospital in Seville, Spain. He reported the results at the American Society of Clinical Oncology’s (ASCO) annual meeting (abstract LBA7507).

Most patients with lung cancer have stage IIIB/IV NSCLC when diagnosed, and the recommended first-line treatment is a platinum-based combination, including pemetrexed (Alimta, Eli Lilly) and cisplatin. Maintenance therapy with pemetrexed has shown efficacy following a non-pemetrexed platinum doublet.

In the new study, patients with stage IIIB/IV NSCLC who received four cycles of induction pemetrexed-cisplatin were randomized to receive pemetrexed maintenance plus BSC or placebo maintenance plus BSC. The study arms were well balanced for performance status of 0 or 1, disease stage and response to induction.

Patients in each arm received a median number of four cycles of maintenance.

Median follow-up was 12.5 months overall and 24.3 months for all patients who were alive at the time of survival analysis. Median overall survival from randomization was 13.9 months in the pemetrexed arm (n=359) and 11 months in the placebo arm (n=180) (hazard ratio [HR], 0.78; P=0.0195). Benefit was seen in all subgroups of patients, including response to induction therapy. Last year, interim results showed an improvement in progression-free survival and this continued to be seen (HR, 0.60).

Patients receiving pemetrexed had increased rates of grade 1/2 fatigue (17.5% vs. 10.6%), nausea (13.4% vs.

2.2%), anemia (11.7% vs. 4.4%) and vomiting (7.5% vs. 1.1%), as well as higher rates of grade 3/4 fatigue (4.7% vs. 1.1%), anemia (6.4% vs. 0.6%) and neutropenia (5.8% vs. 0).

“We should share with our patients the information about the role of maintenance treatment, but it doesn’t mean

that every single patient should be treated in this way,” said Dr. Paz-Ares.

Some clinicians do not believe the study sets a new standard because of the way it was designed, with four cycles of induction therapy. Current guidelines from the National Comprehensive Cancer Network and ASCO recommend four to six cycles of first-line chemotherapy.

“We have learned that platinum is really, really important and the reason for the four courses in the recommendation was based on the cumulative toxicities of the other partners, usually taxanes,” said Martin Edelman, MD, the director

of solid tumor oncology and co-leader of the Experimental Therapeutics Program at the University of Maryland Greenebaum Cancer Center. “If we really want to push to the most active drug that we own, it is platinum. I disagree with the [study] conclusion because the standard is really six courses of platinum-based therapies.” He pointed out that further tumor shrinkage is frequently observed between the fourth and sixth cycle of chemotherapy ((J Natl Compr Canc Netw 2010;8:740-801).

Dr. Edelman and others also questioned the validity of the results given

the relatively low use of second-line chemotherapy in the control arm.

“I discuss the issues of maintenance with my patients, but I do not recommend it,” said Dr. Edelman.

—Kate O’Rourke Dr. Paz-Ares disclosed a consultant or advisory role and honoraria from Bayer, Lilly, Pfizer and Roche. Dr. Edelman is on the data safety monitoring boards for Boehringer Ingelheim, Genentech and Lilly and has received research funding from Bristol-Myers Squibb, Genentech and Tragara.

Oncology gy Education Collaborative ĚƵĐĂƟŽŶ dŚĂƚ DĂƚĐŚĞƐ zŽƵƌ WƌĞĨĞƌƌĞĚ >ĞĂƌŶŝŶŐ ^ƚLJůĞ͘ Five leading CME organizations joined forces to create the Oncology Education Collaborative.

We help learners identify educational activities in the learning formats they prefer.

Our broad selection of educational opportunities includes live meetings, online programming, podcast downloads, mobile app education, print education, satellite radio broadcasts, and more.

Learn more today at www.OncologyCollaborative.org.

AT A GLANCE Maintenance Pemetrexed Benefit was seen in all patient subgroups

www.CMECorner.com

Only four cycles of induction therapy were given, potentially limiting the effect of platinum-based therapies Side effects were significant, with high rates of fatigue, nausea and anemia

www.Imedex.com

www CM www.CMEZone.com

www.OmniaEducation.com

www.ProvaEducation.com

7

8

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

VISMODEGIB

AT A GLANCE How it works

continued from page 1

because there are no effective therapies for advanced or metastatic BCC, which, although rare, cause disfigurement and are life-threatening, said Aleksandar Sekulic, MD, PhD, a dermatologist associated with Mayo Clinic in Scottsdale, Ariz. Results of the Phase I trial were first presented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 8579) but more recently were published in The New England Journal of Medicine (2012;366:2171-2179).

BCC is the most common malignancy in humans, but cases of metastatic BCC are rare. The efficacy of a hedgehog signaling inhibitor is a reassuring sign that a key pathophysiologic mechanism has been isolated.

In this study, 33 patients with metastatic BCC and 63 with locally advanced BCC were enrolled in a nonrandomized study.

All patients had inoperable BCC (38%) or were patients in whom further surgery was expected to increase disfigurement with a low likelihood of persistent benefit (62%). Nearly 90% of patients had

The hedgehog signaling pathway gives cells critical information during embryonic development

Vismodegib (above, at right, in green) is an antagonist of the smoothened receptor that blocks the hedgehog signaling pathway and prevents transcription of factors GLI1 and GLI2.

received prior surgery and a substantial proportion had received prior radiation.

All patients were treated with 150 mg of daily oral vismodegib. The primary end point was an objective response (OR).

The objective response rate (ORR) was 30% in those with metastatic BCC and 43% in those with locally advanced BCC. Additionally, 64% of those with metastatic disease and 38% of those with locally advanced BCC achieved stable disease. The median progression-free survival (PFS) was 9.3 months (Table).

Due the presumed importance of blocking the hedgehog pathway for controlling BCC, patients were permitted

Table. Vismodegib Activity in BCC Metastatic BCC (n=33)

Locally Advanced BCC (n=63)

Response rate, %

30 (95% CI, 16-48)

43 (95% CI, 31-56)

Median DOR,1 mo

7.6

7.6

9.3

12.9

1

2

Median PFS, mo

BCC, basal cell carcinoma; CI, confidence interval; DOR, duration of response; PFS, progression-free survival 1. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171-2179, PMID: 22670903.

2. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of the hedgehog pathway inhibitor vismodegib in patients with advanced basal cell carcinoma (BCC): ERIVANCE BCC study update. J Clin Oncol.

2012;suppl: 0 ;supp abstr abst 8579.

85 9

to remain on treatment indefinitely, but the median duration of treatment in the results presented was 10 months.

Approximately 50% of patients had discontinued the study treatment by the time these data were analyzed. The most common reason for discontinuing treatment in the metastatic cohort was disease progression, but a substantial proportion of both groups discontinued therapy due to adverse events (AEs). Grade 3 or greater severity AEs included muscle spasms, fatigue and loss of appetite secondary to taste disturbances.

Vismodegib, which is now being studied in both the treatment and prevention of basal cell nevus syndrome, has a relatively rapid onset and offset, suggesting that some kind of intermittent dosing may be possible to provide sustained control of basal cell cancers while permitting drug holidays to reduce the effects of AEs. Trials to test this strategy are under way.

“A number of other hedgehog pathway inhibitors are under investigation, and it will be interesting to see what differences emerge,” John T. Lear, MD, a dermatologist at Salford Royal Hospital in Manchester, United Kingdom, wrote in an editorial accompanying the study in The New England Journal of Medicine.

“The development of intermittent-dosing therapy protocols, particularly for

The pathway is involved in more than 90% of basal cell carcinomas In adults, hedgehog signaling has a limited role, however it likely regulates adult stem cells involved in maintenance and regeneration Mutations in the receptor proteins Patched (PTCH) and Smoothened (SMO) result in abnormal activation of the hedgehog pathway in adults Heightened activity of the pathway probably leads to transformation of adult stem cells into cancer stem cells Vismodegib is a cyclopaminecompetitive antagonist that binds to the smoothened protein, thus interfering with cell growth and survival

patients with basal cell nevus syndrome, might allow more patients to benefit since it would be of great therapeutic value to prevent new lesions.”

—Ted Bosworth Drs. Sekulic and Lear have no relevant financial relationships to disclose.

FDA Approves Ziv-aflibercept

T

he FDA has approved Ziv-aflibercept (Zaltrap, Sanofi-aventis) for use in combination with a FOLFIRI (folinic acid, fluorouracil and irinotecan) chemotherapy regimen for metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatincontaining regimen.

The drug is a vascular endothelial

growth factor-A (VEGF-A), VEGF-B and placental growth factor (PLGF) inhibitor.

In the approval study, patients who received ziv-aflibercept plus FOLFIRI lived for one month longer than those given FOLFIRI plus placebo (13.5 vs. 12 months; hazard ratio, 0.817; 95% confidence interval, 0.714-0.935; P=0.0032).

The most common side effects in the

study were leukopenia, diarrhea, neutropenia, proteinuria, aspartate aminotransferase increases, stomatitis, fatigue and thrombocytopenia, among others occurring with lesser frequency.

The most common grade 3/4 adverse events were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria and asthenia, all of

Get the latest news delivered directly to your computer and PDA.

Register for free

in Your Inbox

@ www.clinicaloncology.com

which occurred in at least 5% of patients and were common on the ziv-aflibercept treatment arm.

The drug will come with a boxed warning because it has been associated with gastrointestinal hemorrhage and gastrointestinal perforation.

—Gabriel Miller

AVA I L A B L E FR O M H O SPI R A

O XAL IPL AT IN IN J E CT IO N (5 m g / m L )

50 mg/10 mL single-dose vial 100 mg/20 mL single-dose vial

As the complexity of healthcare evolves, we’re doing our part to improve cost savings,

See Black Box Warning Below

optimize workflow and enhance patient care.

With our generic oncology portfolio we provide

ONE solution for ALL.

FOR PHARMACISTS—FAMILIAR STRENGTHS AND FLEXIBLE DOSING

FOR ADMINISTRATORS—MULTIPLE-DOSE VIALS LEAD TO LESS WASTE

FOR CLINICIANS—UNIQUE ONCO-TAIN ™ VIALS REINFORCE SAFETY 1

FOR YOUR INSTITUTION—HIGH-QUALITY MEDICATION AT A LOWER COST DO CE TAXE L IN J E CT IO N (10 m g / m L )

U N I Q UE O N C O - TA IN SA FE TY FE ATU R E S 1

PVC BOTTOM offers shatter resistance.

2

SHRINK-WRAPPED SLEEVE provides surface protection that acts as a barrier between any cytotoxic residue that may remain on the surface of the vial and persons handling the products.

3

GLASS CLARITY allows for easy inspection of the vial as a final safety check before administration.

4

PREWASHED VIALS reduce cytotoxic residue.

160 mg/16 mL multiple-dose vial 80 mg/8 mL multiple-dose vial 20 mg/2 mL single-dose vial See Black Box Warning Below

For more information, contact your

Hospira representative or call 1-877-946-7747.

Or visit us at products.hospira.com.

Docetaxel: WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION Oxaliplatin: WARNING: ANAPHYLACTIC REACTIONS

GE MCITAB IN E IN J E CT IO N (38 m g / m L )

Please refer to Black Box Warnings and see Brief Prescribing Informations on back page.

2 g/52.6 mL single-dose vial Reference: 1. Data on file. Hospira, Inc. Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045

1 g/26.3 mL single-dose vial P12-3707-10.5x13-Jul., 12

200 mg/5.26 mL single-dose vial

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

TDM-1 continued from page 1

the antibody conjugate, called TDM1, which was tested in women whose tumor had worsened on prior therapy including trastuzumab (Table 1).

TDM-1 seems to be a “nice” drug. It causes no alopecia, little neutropenia and only moderate thrombocytopenia.

It requires only a short infusion every

In 2012, we know only one thing about lapatinib in metastatic HER2-positive breast cancer: Do not use it without trastuzumab! three weeks, lacks cumulative toxicity and has a response rate as first-line chemotherapy that is about the same as that of docetaxel and trastuzumab with apparently longer remissions—median duration 14.2 versus 9.2 months as cited

by Kimberly Blackwell, MD, in her ASCO plenary presentation (E. Perez, personal communication). It is indeed representative of a new class of very promising drug–antibody conjugates, of which brentuximab vedotin for Hodgkin’s lymphoma is a shining example.

How Do We Interpret the TDM-1 Phase III Trial?

We cannot interpret it, because all the data available in 2012 suggest that the control arm, lapatinib and capecitabine, is distinctly suboptimal and does not represent a standard of care. We do know that lapatinib-capecitabine is modestly superior to capecitabine alone in women whose tumor grew on other chemotherapy plus trastuzumab (Table 2).1 Alas, we still do not know if it is superior or even equal to capecitabine with continued trastuzumab in the same population.

Perhaps it is even inferior to capecitabine plus lapatinib plus trastuzumab.

Stopping Trastuzumab for Even Six Weeks Costs Four Months In Median Survival in a Heavily Pretreated Population Unfortunately, in 2012, we know very little about how and when to use lapatinib. Based on a study just published for the third time by Dr. Blackwell, all we know is how not to use it: We should not use it without trastuzumab.2 The authors of this paper, a very distinguished group indeed, concluded that their study showing the superiority of lapatinib plus trastuzumab over lapatinib alone supports the use of dual HER2 blockade (Table 3).

An attractive, simpler explanation is that it demonstrates the importance and

Table 1. The EMILIA Trial Comparing TDM-1 With Capecitabine and Lapatinib for Metastatic HER2-Positive Breast Cancer Worsening on Trastuzumab (N=991) TDM-1

Capecitabine + Lapatinib

Overall response rate, %

44

31

Median duration of response, mo

12.6

6.5

Median PFS, mo

9.6

6.4

Survival at 1 y, %

85

77

Survival at 2 y, %

65

48

Treatment stopped for toxicity, %

6

11

Toxicity >grade 3, %

41

57

Diarrhea, %

23

80

Hand–foot syndrome, %

1

58

Nausea, %

39

45

Vomiting, %

19

29

Fatigue, %

35

28

Increased AST, %

22

97

Mucositis, %

7

19

Neutropenia, %

6

9

Thrombocytopenia, %

28

3

AST, aspartate aminotransferase; PFS, progression-free survival Blackwell KL, Miles D, Gianni L, et al. Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. J Clin Oncol.

2012;suppl: abstr LBA1.

How do we interpret the TDM-1 Phase III trial?

We cannot interpret it, because all the data available in 2012 suggest that the control arm— lapatinib and capecitabine—is distinctly suboptimal and does not represent a standard of care. value of continuing trastuzumab even after disease progression on multiple lines of trastuzumab-containing chemotherapy. The large deleterious effect on median survival of even a short hiatus off trastuzumab—4.5 months when prolongation of disease progression was just a few weeks (Table 2)—argues that continued trastuzumab has a major effect on disease progression that causes death even as disease continues to worsen on trastuzumab.

Major Benefit From Continued Trastuzumab After Disease Progression on Trastuzumab Plus Other Chemotherapy Gunther von Minckwitz, MD, and the German Breast Group showed that, even after a switch to capecitabine chemotherapy due to worsening disease, continued trastuzumab has benefits comparable to those of adding lapatinib (Table 3).3 Clearly, if symptomatic metastatic breast cancer is worsening despite trastuzumab and some chemotherapy, the degree of further benefit from continued trastuzumab is limited. In 2012, however, based on Dr. von Minckwitz’s data, any chemotherapy comparator for

HER2-positive metastatic breast cancer has to include continued trastuzumab.

Failure of lapatinib without trastuzumab was again demonstrated this year in an ASCO presentation of NCI-Canada MA.38 by Rebecca Sue Gelman, MD, PhD, comparing taxane plus trastuzumab with taxane plus lapatinib as first-line therapy for HER2-positive metastatic breast cancer (LBA 671). The study was closed early because the lapatinib arm was clearly less effective and more toxic.

Median progression-free survival was 11.4 months for trastuzumab plus taxane and only 8.8 months for lapatinib plus taxane.

The difference was even greater (13.7 vs. nine months) if the analysis was confined to those women with centrally confirmed HER2-positive tumors. In 2012, we know only one thing about lapatinib in metastatic HER2-positive breast cancer: Do not use it without trastuzumab!

Several Points Remain Choice of inferior comparators is common It is common for pharmaceutical companies to choose inferior comparators in Phase III trials, as was done in EMILIA. Recent examples include using the “Mayo

EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, New York City

Clinic regimen” of low-dose 5-fluorouracil plus leucovorin as the comparator for adjuvant capecitabine for resected colon cancer and for capecitabine-oxaliplatin as chemotherapy for metastatic disease.

Roche similarly used docetaxel rather than vinorelbine as the drug partner for trastuzumab in the control arm of a Phase II trial of TDM-1 as first-line chemotherapy for metastatic breast cancer.4 It has long been obvious that vinorelbine is less toxic than docetaxel, and this has been recently documented in the published Phase III HERNATA (Herceptin Plus Navelbine or Taxotere) trial that found similar response rates but longer remissions with vinorelbine–trastuzumab, presumably because the chemotherapy partner could be given longer, with docetaxel having been stopped early more often because of toxicity. As Dr. Blackwell mentioned in her ASCO plenary presentation, in the Roche trial reported by Dr. Hurwitz at ESMO 2011, the advantage of TDM-1 was that remissions with TDM-1 seemed longer than those with the control arm of docetaxel-trastuzumab.

Drug companies choose to rely on marketing and sales skills, rather than convincing data, to sell their wares when their studies have weak or suboptimal control arms.

EMILIA was a very large study that proved little It is really too bad that this study chose an inferior comparator because it is one of the largest studies of chemotherapy for metastatic HER2-positive breast cancer. With 991 patients, it is the largest trial I could identify for these women. The Genentech study proving a four-month increase in survival with trastuzumab had 469 patients randomized. EGF 104900, which looked at lapatinib plus trastuzumab, had 291 see TDM-1, 1 page 12

What are your thoughts?

Clinical Oncology News welcomes letters to the editor.

Do you have thoughts on Dr. Vogl’s commentary?

Please send comments to gmiller@mcmahonmed.com

11

12

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

Table 2. EGF 104900: Lapatinib Alone or With Trastuzumab for Heavily Pretreated HER2-Positive Metastatic Breast Cancer (N=291)

TDM-1 continued from page 11

subjects; GBG 26 (capecitabine with or without trastuzumab) had 156; HERNATA (trastuzumab with docetaxel or vinorelbine) had 284; CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) had 808; MA.31 closed at 652; two studies looking at the addition of carboplatin to trastuzumab plus taxane had 196 and 263 each.

TDM-1 does not meet goals of a major advance TDM-1, while subjectively well tolerated and low on serious toxicity, does not achieve the goals we really want to advance systemic therapy for metastatic breast cancer (Table 4). Data available to date suggest that TDM-1 provides at most a small incremental benefit without a major change in prognosis for these women.

TDM-1 likely to be very expensive Roche likely will charge a steep premium for TDM-1 compared with trastuzumab plus chemotherapy. I predict that

It is common for pharmaceutical companies to choose inferior comparators in Phase III trials, as was done in EMILIA. Roche will commission studies of costeffectiveness based on lower administration costs and cheaper treatment for toxicity (although compared with unnecessarily toxic “standard treatments”). It is not fashionable to discuss costs at medical meetings or in journals, but drug companies were careful to pay their lobbyists to induce Congress to forbid Medicare from negotiating prices in the legislation authorizing Medicare Part D prescription plans. Drug prices now seem to be set at the estimated maximum the market will bear (with secret discounts to large customers in a position to negotiate on price).

A rational purchaser of chemotherapy who is morally conscientious but frugal could not use currently available data to support purchasing TDM-1 at a substantial cost premium over trastuzumab plus generic chemotherapy (like paclitaxel, docetaxel, cyclophosphamide, gemcitabine, cisplatin, carboplatin, fluorouracil and vinorelbine, alone or in combination) or capecitabine. American taxpayers and those who purchase health insurance, be they employers or individuals, unnecessarily spend a great deal of money because they have not insisted on rational control of medical

Lapatinib + Trastuzumab

Lapatinib

ORR, %

10

6

Median PFS, wk

11.1

8.1

Median OS, mo

14

9.5

ORR, overall response rate; OS, overall survival; PFS, progression-free survival 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. 2012;30:2585-2592, PMID: 22689807.

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. 2010;28:1124-1130, PMID: 20124187.

All of those women treated during EMILIA, all of that money spent, all of that time taken, and we still do not know whether it is better to give TDM-1 as second- or third-line therapy or continued trastuzumab plus alternate chemotherapy.

Table 3. Two Studies in One Table: Capecitabine Alone or With Continued Trastuzumab or Lapatinib in Women Whose Cancer Worsened on Chemotherapy Plus Trastuzumab German Breast Study 6261 (N=156)

Glaxo Lapatinib Study2 (N=324)

Capecitabine + Trastuzumab

Capecitabine

Capecitabine

Capecitabine + Lapatinib

ORR, %

48

27

14

22

Median duration of response, mo

3.9

3.4

Median PFS, mo

8.2

5.6

4.1

8.4

Median OS, mo

25.5

20.4

13.8

13.8

ORR, overall response rate; OS, overall survival; PFS, progression-free survival von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009;27:1999-2006, PMID: 19289619.

Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. ca ce N Engl g J Med ed. 2006;355:2733-2743, 00 06;355 33 3, PMID: 17192538.

9 538

charges. It is likely that TDM-1 will add to these costs. Hopefully we will one day have a government that can help us spend our resources wisely.

Pertuzumab is very active, making the role of TDM-1 uncertain The CLEOPATRA study does indeed suggest that dual antibody therapy with pertuzumab plus trastuzumab in addition to docetaxel is preferable to trastuzumab alone for HER2-positive metastatic breast cancer, although survival data are not yet mature.5 Adding pertuzumab increased the response rate from 69% to 80%, increased median progression-free survival from 12.4 to 18.5 months, and appeared to decrease the early death rate. Whether pertuzumab should continue with trastuzumab for the lifetime of the patient

as chemotherapy varies is unclear. It is also not clear whether trastuzumab is really necessary in addition to the pertuzumab, or whether pertuzumab should be added to TDM-1.

These are fruitful lines of study rendered difficult to interpret because HER2-positive metastatic breast cancer has become a chronic disease, because these constitute only 20% of breast cancer patients, and because most patients with localized or regional HER2-positive breast cancer are now being cured by adjuvant trastuzumab and chemotherapy, leaving very few who develop metastatic disease later. Like follicular lymphoma, all patients with metastatic disease will likely receive multiple lines of therapy containing many or all of the active agents, and studies will be assessing their order of administration, whether they

Table 4. Attributes of a ‘Really Big’ Advance in the Treatment of Metastatic Breast Cancer

Absent cure, increase the rate of clinical complete remission with resolution of symptoms Absent a high rate of complete remission, produce a high rate of very long partial response with symptom control lasting years rather than months, and without cumulative toxicity

should be administered singly or in combinations of two to four at a time, and their length of administration.

Should we give TDM-1 now?

Absent more data, will I be giving TDM1 if it is approved in 2012? Perhaps, but I will favor it only if the price is right, and if payers restrict the use of pertuzumab to first-line therapy. Now that pertuzumab is approved for first-line therapy based on the very impressive CLEOPATRA results, the appropriate comparator for first-line therapy with TDM-1 alone is now chemotherapy—docetaxel or vinorelbine, with the latter favored because it is less toxic and produces longer time to disease progression—plus trastuzumab plus pertuzumab. Pertuzumab may well need to be included with trastuzumab in the comparators for later rounds of chemotherapy as well.

References 1. Geyer CE, Forster J, Lindquist D, et al.

Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733-2743, PMID: 17192538.

2. 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. 2012;30:2585-2592, PMID: 22689807.

3. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009;27:19992006, PMID: 19289619.

4. Andersson M, Lidbrink E, Bjerre K, et al.

Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011;29:264-271, PMID: 21149659.

5. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119, PMID: 22149875.

Download the

App now available on iTunes Read the latest issue on your iPad 3 Ways to Download: Go to the App Store on your iPad and search for ‘Clinical Oncology News’ Go to www.clinicaloncology. com/apps and click on Available on the App Store icon to download the app from the iTunes store.

Scan this code with your iPad and download the app pp from the iTunes store. ore.

14

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

PROSTATE continued from page 1

Vitamin D was safe at all three doses.

There were no cases of hypercalcemia, hypercalciuria or serious adverse events, and there also were no changes in plasma phosphate, creatinine or liver enzymes.

The patients’ calcitriol levels were increased, with the highest dose of vitamin D associated with the highest levels of both calcitriol and its precursor. Furthermore, prostate-tissue calcitriol levels were significantly correlated with the

‘[Our study] shows there is promise with this approach, but we can’t advise regular use of high vitamin D levels until further research is conducted.’

—Reinhold Vieth, PhD expression of androgen-receptor mRNA and of several forms of microRNAs, all of which are known to slow cancer growth.

Prostate-tissue calcitriol levels also were inversely correlated with Ki67, a protein marker of cancer proliferation rate.

These effects were greatest in people

with the highest quartile of prostate-tissue calcitriol.

The results are congruent with a recently published paper showing vitamin D3 4,000 IU per day is associated with a decrease in positive cores at repeat biopsy in low-risk prostate cancer ((J

Clin Enocrinol Metab 2012;97:2315-2324, PMID: 22508710). Furthermore, another recent study found vitamin D supplementation reduces by 57% the risk for highly aggressive prostate cancer but not of overall prostate cancer (JNCI ( I 2012 April 12 [Epub ahead of print]). “[Our study] shows there is promise with this approach, but we can’t advise regular use of high vitamin D levels until further research is conducted,” Dr. Vieth said. He added that Phase III studies are needed to prove that vitamin D prolongs survival or prevents cancer.

Metformin

ONCOLOGYFellow S UPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS

oncologyfellowadvisor.com

advisor

A Phase II study of neoadjuvant metformin in localized prostate cancer is increasing interest in this diabetes drug.

Twenty-two men who were not being treated for diabetes and who had histologically confirmed prostate cancer involving at least 20% of at least one unfragmented biopsy core were

Metformin molecule.

To obtain educational information for oncology fellows, please visit us online: www.oncologyfellowadvisor.com

included They had a median age of 64 included. years and a baseline prostate-specific antigen (PSA) level of 6 ng/mL (range, 3.22-36.11 ng/mL).

The men were given increasing metformin doses of up to 500 mg three times daily. They continued taking metformin until they underwent radical prostatectomy, for a period of four to 12 weeks and a median of 41 days.

Metformin reduced the Ki67-induced proliferation rate from baseline by 1.65% (a relative decrease of 32.12%; P=0.002).

It also reduced levels of P-4EBP1, another marker of cancer proliferation.

PSA levels fell in some patients, “but it is not clear if it was the drug that caused this,” said Anthony M. Joshua, MD, the lead investigator and an oncologist at the Princess Margaret Hospital in Toronto, adding that his team plans to further study this and other effects in active-surveillance patients.

The investigators also documented a significant lowering of serum insulin-like growth factor 1 (P ( =0.02), fasting glucose (P ( =0.03), body mass index (BMI; P<0.01) and waist-to-hip ratio ( <0.01). They did not find correlations (P between any metabolic-, morphometric- or cancer-related serum values.

“Even if the drug ultimately doesn’t work for cancer—although I believe it probably will—at least we’re heading down a pathway that’s very healthy.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

Metformin has been proven to prevent type 2 diabetes and probably also reduces cardiovascular disease,” said Mark Moyad, MD, the director of preventive and alternative medicine in the Department of Urology at the University of Michigan Medical School in Ann Arbor, who was not involved in either the metformin or vitamin studies. “If you can go after both with one drug that has a long history of clinical use and is dirt cheap, that should make clinicians comfortable recommending a product like this or researching it more.”

He is less bullish about vitamin D. “I’m a huge fan of it for bone health, but I worry that people may be taking too-high doses, based on these early data.

Whereas with metformin, the worst-case scenario is that you lose weight. That makes me happy,” Dr. Moyad said.

Obesity A University of Illinois team of investigators weighed in with an analysis showing that men with clinically localized disease who are overweight or obese are at increased risk for pretreatment PSA failure.

The researchers examined data from 119 men awaiting radical prostatectomy in four urologic clinics in the Chicago area. Men in the third quartile of BMI, that is, a mean BMI of 32 kg/m2, had a 6.52-fold elevated risk for PSA failure compared with subjects in the first BMI quartile. The increase in risk was 7.74 for those in the fourth quartile of BMI, who had a mean BMI of at least 37 kg/m2.

“It is premature to make firm recommendations as to whether and how to incorporate this information into the routine management of patients with prostate cancer,” said lead investigator Vincent Freeman, MD, an associate professor of epidemiology and biostatistics at the University of Illinois. “However, the results suggest that obese men who undergo surgery for clinically organconfined prostate cancer should be monitored closely for evidence of cancer recurrence.”

Omer Kucuk, MD, who was not involved in the study, said the results are congruent with other evidence indicating lower BMI is associated with prevention of more advanced disease.

“There are a lot of studies now showing that patients with a variety of cancers who have a healthy body weight and who exercise during or after cancer treatment live longer and have a lower risk for recurrent disease,” said Dr. Kucuk, a professor of hematology, medical oncology and urology at Winship Cancer Institute at Emory University in Atlanta.

Castration-Resistant Prostate Cancer Castration-resistant prostate cancer (CRPC) is the hardest form of cancer to treat but two AACR studies provided

some optimism. One was the Phase I ARMOR (Androgen Receptor Modulation Optimized for Response)-1 study focused on the safety of galeterone (TOK-001, Tokai). Galeterone is a semisynthetic steroid analogue that has a triple mode of action.

Forty-nine men with CRPC were randomized to daily oral galeterone 650, 975, 1,300, 1,950 or 2,600 mg as either one or two doses. Treatment continued for 12 weeks and patients could continue in an extension phase.

Maximum tolerated dose was not reached. No events of adrenal

mineralocorticoid excess were observed.

Fifteen patients had grade 2 or 3 elevations of liver function tests, all transient and most asymptomatic. Eleven of these patients underwent drug interruptions, with six successfully reentering the study and having no further serious liver-function elevations.

Another nine serious adverse events occurred in the patient population, eight of which were determined to be unrelated to galeterone. The remaining case involved rhabdomyolysis and acute kidney failure in a patient who was on concurrent simvastatin (Zocor,

15

Merck) therapy and had underlying renal insufficiency. The patient subsequently recovered without sequelae.

PSA reductions were seen in most patients, including 24 with reductions of at least 30% from the maximum PSA level. Eleven of these patients had reductions of at least 50% from maximum PSA. “The greatest PSA declines seem to have come in the higher-dose cohorts— with 40% of patients having a reduction of at least 50% in those groups—suggesting that continuing the dose escalation is appropriate in the next phase of clinical see PROSTATE, E page 20

The Greenspan Meeting XXX

November 6-10, 2012, New York City

CHEMOTHERAPY FOUNDATION SYMPOSIUM ® INNOVATIVE CANCER THERAPY FOR TOMORROW Practical Applications for the Practicing Oncologist New Agents, Clinical Trials, Emerging Developments Wednesday, November 7 Pediatric Oncology Therapeutic Advances in Cancers of Childhood

Saturday, November 10 Oncology Nurses, Physician Assistants, Case Managers, Pharmacists Therapeutic Advances, Treatment Related Complications, Supportive Care, Symptom Management, Targeted Therapies Schedule Nov. 6 Pathways and Pipelines, Careers in Oncology Nov. 7 Hematology, GI, Pediatric Oncology Nov. 8 GYN, Head and Neck, Breast Nov. 9 GU, Lung, Melanoma, OncoTechnology Nov. 10 New Perspectives in Oncology Practice

Conference Highlights Wednesday, November 7 Keynote Speaker Norman Wolmark, MD Thursday, November 8 Ezra M. Greenspan Memorial Lecture José Baselga, MD

Complimentary Breakfasts, Lunches, Dinners

A CME Oncology Conference presented by the The Tisch Cancer Institute of the Mount Sinai School of Medicine and The Chemotherapy Foundation

Register on line at www.chemotherapyfoundationsymposium.org Contact: jaclyn.silverman@mssm.edu, (212) 866-2813

16

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

Siteman Cancer Center:

Transforming Cancer Care T

he Siteman Cancer Center at BarnesJewish Hospital and Washington University School of Medicine in St. Louis is helping lead the fight against cancer through advances in genomic discovery and application, oncologic imaging and prevention.

Siteman has more than 350 Washington University physicians and investigators who treat over 8,500 newly diagnosed cancer patients each year. These faculty members hold approximately $170 million in annual research and training grants and serve as

principal investigators for about 250 therapeutic clinical trials, putting nearly 20% of new cancer patients on therapeutic clinical trials. Patient care is delivered at a main campus and two satellite facilities in adjacent counties, with a third under construction. In all, Siteman treats nearly 45,000 patients per year, making it one of the largest cancer centers in the United States.

In conjunction with Washington University’s Genome Institute—one of three large-scale federally funded genome centers in the United States—Siteman has pioneered a whole-genome

MRI Breast Surveillance Stands Up to Expectations From the British Journal of Cancer

A

study comparing magnetic resonance imaging (MRI) with mammography in breast cancer screening has demonstrated that the former is significantly more effective in identifying the disease at a very early stage.

However, the authors acknowledge that longer follow-up is required to confirm the safety of breast surveillance via MRI. The study, conducted by K. Passaperuma, MD, and a team of Canadian researchers and published in the June 26 issue of the British Journal of Cancer (107:24-30; ( PMID: 22588560), tracked 496 women with known

BRCA 1/2 mutations at multiple cancer centers in Canada from 1997 to 2009. The patients ranged in age from 25 to 65 years; 380 of the women had no prior history of cancer at the time of enrollment. Each patient underwent annual screening with MRI and mammography.

After 1,847 screening rounds, 57 cancers were identified—53 by screening—of which 37 (65%) were invasive.

In all, 89% of the invasive cancers were detected by MRI compared with only 15% by mammography ((P<0.0001).

Overall, MRI sensitivity (defined as the number of biopsy-proven cancers detected, divided by the total number of cases detected by all modalities,

EXPERT INSIGHT Susan Holley, MD, PhD Staff Physician, Siteman Cancer Center and Barnes-Jewish Hospital, Instructor of Radiology, Washington University in St. Louis

A

nnual MRI breast screening is recommended by the American Cancer Society in patients at high risk for breast cancer (>20% lifetime risk, which includes patients with BRCA mutations). Although the increased sensitivity of MRI in cancer detection suggests that it is well suited to screen a high-risk population, actual quantification of its effects on patient outcomes are now beginning to be evaluated as MRI has become more widely used for this purpose.

Passaperuma et al conducted a prospective evaluation of a combined mammography/MRI screening

protocol in patients with BRCA 1/2 mutations. They evaluated its effect on breast cancer–associated mortality. Given a median follow-up time of eight years, they also evaluated associated surrogate markers of improved survival (i.e., interval cancer rate, proportion of early stage cancers and rate of distant recurrence).

Their findings validate the use of MRI breast screening in this population. In this cohort, 54 cancers were detected in 496 patients over multiple rounds of screening (detection rate, 2.9%). Only a single patient developed an interval cancer. Nearly all (97%) of the incident

plus interval cases and incidental cancers in the one-year period following the last screen) was 86% over the entire study period, compared with 19% for mammography (P ( <0.0001).

However, the sensitivities of both modalities varied greatly over the course of the study. In the first phase, from 1997 to 2002, MRI sensitivity was 74% compared with 35% for mammography (P ( =0.02); in the second phase, from 2003 to 2009, MRI sensitivity was 94% compared with 9% for mammography (P ( <0.0001). The reason for this discrepancy is unclear, however it may be attributable to technological innovation or changes in the level of operator/radiologist

expertise. Patient age also may have been a factor: Over the course of the study, for both methods, detection rates were 0% for women between the ages of 25 and 29 (59 screens), 2.4% for women between the ages of 30 and 49 (28 of 1,188 screens), 3.8% for women between the ages of 50 and 59 (18 of 479 screens), and 5.8% for women aged 60 years and older (seven of 121 screens).

The authors concluded that MRI surveillance can detect “the majority of breast cancers” at an early stage in women with BRCA 1/2 mutations.

They advised longer follow-up to ascertain the safety of this mode of breast surveillance.

cancers were stage 0 or 1; of all 54 cancers, only four were node-positive. One patient (who was diagnosed with a 3-cm cancer plus axillary nodal involvement at her initial screening exam) developed distant recurrence.

As expected, breast MRI demonstrated greater sensitivity than film screen mammography (94% vs. 9%). Digital mammography was only used for the last year of the study, and thus its effects could not be assessed. However, it seems likely that even with the increased sensitivity of digital mammography in certain populations,1 MRI still retains an overall higher sensitivity in cancer detection.2 In a population with an extremely high pretest probability for cancer, MRI also enjoys a high specificity (90% overall in this trial).

This study strongly supports the use of annual MRI breast screening in BRCA-positive patients. These findings should bolster the confidence of both patients and physicians: Annual mammographic and MRI screening can be

effectively employed in this population, with excellent sensitivity and specificity. Moreover, the promising results from this early outcome data suggest that screening BRCA-positive patients in this manner is viable and safe, and may provide an alternative to prophylactic mastectomies. As more time elapses, additional data on MRI breast screening and patient outcomes should allow further refinement of screening strategies for the individual patient.

References 1. Pisano ED, et al. Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med. 2005;353:1773-1783; PMID: 16169887.

2. Berg WA, et al. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307:1394-1404; PMID: 22474203.

Dr. Holley reported no financial disclosures relevant to this study.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

sequencing approach to uncovering genetic mutations in cancer. In 2008, researchers at Siteman and the Genome Institute were the first to decode the complete DNA of a cancer patient, a woman with acute myeloid leukemia. They have since identified key mutations in leukemia and breast, lung and other cancers, as well as potential diagnostic applications.

Significant grants to Siteman in 2011 resulted in the establishment of centers to study cancer proteomics and the connection between obesity and cancer. Additionally, Washington University was chosen to create and host The Cancer Imaging Archive, which makes millions of tumor images—and associated genetic data—available to researchers and the public.

Recent clinical milestones include the completion of 5,000 bone marrow or stem cell transplants. Washington University physicians performed more than 400 of these transplants in 2011, making Siteman one of the largest transplant centers in the country. In addition, construction of the new Kling Center for Proton Therapy is nearing completion. The singlevault center is the first to employ a compact superconducting synchrocyclotron to deliver treatment. The first patient treatment using this new technology is scheduled for this fall.

In addition to advanced treatment and research programs, Siteman pursues an active outreach program of cancer screening and education that involves tens of thousands of

individuals. The center’s Program for the Elimination of Cancer Disparities aims to create a national model for reducing inequalities in cancer care. This includes programs to evaluate accrual of minority patients in the institution’s clinical trials.

An NCI-designated Comprehensive Cancer Center, Siteman also is a member of the National Comprehensive Cancer Network.

In July, U.S. News & World Reportt named Siteman a top 10 U.S. cancer center. Parent institutions Barnes-Jewish Hospital and Washington University School of Medicine also are nationally recognized, with U.S. News & World Reportt consistently ranking both among the best in the country.

Cross-Resistance Found in Metastatic Prostate Cancer Therapy From Annals of Oncology

A

retrospective analysis of Phase I/ II clinical trial data has identified potential evidence of cross-resistance to abiraterone acetate (Zytiga, Janssen) and docetaxel (Taxotere, Sanofi-aventis) among patients with metastatic castration-resistant prostate cancer.

The analysis, the results of which were published online by the journal Annals of Oncology (2012 Jul 5. [Epub ahead of print], PMID: 22771826), reviewed the records of patients treated in the Royal Marsden NHS Foundation Trust, a cancer center in London, as part of a continuous dosing Phase I/II clinical study of abiraterone acetate ((J Clin Oncoll 2009;27:3742-3748, PMID:

19470933). Patients with evidence of disease progression on abiraterone acetate treatment who subsequently received docetaxel (75 mg/m2 every three weeks) were included. Abiraterone acetate and docetaxel are both approved treatments for men with metastatic castrationresistant prostate cancer; abiraterone acetate received FDA approval in 2011 for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel.

The study found evidence that prior abiraterone acetate therapy adversely influences docetaxel efficacy in patients with metastatic castrationresistant prostate cancer, an indication

EXPERT INSIGHT Bruce J. Roth, MD Director of Medical Oncology, Siteman Cancer Center-South County, Professor of Medicine, Washington University in St. Louis

T

he approval of a number of new agents for the treatment of advanced, castrate-resistant prostate cancer (and the expected approval of several others) has occurred in a relatively short interval. Similar to the situation in advanced renal cell carcinoma, these rapid approvals have outstripped our ability to conduct trials regarding the optimal sequencing of agents.

One of the most active new agents, abiraterone acetate, is an androgen synthesis inhibitor and was approved by the FDA in 2011 for use in patients

who had previously received docetaxel-based chemotherapy. While on the surface, one might not infer any logical mechanism of cross-resistance between an androgen synthesis inhibitor and a microtubular inhibitor, initial studies of abiraterone clearly demonstrated less activity in those who had received prior chemotherapy compared to chemotherapy-naive patients. A recently completed study of the use of abiraterone pre-chemotherapy was presented at the 2012 American Society of Clinical Oncology annual meeting, with

that cross-resistance between the two agents may be an issue. In all, of the 54 patients in the Royal Marsden NHS Foundation Trust database treated with abiraterone acetate, 35 subsequently received docetaxel. In only nine (26%) of these patients, docetaxel resulted in a prostate-specific antigen (PSA) decline of at least 50%, with a median time to PSA progression of 4.6 months. PSA declines of at least 30% were reported in 13 (37%) patients. Median overall survival was 12.5 months (95% confidence interval, 10.6-19.4).

Notably, eight patients who failed to achieve a PSA decline on abiraterone acetate and were determined to be abiraterone-refractory also were docetaxel-refractory. In the

24 patients with radiologically evaluable disease, only four (11%) achieved a partial response, and none were abiraterone-refractory.

The authors, led by Janusz Mezynski, MD, from The Royal Marsden NHS Foundation Trust, acknowledged that the lower antitumor activity of docetaxel following abiraterone could be a function of patients having more advanced disease. However, they also noted that this would fail to explain docetaxel’s lack of effect based on the most frequently used measures of anticancer activity. Their findings are limited somewhat by the small sample size, the retrospective nature of the study and the single-institution patient population.

impressive results in terms of delaying time to chemotherapy, time to decline in performance status and so on.

It is certainly possible that within the near future, the label for abiraterone could be expanded, and if this occurs, a significant number of patients receiving docetaxel already may have received abiraterone.

In this light, the article from Drs. Attard and deBono et al provides some initial interesting observations, suggesting that prior exposure to abiraterone might negatively influence the subsequent response rate to docetaxel. Whether this potential interaction occurs via the proposed effect of docetaxel on the androgen-signaling pathway or some other mechanism is unclear. Clearly this is a small number of patients, and because both drugs have inherent activity against the disease, a Phase III trial would be required to document this effect and determine

its magnitude. Also, other agents, such as cabazitaxel (Jevtana; Sanofi-aventis) and enzalutamide (formerly MDV3100; Medivation), have demonstrated survival benefit in the post-docetaxel setting, and differential exposure to either or both of these as subsequent therapy in the two arms of a Phase III trial might confound any observed survival differences. Documentation of any mitigating effect of one of these drugs on the other and the magnitude of such interaction is important, however, particularly as trials of the simultaneous administration of these compounds are being proposed and designed. The present study’s results may serve as an early warning sign regarding potential interactions between hormonal agents and classic chemotherapy compounds in this disease.

Dr. Roth reported no relevant financial disclosures.

17

18

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

Novel Regimen Effective in Acute Promyelocytic Leukemia From Blood

Table. Dosing Schedule Induction

I

n recent years, the advent of novel therapies—notably all-trans retinoic acid (ATRA; available in several branded forms), anthracycline-based chemotherapy, and arsenic trioxide (ATO; Trisenox, Teva)—has significantly improved outcomes in the treatment of acute promyelocytic leukemia (APL). Now, a team of researchers from Australia and New Zealand has combined the three approaches (the so-called APML4 regimen) and achieved positive results.

The researchers, part of the Australasian Leukemia and Lymphoma Group, evaluated the combination approach in 124 newly diagnosed patients from hospital centers in the two countries. Their findings were published online by the journal Blood ( (Blood 2012 Jun 19. [Epub ahead of print], PMID: 22715121).

For this single-arm, Phase II study, ATO was, according to the authors, “superimposed” on a regimen of ATRA and idarubicin (Idamycin, Pfizer) at induction. Dose scheduling (Table) was designed to take advantage of the combination’s “anti-leukemic

ATRA: 45 mg/m2 per day PO; days 1-36 in divided doses Idarubicin: 12 mg/m2 per day IV; days 2, 4, 6 and 8 (dose lowered to 9 mg/m2 per day IV, ages 61-70 y; and 6 mg/m2 per day IV, ages >70 y) ATO: 0.15 mg/kg per day as 2-h IV infusion; days 9-36 (supplemental potassium and magnesium as needed) Prednisone: 1 mg/kg per day PO; days 1-10 Consolidation Cycle 1 (3-4 wk post-induction) ATRA: 45 mg/m2 per day PO; days 1-28 ATO: 0.15 mg/kg per day as 2-h IV infusion; days 1-28 Consolidation Cycle 2 (3-4 wk after consolidation cycle 1) ATRA: 45 mg/m2 per day PO; days 1-7, 15-21, 29-35 ATO: 0.15 mg/kg per day as 2-h IV infusion; days 1-5, 8-12, 15-19, 22-26, 29-33 Maintenance (8 cycles, beginning 3-4 wk after consolidation cycle 2) ATRA: 45 mg/m2 per day PO; days 1-14 Methotrexate: 5-15 mg/m2 per week PO; days 15-90 6-mercaptopurine: 50-90 mg/m2 per day PO; days 15-90 ATO, arsenic trioxide; ATRA, all-trans retinoic acid; PO, by mouth

synergy” while also limiting the potential for cardiotoxicity and the severity of differentiation syndrome, two adverse effects commonly associated with components of the regimen.

All patients received prophylactic prednisone.

EXPERT INSIGHT Geoffrey L. Uy, MD Staff Physician, Siteman Cancer Center and Barnes-Jewish Hospital, Assistant Professor of Medicine, Washington University in St. Louis

S

ince the 1997 report of the remarkable efficacy of ATO in patients with relapsed or refractory APL by Shen and colleagues from the Shanghai Institute of Hematology, investigators have been seeking to incorporate ATO into the initial treatment of patients with APL.1 The most notable of these studies include the addition of two five-week cycles of ATO consolidation in the North American Intergroup Study2 and a chemotherapy-free ATRA plus ATO regimen by both the Shanghai and MD Anderson groups.3 This study by the Australasian Leukemia and Lymphoma Group adds to the growing list of regimens for APL, all of which produce excellent clinical

outcomes, particularly in the low-risk population (white blood count ≤106/ mm3). Both ATO- and ATRA-based induction regimens result in CR rates exceeding 90%, with treatment failures almost exclusively due to early death rather than disease resistance.

The choice of a specific treatment is still largely governed by convenience and the treating physician’s familiarity with the regimen. The advantage of the APML4 regimen is the relatively low dose of anthracycline used in treatment and only during induction. One potential obstacle to the widespread adoption of the APML4 regimen may be the use of 28 consecutive ATO IV infusions during consolidation, which

Most notably, the consolidation phase of the treatment protocol consisted of two cycles of ATRA and ATO, without chemotherapy. Patients were then given maintenance therapy—a somewhat controversial approach given conflicting data—with ATRA, oral

can present logistical difficulties for patients and their providers.

One notable feature of this study is the relatively low early death rate of 3.2%. Although this partly may be due to patient selection, this protocol implemented specific supportivecare guidelines regarding the use of steroids as prophylaxis against differentiation syndrome and the establishment of specific targets for transfusion support. This reinforces the concept that a key component to the success of treatment of any patient with APL is prompt recognition and diagnosis, early initiation of ATRA and aggressive supportive care by physicians familiar with the management of APL. Current and planned studies in APL are using a risk-adapted approach based on the presenting white blood cell count. For low-risk patients, the focus is on reducing the intensity of treatment by either reducing or eliminating anthracyclines and/or the need for maintenance treatment. Promyelocytes are known to express high levels of CD33, and the addition of

methotrexate (available in the United States as Rheumatrex, Dava), and 6-mercaptopurine (Purinethol) for a period of two years.

Of the 124 patients in the study population, 118 (95%) achieved hematologic complete remission (CR) and all 112 patients who initiated the consolidation phase of treatment attained molecular CR. Overall survival was 93.2%; there were four early deaths.

Additionally, the two-year rate for “freedom from relapse” for the study population was 97.5% ((P=0.006) and the “failure-free” survival rate was 88.1% ((P=0.01), which the authors considered to be excellent outcomes coupled with substantially reduced anthracycline exposure. These latter figures, the authors added, marked significant improvements over their findings with an ATRA-idarubicinbased regimen in a similar patient population in a study published earlier this year ((Haematologica 2012;97:227234, PMID: 21993673). The most common adverse event associated with the combination regimen used in the Blood study was infection, although a significant number of hepatic- and gastrointestinal-related toxicities also were reported.

gemtuzumab ozogamycin for high-risk patients is currently being explored in multiple studies. The success of ATRA and ATO in the treatment of APL has been remarkable in transforming this disease into the most curable subtype of acute myeloid leukemia.

References 1. Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:33543360; PMID: 9129042.

2. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood.

2010;116:3751-3757; PMID: 20705755.

3. Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin.

J Clin Oncol. 2009;27:504-510; PMID: 19075265.

Dr. Uy reported no financial disclosures relevant to this study.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

19

Maintenance Therapies Fail in Ovarian Cancer Erlotinib produces no benefit; PARP inhibitor olaparib produces modest PFS improvement Chicago—After front-line chemotherapy, maintenance erlotinib (Tarceva, Genentech) failed to show any significant benefit in patients with ovarian cancer, according to results of a Phase III trial presented at the 2012 annual meeting of the American Society of Clinical Oncology (abstract LBA5000).

The disappointing results appear to rule out targeting the epidermal growth factor receptor (EGFR) pathway in ovarian malignancy.

The study, which included 835 patients, was negative overall, and a series of analyses have been unable to identify benefit in any patient subgroup, including those defined by EGFR mutations or the degree of response to the initial chemotherapy, said Ignace B. Vergote, MD, of the University Hospital in Leuven, Belgium.

The study was powered to detect a 20% difference in progression-free survival (PFS), the primary end point, but there was no signal for any significant activity.

The patients who enrolled in this study had high-risk epithelial ovarian, peritoneal or fallopian tube cancer. They received first-line therapy with six to nine cycles of a platinum-based chemotherapy and had no signs of progression at the time that they were randomized to either 150 mg daily of maintenance erlotinib for two years or no EGFR inhibition.

Forty percent of patients had immunohistochemistry and fluorescence in situ hybridization analyses.

After a median follow-up of 51 months, PFS was 12.7 months in those randomized to erlotinib and 12.4 months in controls ((P=0.914). Overall survival was 51 and 59 months, respectively (P ( =0.903).

Of the patients on erlotinib, 25% discontinued therapy due to side effects. About two-thirds of these discontinuations were caused by rash.

Conversely, in a Phase II trial, maintenance olaparib, which inhibits the poly(ADP-ribose) polymerase pathway, improved PFS. Of patients with platinumsensitive recurrent serous ovarian cancer, 162 received six cycles of paclitaxel-carboplatinum; the experimental arm also received 200 mg of olaparib twice daily over the course of the chemotherapy and then as maintenance monotherapy, whereas the control arm did not receive any additional therapy.

The overall response rate was similar at the end of chemotherapy (64% for patients administered olaparib versus 58% for patients not receiving the drug), however, the hazard ratio for PFS was improved by almost 50% (hazard ratio, 0.51; 95% confidence interval, 0.34-0.77; P=0.0012), reported lead author Amit M. Oza, MD, of Princess Margaret Hospital in Toronto. The average PFS in the

experimental and control arms was 12.2 and 9.6 months, respectively. Subgroup analyses indicated that the benefit was well distributed across factors such as previous platinum therapy and presence of a BRCA mutation. Safety and tolerability were seen as acceptable.

However, in discussing the data, Michael Seiden, MD, PhD, the president and CEO of Fox Chase Cancer Center in

Philadelphia, expressed doubt about the value of any targeted therapy, including olaparib, in the treatment of ovarian cancer. Targeted therapies will likely never provide a survival benefit in ovarian cancer, even if they provide a PFS advantage, Dr. Sieden said. He argued that oncogenes are far more important than pathways of tumor proliferation in ovarian malignancies and predicted that

long-term follow-up will prove that targeted therapies offer very limited benefits in this disease.

—Ted Bosworth Drs. Vergote and Seiden have no relevant relationships to disclose; Dr. Oza has received research funding from AstraZeneca.

®

Now Available...

Tailoring Therapy in Metastatic Breast Cancer Novel Clinical Approaches To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN113” Release Date: October 1, 2011

Expiration Date: October 1, 2012

This activity is based on a live educational symposium held May 21, 2011, in Philadelphia, Pennsylvania.

Co-Chairs

Learning Objectives

Tessa Cigler, MD, MPH

Upon completion of this activity, participants will be better prepared to:

Assistant Professor of Medicine, Weill Cornell Medical Center Attending Physician, NewYork-Presbyterian Hospital New York, New York

Paula D. Ryan, MD, PhD Associate Professor, Clinical Investigator, Section of Breast Oncology Medical Oncology, Fox Chase Cancer Center Philadelphia, Pennsylvania

Target Audience Oncologists, physicians, physician assistants, and other health care professionals involved in the treatment of patients with metastatic breast cancer (MBC). There are no prerequisites or fees.

Credit Designation Global Education Group designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Jointly sponsored by

1 Review recent studies that may have clinically important therapy implications for patients with locally recurrent breast cancer or MBC. 2 Describe a treatment algorithm that reflects evidence-based management of advanced human epidermal growth factor receptor 2 (HER2)-negative and HER2-positive breast tumors and novel strategies for circumventing treatment resistance.

3 Explain core guideline-recommended approaches to MBC management that take into consideration the heterogeneity of patient and tumor characteristics.

4 Compare the mechanisms, synergies, and evolving roles of current and emerging targeted therapies with activity in MBC, particularly in terms of novel combinations and sequences.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide CME for physicians.

Method of Participation To receive CME credit, participants should complete the pre-test, read the monograph, and complete the post-test and evaluation either online at www.CMEZone. com (enter keyword MN113). Completed forms also can be faxed to (303) 6485311 or mailed to 5575 S. Sycamore Street, Suite 200, Littleton, CO 80120. CME certificates will be issued within 6 to 8 weeks upon receipt of completed evaluations. A score of at least 70% is required to complete this activity.

Supported by an educational grant from

Distributed via

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN113”

20

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

Carfilzomib Promising in Relapsed and Refractory Multiple Myeloma From Blood

T

he selective epoxyketone proteasome inhibitor carfilzomib (Kyprolis, Onyx Pharmaceuticals) continues to show promise in the treatment of relapsed/refractory multiple myeloma (MM).

The FDA granted carfilzomib accelerated approval in July for patients with MM who have received at least two prior therapies, such as bortezomib (Velcade, Millennium) or an immunomodulatory agent.

Earlier Phase I trials had indicated that this activity is associated with promising results and

acceptable toxicity.

In this latest multicenter, openlabel, Phase II trial, which was published in the June 14 issue of Blood (2012;119:5661-5670, PMID: 22555973), 129 bortezomib-naive patients (with a median of two prior therapies) with relapsed/refractory MM were separated into two treatment cohorts. Patients in cohort 1 (n=59) received 20 mg/m2 carfilzomib for a median of 20 cycles; those in cohort 2 (n=70) received 20 mg/m2 for cycle 1 and then 27 mg/ m2 for all subsequent cycles (median number of cycles: 6.5). The study, from Ravi Vij, MD, and colleagues, was not designed to compare safety and efficacy between the two cohorts.

EXPERT INSIGHT Ravi Vij, MD Staff Physician, Siteman Cancer Center and Barnes-Jewish Hospital, Associate Professor of Medicine, Washington University in St. Louis

C

arfilzomib is a novel, potent, irreversible epoxyketone proteasome inhibitor that selectively targets the chymotrypsin-like activity of the 20S proteasome. In laboratory models, carfilzomib appears to overcome bortezomib resistance. The drug was recently granted approval by the FDA for the treatment of patients who have received at least two prior therapies— including treatment with bortezomib and an immunomodulatory therapy—based on the results of the Phase IIb PX-171-003A1 trial. In this trial, patients had a median of five prior lines of therapy, including bortezomib, lenalidomide and thalidomide. ORR

PROSTATE continued from page 15

development,” lead investigator Bruce Montgomery, MD, an associate professor of medical oncology at the University of Washington School of Medicine in Seattle, told Clinical Oncology News.

Results of a post-hoc analysis of the Phase III COU-AA-301 trial of abiraterone acetate (Zytiga, Janssen Biotech) in metastatic CRPC were also presented at the meeting. The study involved patients randomized to either abiraterone acetate 1,000 mg once daily plus oral prednisone 5 mg twice daily, or to placebo plus oral prednisone at the same dose.

was 23.7%, with a median DOR of 7.8 months. Median OS was 15.6 months.

The ORR with single-agent carfilzomib in patients refractory to bortezomib in their last line was 18.6%, and was 15.4% in patients refractory to both bortezomib and lenalidomide. The PX-171-004 study looked at carfilzomib in a less heavily pretreated group of patients.

Combination therapy with carfilzomib, lenalidomide and low-dose dexamethasone (CRd) in a Phase I/II clinical trial (PX-171-006) in patients with relapsed/refractory MM has shown an ORR of 78% with a complete remission (CR)/stringent CR (sCR) of

The researchers reported that the overall response rate (ORR; the study’s primary end point) was 42.4% in cohort 1 and 52.2% in cohort 2. Clinical benefit response rates, which combined those patients achieving overall response with those achieving only minimal response, were 59.3% and 64.2%, respectively. Within both cohorts, median duration of response (DOR), which was not reached, was 13.1 months; median time to disease progression, which also was not reached, was 8.3 months.

The most common adverse events (AEs) associated with carfilzomib in the trial were fatigue (62%), nausea (48.8%), anemia (41.9%) and dyspnea

(38.8%). Notably, at least with this study population, single-agent carfilzomib elicited a low incidence of peripheral neuropathy (17.1%; with one grade 3 and no grade 4 events), a common, dose-lowering AE associated with bortezomib therapy. The authors reported that a “substantial percentage” of patients (35.7%) received the study drug for at least 12 months without experiencing significant toxicities. They believe this finding supports the use of carfilzomib over extended treatment periods and in patients with “significant comorbidities.” Additionally, its favorable toxicity profile also makes the drug a candidate for combination therapy.

18%. Additional studies are accruing patients at carfilzomib doses of up to 56 mg/m2. A Phase I/II trial that evaluated a combination of carfilzomib, lenalidomide (Revlimid, Celgene) and dexamethasone in 53 newly diagnosed MM patients demonstrated an ORR of 98%, with 61% of patients achieving an sCR after completing eight cycles of treatment. Additionally, preliminary data on combination therapy with carfilzomib-melphalan-prednisone, cyclophosphamide-carfilzomibthalidomide-dexamethasone, and carfilzomib-thalidomide-dexamethasone were presented at the ASCO 2012 meeting.

One of the major advantages of the drug is the low rate of neuropathy. In a combined analysis of 527 patients treated in multiple studies, the incidence of any grade peripheral neuropathy was 14%, with only 1.3% experiencing at least grade 3 toxicity. The most common noted AEs associated with carfilzomib included fatigue (55%), anemia (47%), nausea (45%), thrombocytopenia

(36%), dyspnea (35%), diarrhea (33%) and pyrexia (30%).

Currently, data from the ASPIRE (Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone for the treatment of Patients with Relapsed Multiple Myeloma [PX-171-009]) and FOCUS (trial comparing carfilzomib to best supportive care in patients with relapsed and refractory myeloma who have received at least three prior therapies [PX-171-011]) are awaited.

The ENDEAVOR (Randomized, OpenLabel, Phase III Study of Carfilzomib Plus Dexamethasone Vs Bortezomib Plus Dexamethasone in Patients With Relapsed Multiple Myeloma) trial is evaluating carfilzomib in patients who have relapsed after one to three prior treatment regimens.

Dr. Vij is the first author of the present study discussed in this article, and disclosed that he has received financial compensation from Onyx Pharmaceuticals for serving on its advisory boards.

‘There are a lot of studies now showing that patients with a variety of cancers who have a healthy body weight and who exercise during or after cancer treatment live longer and have a lower risk for recurrent disease.’

—Omer Kucuk, MD The post-hoc analysis showed that higher baseline serum androgens—testosterone, androstenedione and dehydroepiandrostenedione—were associated with significantly longer overall survival (OS). This was true both for the placebo arm and the active-treatment arm, although OS was greater in the activetreatment patients who had both low and high androgen titers.

Mark Stein, MD, an assistant professor

of medicine at The Cancer Institute of New Jersey in New Brunswick, who was not involved in the study, said the results were exciting.

“This analysis confirms that hormones produced in the adrenal gland can have a large [effect] on the growth of advanced prostate cancer, a fact that was long suspected but never confirmed,” Dr. Stein said. “Perhaps most importantly, this study allows investigators to focus

attention on those patients expected to benefit least from abiraterone, to figure out what additional treatments can be brought to bear on their disease.”

—Rosemary Frei, MSc Drs. Vieth, Joshua, Moyad, Freeman, Kucuk, and Stein do not have any conflicts of interest to disclose.

Dr. Montgomery has received research funding from Tokai.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

Colorectal Cancer Screening: 10 Years to Benefit Screening should be targeted to those who will benefit beyond a decade Seattle—Screening for colorectal cancer (CRC) should be targeted to patients with a life expectancy greater than 10 years, according to a new study.

The survival meta-analysis found that overall health status and not just chronological age should be considered when offering patients CRC screening. The results were presented at the American Geriatrics Society’s 2012 annual meeting (abstract P1).

“When you do a colorectal cancer screening test, you are looking for a cancer that would cause problems in 10 years.

So, it probably doesn’t make sense to offer it to patients with a life expectancy of less than 10 years,” said lead study investigator Sei Lee, MD, who is with the University of California in San Francisco.

Current U.S. guidelines recommend targeting CRC screening to healthy patients whose life expectancy exceeds the cancer screening’s lag time to benefit—the time between screening and when the benefits of screening are seen.

However, Dr. Lee said the lag time of CRC screening is uncertain.

The researchers conducted a survival meta-analysis of randomized clinical trials (RCTs) of CRC screening focusing on patients over the age of 50, using studies identified by the Cochrane Collaboration and the U.S. Preventive Services Task Force as high quality. The investigators also included in their meta-analysis four population-based RCTs of fecal occult blood testing from Denmark, England, Sweden and the United States (N=327,043).

The researchers found that 4.9 years (range, 2.1-9.5) passed before one CRC death was prevented for 5,000 individuals screened (absolute risk reduction [ARR]=0.0002). They also found that it took 10.4 years (range, 6.1-16.6) before one CRC death was prevented for 1,000 persons screened and 14.6 years (range, 9.721.2) for two CRC deaths to be prevented for every 1,000 persons screened.

The investigators concluded that the lag time to prevent one CRC death per 1,000 individuals screened is 10.4 years, suggesting that CRC screening should be targeted to patients with a life expectancy longer than 10 years.

“What this research suggests is that the key component is life expectancy,” said Dr. Lee. “We need to look at their overall health status and not just use chronological age.”

John Morley, MD, a geriatrician at St. Louis University School of Medicine in Missouri, said this study is important because some older adults may be receiving CRC screening unnecessarily. “Some guidelines say stop screening at [age] 75 and that makes sense. Screening is not

without issues and dehydration can be a problem in older adults,” Dr. Morley said.

Geriatrician Ellen Binder, MD, from Washington University School of Medicine in St. Louis, said the meta-analysis highlights the need to individualize each patient’s therapy. She said an older adult may not have a life expectancy longer than 10 years but if this person has a history of polyps, he or she still

might need to be screened.

“It is always important to individualize therapy for individual patients.

In general, most 85-year-olds do not have a life expectancy beyond 10 years, and therefore there would have to be a very compelling reason to push for colorectal screening for a patient age 85 years and older. There also are younger patients with multiple comorbidities

and serious illnesses who may have a limited life expectancy, but this needs to be carefully evaluated for each individual patient,” Dr. Binder said.

—John Schieszer Drs. Lee and Morley did not report any conflicts of interest; Dr. Binder has reported a consulting relationship with Eli Lilly.

Your opinion counts!

Breast Cancer Prevention and Survivorship Survey Please take a moment to help us gather important information on your educational needs in the area of breast cancer screening and survivorship care.

Visit http://www.surveymonkey.com/s/b_c_s to participate in a brief, 5-question survey.

Each survey participant will be entered into a drawing for an iPad or an AMEX gift certificate worth $600 (winner to be announced this summer).

21

22

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

Focus on ASCO: Part II

QUESTIONS

1. True

or False. Selumetinib (AZD6244, Array) plus docetaxel was associated with significant nonmanageable toxicity without clinical benefit when compared with single-agent docetaxel as second-line therapy in patients with KRAS-mutant non-small cell lung cancer (NSCLC).

2. True or False. The Phase III LUX-

Lung 3 trial demonstrated that afatinib (Tomtovok, Boehringer Ingelheim) delayed worsening of disease-related symptoms and improved quality of life when compared with first-line combination therapy of cisplatin plus pemetrexed in epidermal growth factor receptor (EGFR) mutation–positive NSCLC.

3. True or False. ROS1 chromosom-

al rearrangement appears to be a promising therapeutic target in patients with advanced NSCLC.

ANSWERS

1. False. Selumetinib is a selective

inhibitor of MEK1 and MEK2, downstream targets of KRAS. KRAS mutations represent the largest (20%-25%) defined molecular subset of NSCLC. Patients with this mutation may be less responsive to available therapies. In the prospective Phase II study, selumetinibdocetaxel was associated with significantly longer median progressionfree survival (PFS) versus placebo plus docetaxel in patients with KRAS-mutant NSCLC after failure to first-line therapy and had a manageable toxicity profile.

Janne PA, Shaw AT, Pereira JR, et al. Phase II double-blind, randomized study of selumetinib (SEL) plus docetaxel (DOC) versus DOC plus placebo as second-line treatment for advanced KRAS mutant non-small cell lung cancer (NSCLC). Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 7503.

Mascaux C, Iannino N, Martin B, et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer. 2005;92:131-139, PMID: 15597105.

Kim K, Infante J, Cohen R, et al. A phase I dose-escalation study of selumetinib in combination with docetaxel in patients with advanced solid tumors. Presented at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 12-16, 2011; San Francisco, CA. Abstract B225.

Eberhard DA, Johnson BE, Amler LC, et al.

4. True or False. The

MA.27 exploratory analysis showed that diagnosis and treatment of osteoporosis improved outcomes in postmenopausal patients treated with adjuvant exemestane or anastrozole therapy.

5. True or False. In a subanalysis of

several cancer types, including melanoma and hepatocellular, renal cell, prostate, breast and thyroid cancers.

AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, benefit from adjuvant zoledronic acid was demonstrated in all patients with stage II and III breast cancers.

9.

True or False. A weekly paclitaxel-based regimen does not provide the best overall efficacy and safety profile when compared with nab-paclitaxel– based regimens.

6.

True or False. Afatinib is being tested in head and neck, lung and breast cancers.

7. True or False. The GRID (GIST–

Regorafenib in Progressive Disease) randomized international Phase III trial showed that regorafenib significantly increased recurrence-free survival versus placebo in patients with metastatic gastrointestinal stromal tumor (GIST)

that progressed despite prior standard therapies.

10. True or False. The RTOG (Radi-

8. True or False. Cabozantinib (Exe-

ation Therapy Oncology Group) 980 trial is a prospective randomized trial for patients with “intermediate-risk” ductal carcinoma in situ (DCIS) receiving radiation therapy.

Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23:59005909, PMID: 16043828.

showed potent antitumor activity with an objective response rate (ORR) of 57% and a disease control rate of 79%, which is nearly similar to the results observed in ALK-positive NSCLC patients.

(OS) were significantly prolonged with the addition of zoledronic acid but only in postmenopausal women with early breast cancer.

2.

Shaw AT, Camidge DR, Engelman JA, et al.

Clinical activity of crizotinib in advanced nonsmall cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 7508.

True. Afatinib is a tyrosine kinase inhibitor that irreversibly blocks ErbB family receptors (i.e., EGFR, HER2, HER3 and HER4). The Phase II LUXLung 2 trial demonstrated activity in EGFR mutation–positive lung cancers, including those with del(19) and L858R mutations. In the Phase III LUX-Lung 3 trial, it showed superiority to cisplatin and pemetrexed as first-line treatment in patients with EGFR mutation–positive NSCLC. Yang JC-H, Schuler MH, Yamamoto N, et al.

LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract LBA7500.

Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012;13:539-548, PMID: 22452895.

3. True. ROS1 chromosomal rear-

rangement identifies a rare but molecularly distinct subgroup of patients with NSCLC. Crizotinib (Xalkori, Pfizer)

lixis), an inhibitor of MET and vascular endothelial growth factor receptor (VEGFR)2, has shown activity in

Kwak EL, Camidge DR, Clark J, et al. Clinical activity observed in a phase I dose escalation trial of an oral c-Met and ALK inhibitor, PF-02341066.

Presented at the 2009 Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2009; Orlando, FL. Abstract 3509.

4. True. Osteoporosis therapy is asso-

ciated with improved event-free survival and distant disease–free survival in postmenopausal patients with hormone receptor–positive early breast cancer.

Shepherd LE, Chapman JW, Ali SM, et al.

Effect of osteoporosis in postmenopausal breast cancer patients randomized to adjuvant exemestane or anastrozole: NCIC CTG MA.27. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 501.

5. False. The subgroup analysis inves-

tigated the effect of menopause status on outcomes with zoledronic acid in the AZURE trial. Invasive diseasefree survival (DFS) and overall survival

Marshall H, Gregory W, Bell R, et al. Adjuvant therapy with zoledronic acid (AZURE-BIG 01/04): the influence of menopausal status and age on treatment effects. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 502.

6. True. This drug is being tested in

several solid tumor types. Please visit www.clinicaltrials.gov for trial status.

Yang JC-H, Schuler MH, Yamamoto N, et al.

LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract LBA7500.

Machiels JH, Licitra LF, Haddad RI, et al.

LUX-H&N 1: A phase III, randomized trial of afatinib versus methotrexate (MTX) in patients (pts) with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who progressed after platinum-based therapy. J Clin Oncol.

2012;suppl: abstr TPS5598.

Harbeck N, Im S, Huang C, et al. LUX-breast 1: Randomized, phase III trial of afatinib and vinorelbine versus trastuzumab and vinorelbine in patients with HER2-overexpressing metastatic breast cancer (MBC) failing one prior trastuzumab treatment. J Clin Oncol. 2012;suppl: abstr TPS649.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

7.

True. Regorafenib, an oral agent that targets multiple tyrosine kinases, was associated with a median PFS of 4.8 months, compared with 0.9 months with placebo—a 73% risk reduction ( <0.0001). Disease control—response (P or stable disease of at least 12 weeks— was achieved by 52.6% versus 9.1%, respectively.

Demetri GD, Reichardt P, Kang Y, et al. Randomized phase III trial of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor progressing despite prior treatment with at least imatinib and sunitinib: GRID trial. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract LBA10008.

8. True. Nine clinical abstracts were presented about this drug at the 2012 annual meeting of the American Society of Clinical Oncology. Cabozantinib is an

oral inhibitor of MET, VEGFR2 and RET that appears to have some clinical activity in several cancer types.

Schoffski P, Elisei R, Müller S, et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol. 2012;suppl: abstr 5508.

Cohn AL, Kelley RK, Yang T, et al. Activity of cabozantinib (XL184) in hepatocellular carcinoma patients (pts): Results from a phase II randomized discontinuation trial (RDT). J Clin Oncol.

2012;suppl 4: abstr 261.

9. False.

The randomized, openlabel Phase III CALGB 40502/NCCTG N063H/CTSU 40502 trial showed that weekly nab-paclitaxel or weekly ixabepilone in combination with bevacizumab did not improve efficacy

outcomes compared with weekly paclitaxel plus bevacizumab in chemotherapy-naive patients with locally recurrent or metastatic breast cancer. The trial was amended to allow optional bevacizumab use following an Oncologic Drug Advisory Committee (ODAC) recommendation for withdrawal of approval in metastatic breast cancer. According to the investigators, bevacizumab is unlikely to have affected this comparison.

Rugo HS, Barry WT, Moreno-Aspitia A, et al.

CALGB 40502/NCCTG N063H: randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract CRA1002.

10. False. The RTOG 980 trial is a

prospective randomized trial for “goodrisk” DCIS. The “good-risk” DCIS in this trial is defined as being low- or intermediate-grade with tumor size no greater than 2.5 cm and pathologic margin width of at least 3 mm in asymptomatic patients. Local failure in the ipsilateral breast was significantly decreased in the “good-risk” subset of patients with DCIS following the addition of whole-breast radiation therapy following breast-conserving surgery.

McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for “good risk” ductal carcinoma in situ (DCIS), comparing radiation (RT) to observation (OBS). Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 1004.

Send us your news Clinical Oncology News appreciates news tips and suggestions for coverage from readers.

All submissions will be considered for publication.

Write to managing editor Gabriel Miller at

gmiller@mcmahonmed.com CLASSIFIEDS

www.CMEZone.com Your premier source for practical, relevant and timely continuing medical and pharmacy education

Here are FREE educational activities available now on CMEZone.com Tailoring Therapy in Metastatic Breast Cancer: Novel Clinical Approaches Expires October 1, 2012

Education in the Round: Reflections on ASCO 2011 - Focus on Metastatic Breast Cancer Expires November 1, 2012

Visit www.cmezone.com

MN1113

23

24

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

Expert Editorial Roundtable: Melanoma Even with level 1 evidence, controversies surround sentinel lymph node biopsy for melanoma

S

entinel lymph node biopsy remains a controversial topic in the diagnosis and treatment of melanoma. The most significant landmark trial—the MSLT (Multicenter Selective Lymphadenectomy Trial)-I—made a stir in the oncology community when it demonstrated that wide excision of intermediate-thickness primary melanoma and sentinel lymph node biopsy (SLNB) followed immediately by completion lymphadenectomy (CL) produces similar rates of melanoma-specific survival as wide excision and observation of regional lymph nodes with CL performed only if nodal relapse occurred (N Engl J Med d 2006;355:1307-1317).

Additionally, the mean estimated five-year disease-free survival (DFS) rate was higher in the SLNB group. The investigators also reported that the five-year survival rate in patients with micrometastases found by SLNB was significantly higher than in observation patients who later developed clinically palpable nodal metastases.

A follow-up randomized trial, MSLT-II, is under way and may help

Statement

Do you feel MSLT-1 results clearly support routine SLNB in intermediate-thickness melanoma?

Matthew H. Kanzler, MD: MSLT-1 was designed and appropriately powered to answer only one question: Does performing SLNB increase overall survival of melanoma patients compared with removing clinically detected LN if and when they appear during followup? The results do not support routine SLNB as a therapeutic procedure in intermediate-thickness melanoma. The fact that the authors completely failed to mention the primary outcome results in the abstract of the paper, but instead chose to emphasize

to solve some of the remaining questions (http://clinicaltrials.gov/ ct2/show/NCT00297895). The investigators will focus on whether completion lymph node dissection (CLND) should be performed immediately in patients with intermediate-thickness melanoma who have positive nodes on SLNB, or whether patients should first be observed and undergo CLND only if and when nodal ultrasound detects more positive nodes. The primary outcome is 10-year melanoma-specific survival, with secondary outcomes including 10-year DFS and 10-year recurrence rate. However, the first set of interim results are not expected until at least 2017 and the full 10-year results won’t be reported until at least 2024.

In the meantime, Clinical Oncology News asked experts from across the country how they use this controversial procedure in their patients based on the currently available evidence. Once you’ve read their opinions, we’d love to hear yours. Email managing editor Gabriel Miller at gmiller@mcmahonmed.com.

the results of inappropriate subset analyses of MSLT1 data, clearly shows the authors’ bias regarding this procedure.

Subsequent publications have shown that the small improvements in DFS found on subset analyses were in fact entirely attributable to lead-time bias and lack of inappropriate handling of both false-positive and false-negative patients in the study.

Daniel G. Coit, MD: MSLT-1 is probably the highest-quality data defining the role of SLNB in melanoma. I don’t care how the investigators analyzed the results, I care that the trial has provided top-quality data: The interpretation is up to the readers, clinicians and patients.

And it very clearly confirmed that sentinel node

status is the most important prognostic factor in intermediate-thickness melanoma. This is what has kept SLNB in the forefront of management of patients with intermediate-thickness melanoma.

The other thing it showed us is that it is probable that positive sentinel nodes will evolve into clinical disease. Additionally, it said that SLNB detects about 25% of the nodes that will develop into regional disease—that is, the false-negative rate is about 25%. And also, if you take all comers, SLNB is a staging procedure and not clearly a treatment, because the study could not demonstrate an improvement in melanomaspecific survival. The distant DFS curve is an extremely important curve that has never been shown.

The point that people really struggle with is that the study didn’t show an improvement in melanoma-specific survival even though DFS and nodal recurrence did improve. I believe it’s because the study was underpowered to show a statistically significant difference in melanoma-specific survival.

P ARTICIPANTS Daniel G. Coit, MD, is a professor of surgery at Weill Cornell Medical College, an attending surgeon at Memorial Sloan-Kettering Cancer Center, New York City, and chair of the National Comprehensive Cancer Network (NCCN) Melanoma Guidelines Panel.

Matthew H. Kanzler, MD, is a clinical professor in the Department of Dermatology at Stanford University’s School of Medicine, in California.

Martin S. Karpeh Jr., MD, is chairman of the Department of Surgery at Beth Israel Medical Center, and director of surgical oncology and associate director, Continuum Cancer Centers of New York.

Stanley Leong, MD, is president of the Sentinel Node Oncology Foundation, chief of cutaneous oncology and associate director of the Center for Melanoma Research and Treatment, California Pacific Medical Center, and professor emeritus of surgery at the University of California, San Francisco School of Medicine.

Anna Pavlick, MD, is an associate professor, co-director of the Melanoma Program and assistant director for Clinical Research Education in the Departments of Medicine and Dermatology at the NYU Cancer Institute, New York City.

Jennifer A. Wargo, MD, is an assistant surgeon in the Division of Surgical Oncology at Massachusetts General Hospital and an instructor of surgery at Harvard Medical School, Boston.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

‘The fact that the authors completely failed to mention the primary outcome results in the abstract of the paper, but instead chose to emphasize the results of inappropriate subset analyses of MSLT-1 data, clearly shows the authors’ bias regarding this procedure.’

—Matthew H. Kanzler, MD

Stanley Leong, MD: I agree that the study showed SLN status is irrefutable as a prognostic indicator. And for that reason SLNB is the standard of staging in melanoma. People who criticize MSLT-1 do not even do SLNB. Nothing is perfect, for every study there are always unanswered questions, but the study provided level I evidence that sentinel node status is a very strong prognostic indicator.

Jennifer A. Wargo, MD: I do believe MSLT-1 supports the use of SLNB in intermediate-thickness melanoma for prognostic reasons and for durable regional control, but I do not believe it provides evidence of any survival benefit.

In MSLT-1 there were patients in the SLNB group with microscopic deposits of melanoma that would be unlikely to progress to a palpable nodal recurrence, and these patients were compared with patients who presented with bulky nodal metastases. Additionally, the groups were selected for comparison after randomization, making statistical considerations invalid.

Furthermore, the authors did not include patients in the analysis who had a false-negative SLNB result and later presented with nodal recurrence.

Anna Pavlick, MD: I do not believe all disease detected is clinically significant, especially micromets. The amount of disease and location of the disease is more clinically meaningful.

Many retrospective trials in the past five years have tried to answer that question and most of the data suggest that the amount and location are the most clinically relevant.

Dr. Wargo: I disagree that all disease detected by SLNB including micrometastases is clinically significant. There is clearly heterogeneity within stage III patients that contributes to the widely variable survival rates seen in this group. At one extreme are patients with a single melanoma cell identified within one sentinel node and at the other are patients who present with bulky nodal metastases. Based on survival rates, it is fairly clear that there are patients with minimal microscopic disease who will never have a recurrence.

‘I do not believe all disease detected is clinically significant, especially micromets.’

—Anna Pavlick, MD

Statement

Is all disease detected

by SLNB, including micrometastases, clinically relevant?

Dr. Coit: It clearly is. The patients with even micrometastases in their lymph nodes do worse than patients with negative lymph nodes. That’s well documented. And that’s the basis of the American Joint Committee on Cancer (AJCC) staging—that even isolated tumor cells in a lymph node are clinically significant. It’s not as clinically significant as macro disease, but when it is actionable is a different question.

Dr. Leong: We know that cancer is an aggressive disease. We published a paper a year ago showing that different levels of tumor burden in melanoma SLNs are associated with different levels of survival. So that confirms it’s a spectrum, and hence early diagnosis and early eradication of growing cells in the SLN are intuitively beneficial. The only problem is we can’t demonstrate yet that they’re therapeutically beneficial.

‘It clearly is. The patients with even micrometastases in their lymph nodes do worse than patients with negative lymph nodes.’

Statement

Should SLNB be the standard of care in melanoma in the United States?

Dr. Kanzler: From a therapeutic perspective, the answer is fairly clear: There is no role for SLNB in the standard care of patients with melanoma. And although it clearly has been shown that as a single prognostic factor, the status of the SLN is the strongest predictor of outcomes, the procedure is expensive, invasive and leads to complications in 10% of patients undergoing the procedure.

What has not been investigated to date is whether or not a combination of other important noninvasive prognostic factors would result in prognostic information comparable to SLNB data. In fact, predicted survival rates can currently be obtained by inputting specific known prognostic data for a particular patient into a large computer database containing known outcomes for patients with similar demographic information (http://cancer.lifemath.net/melanoma/outcome/). The accuracy of this mathematical database has been confirmed with data on hundreds of thousands of patients in Surveillance, Epidemiology and End Results national data sets. Use of such a database can provide excellent prognostic information to melanoma patients and should be offered to patients as an alternative to invasive SLNB procedures.

Dr. Wargo: As of 2012, SLNB should be offered as standard of care in melanoma in the United States.

SLNB clearly has prognostic benefit as well as potential benefit with durable regional control.

Dr. Coit: I can’t answer that question because “standard of care” is a legal term. I think it’s more appropriate to say that for patients with invasive melanoma, you should have a discussion about the pros and cons of SLNB. The NCCN guidelines include phrases like “discuss SLNB” and “offer SLNB,” but nowhere is SLNB mandated. Because the information gleaned from it is primarily prognostic, and I don’t think you can mandate a prognostic test—it depends on whether the patient wants the information.

—Daniel G. Coit, MD

Dr. Kanzler: MSLT-1 authors imply that all microscopically involved nodes will progress to macroscopic disease. If such an assumption were correct, 19.4% of the patients randomized to the SLNB intervention arm of the study would have been expected to develop clinically palpable nodes by the end of the study—that is, the sum of the 16% of patients with positive SLNB results plus the 3.4% of patients who initially had a negative SLNB result but who later developed nodal disease during follow-up. This incidence is 24% higher than the actual incidence of 15.6% found during follow-up for patients assigned to the observation arm. The discrepancy only can be explained if one-fourth of patients with positive sentinel nodes in the SLNB arm would never have developed palpable nodes if followed by observation.

Statement

Under what conditions should clinicians counsel patients that it’s advisable to go ahead with SLNB?

Dr. Pavlick: Patients need to be educated about the negative risk factors associated with melanoma, the percentage of risks such as infection and lymphedema versus benefit of this procedure and how this procedure would increase the patients’ access to adjuvant clinical trials. There should be an informed decision made by the patient and his or her melanoma team after all of the pros and cons have been discussed.

ROUNDTABLE, E page 26

25

26

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

ROUNDTABLE

and the patients’ informed decision also factor heavily into making the final decision.

enter into MSLT-II, because it will be the holy grail of this question.

continued from page 25

Dr. Coit: Probably the single most controversial issue in SLNB is where the cutoff of probability of having a positive SLN for going ahead with SLNB. Right now it seems to be somewhere between 5% and 10%, but where it is in that spectrum depends enormously on a number of factors, including patient age. In an editorial we wrote for the Annals of Surgical Oncology—and the NCCN guidelines—SLNB is generally not recommended for patients with melanoma under 0.75 mm in thickness. For many patients with a thickness of 0.75 to 1 mm, SLNB should be discussed and offered, and most patients with melanoma greater than 1 mm thick will end up having SLNB because the probability of positive sentinel nodes is significantly higher in this group.

Dr. Kanzler: Since publication of the MSLT-1 data, several physicians have advocated including patients with increasingly thinner melanomas into the appropriate candidate pool, including patients with melanomas thinner than 1 mm if they are found to have other negative prognostic characteristics such as increased mitotic rates. This has been done despite the lack of evidence that SLNB has clinically significant prognostic benefits in these groups of people.

A recent meta-analysis of 3,651 patients enrolled in 34 studies involving patients with melanomas of no more than 1 mm was performed. The SN positivity rate in these patients was only 5.6%, well below the cutoff suggested by an expert panel headed by Charles Balch, MD, from Johns Hopkins in Baltimore, who suggested that SLNB should be discussed with patients whose risk for harboring clinically occult nodal disease is 10% or greater. More importantly, analysis of survival data from these patients with thin melanomas showed an equal number of melanomarelated deaths in the SNB-positive and SNB-negative groups, making the prognostic utility of this procedure doubtful in this group. These patients all had at least one additional risk factor, including ulceration, regression or invasion to Clark level 4 or 5.

Also, the utility of SLNB in patients under age 20 and over age 60 years has been questioned as it appears that the accuracy of predicting outcomes in these patients by SLNB status is poor—for example, young patients have higher rates of SLNB positivity yet excellent prognosis, whereas elderly patients, whose prognosis is poorer, have a low rate of SLNB positivity.

Dr. Karpeh: My preference is to perform SLNB in patients with intermediate-thickness melanomas or those with thin melanomas between 0.75 and 1 mm that show evidence of ulceration or increased mitotic rate. There is as high as a 10% chance of having positive nodes in that subgroup of thin melanomas and I do recommend SLN mapping. The morbidity is fairly low and the information gained is clearly prognostic and may be helpful as new therapies for melanoma are developed. Having said that, I feel each patient has to be counseled individually and that comorbidities, age

Statement

Should SLNB plus completion lymphadenectomy of biopsy-positive patients be the standard of care in melanoma in the United States?

Dr. Kanzler: No. A recent 16-center comparative study involving 298 melanoma patients with positive SLNB found that patients had similar survival rates whether a CL was performed immediately after SLNB or was delayed until clinically palpable nodes developed. Thus, while the SLNB does provide prognostic information, to date there is no evidence that performing a CL of biopsy-proven SLNs improves survival. Additionally, although the SLNB procedure is associated with only 10% complications, adding a CL procedure increases the complication rate to 37%, and these complications are typically much more significant, including permanent lymphedema.

Until MSLT-II is completed, the best data available to date shows that lymphadenectomies in the absence of palpable disease—either with or without SNB procedures—do not improve the survival of melanoma patients, and should be avoided outside of the MSLTII setting.

‘From a therapeutic perspective, the answer is fairly clear: There is no role for SLNB in the standard care of melanoma patients.’

—Matthew H. Kanzler, MD

‘As of 2012, SLNB should be offered as standard of care in melanoma in the United States.

SLNB clearly has prognostic benefit as well as potential benefit with durable regional control.’

—Jennifer A. Wargo, MD

Dr. Coit: Increasingly, as patients with positive sentinel nodes hear this discussion, they are choosing not to have a CLND. It becomes a patient choice, and right now we’re in a bit of a conundrum. We have enormous experience with CLND, so that’s our standard recommendation for any patients with positive sentinel nodes including micromets. The problem is it’s a morbid procedure and we don’t know whether it makes any difference. So we are very much encouraging patients with positive sentinel nodes to

Dr. Pavlick: SLNB and CL of biopsy-positive patients should not be the standard of care anywhere. Clinical judgment is vital in helping patients make that decision. I believe the extent of tumor within the SLNB and its location must play a role in this decision making.

Dr. Wargo: As of 2012, CL following a positive SLNB should be discussed with and offered as standard of care in melanoma in the United States. However, this clearly has less strength than the arguments made for SLNB alone. The majority of patients will not have an additional positive node, and will be subjected to potential morbidity of a CL. The key in the future will be to determine who is most likely to benefit from CL and to do it selectively for highrisk patients. In addition, as we get better adjuvant therapy and biomarker data, the role of CL is likely to diminish significantly. The results of MSLT-II should be helpful in guiding us.

Dr. Leong: I do support CL. Because prognostically you can identify the patients who would do much worse if their CLND is positive. As a surgeon, it is critical that we intervene in the early stages, before the disease spreads from the sentinel nodes to nonsentinel nodes and then beyond.

Dr. Karpeh: I think it should be presented to patients as a common practice that will probably benefit 16% to 20% of patients. The fact that in MLST-1 patients undergoing delayed CL had a greater volume of disease than those having early CL for positive SLNB is further evidence that the residual disease does progress over time. The argument against doing the early CL is that there is no survival benefit, but the study was not powered to answer the question of survival benefit in the subset of SLNBpositive patients. This question is being addressed in MSLT-II and I think all patients should be encouraged to enter the trial. My practice is to discuss all the pros and cons of CL with my patients but I do recommend CL in the subset of patients with H&E [hematoxylin and eosin] stain–positive sentinel nodes since we continue to struggle with successfully treating recurrent disease. However, in patients who have immunohistochemistry-positive sentinel nodes only, the data suggests that CL may be overtreatment because the vast majority of the residual nodes are negative.

Daniel G. Coit, MD, Matthew H. Kanzler, MD, Martin S. Karpeh Jr., MD, Stanley Leong, MD, Anna Pavlick, MD, and Jennifer A. Wargo, MD, each report that they have no relevant disclosures.

Interviews and text by Rosemary Frei, MSc

MCMAHONMEDICALBOOKS.COM An Online Bookstore

ORDER BOOKS ONLINE

THE BOOK PAGE PUBLISHER’S TOP PICKS OF THE MONTH ON MCMAHONMEDICALBOOKS.COM These books and thousands more...

1

1

2

3

4

5

6

7

8

Atlas of Diagnostic Oncology: Expert Consult—Online and Print: Fourth Edition

Arthur T. Skarin December 23, 2009 This book is an unrivaled collection of more than 2,500 images and drawings—combined with succinct, clinically focused text—equips you with essential information on pathology, diagnostic studies, staging and clinical manifestations.

Scan here for our complete catalog of medical books.

ORDER ONLINE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com.

We can supply any medical book in print, so if you don’t find the book you want, email your request with billing information to RMcMahon@McMahonMed.com.

If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@McMahonMed.com.

2

Cancer Metastasis: Biologic Basis and Therapeutics

David Lyden; Danny R. Welch; Bethan Psaila April 25, 2011 This text covers the processes underlying cancer metastasis and the clinical treatment of metastatic disease. More than a compendium of laboratory research articles, the internationally renowned authors of this volume have summarized the state-of-the-art research in the metastasis field.

3

Central Nervous System Malignancies, An Issue of Hematology/Oncology Clinics of North America

Jill Lacy September 11, 2012 This issue of Hematology/Oncology Clinics of North America a includes topics such as neoplastic meningitis and epidural metastases, management of brain metastases, meningiomas/nerve sheath tumors/pituitary tumors, medulloblastoma/primitive neuroectodermal tumor and germ cell tumors, primary CNS lymphoma, anaplastic gliomas, low grade gliomas and glioblastoma multiforme.

4

Diagnostic Imaging: Musculoskeletal: Non-Traumatic Disease

B.J. Manaster; Cheryl A. Petersilge; Catherine C. Roberts; Christopher J. Hanrahan; Sandra Moore March 26, 2012 With more than 300 diagnoses, thousands of images, illustrations and graphics, this reference guides practicing radiologists through the intricac es of cies o musculoskeletal uscu os e eta diseases. d seases

5

Gynecologic Oncology: Clinical Practice & Surgical Atlas

Beth Karlan; Robert Bristow; Andrew Li June 22, 2012 This book brings together a skill-sharpening reference and full-color atlas to deliver an unmatched introduction to the field. As the most comprehensive, evidence-based gynecologic oncology resource available, this all-in-one resource offers high-yield coverage of the discipline’s underlying principles and proven management strategies.

6

New Drugs for Malignancy, An Issue of Hematology/ Oncology Clinics of North America

Franco Muggia June 28, 2012 Topics in this issue include targeting IGF-1R, tyrosine kinase inhibitors in lung cancer, targeting mTOR, targeting hedgehog, mitotic inhibitors, topoisomerase I inhibitors, and new strategies and drugs inhibiting folate pathways.

7

Outcomes Research in Surgical Oncology, An Issue of Surgical Oncology Clinics

Clifford Ko June 20, 2012 In this issue of Surgical Oncology Clinics of North America, guest editor Clifford Ko, MD, has assembled the top experts concerning outcomes research in oncology.

8

Surgical Oncology

David Bartlett; Pragatheeshwar Thirunavukarasu; Matthew D. Neal May 4, 2012 Surgical Oncology y is a full-color text that incorporates the basic tenets of surgical practice with the innovations of modern technology in an evidence-based fashion.The goal of the book is to present the opinions of experts in the field alongside an analytical and unbiased review of the evidence. Each chapter contains not only a summary of the relevant data,, but also presents p succinctlyy a list of landmark studies.

CO0812

28

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

For Anti-EGFR Therapy, Not All KRAS S Mutations Created Equal From the Journal of Clinical Oncology

A

study by a team of European researchers has demonstrated a possible role for the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab (Erbitux, ImClone) as first-line therapy for the treatment of chemorefractory KRAS G13D–mutated metastatic colorectal cancer (CRC).

The team, led by Sabine Tejpar, MD, PhD, of University Hospital Gasthuisberg in Leuven, Belgium, analyzed updated data sets from the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Chemotherapy for Metastatic Colorectal Cancer) and OPUS (Oxaliplatin and Cetuximab

EXPERT INSIGHT Benjamin Tan, MD Staff Physician, Siteman Cancer Center and Barnes-Jewish Hospital, Associate Professor of Medicine, Washington University in St. Louis

C

urrently, patients with any KRAS mutations, irrespective of genotype, are not treated with anti-epidermal growth factor therapy. However, RASCAL ((KRAS in-colorectal-cancer

in First-Line Treatment in Metastatic Colorectal Cancer) studies (J ( Clin Oncol 2011;29:2011-2019, PMID: 21502544; and Ann Oncoll 2011;22:15351546, PMID: 21228335, respectively).

Their stated objective was to identify associations between tumor KRAS mutation status (including wild-type, G13D, G12V or other mutations) and progression-free survival (PFS), overall survival (OS) and treatment response.

Merck KGaA, manufacturer of the study drug, supported the research.

The researchers’ analysis, which was published online on June 25 in the Journal of Clinical Oncology (2012 Jun 25. [Epub ahead of print], PMID: 22734028), included data from 1,378 evaluable patients from the CRYSTAL and OPUS studies. Of the 533 patients

(39%) with KRAS-mutant tumors, 125 (23%) had G12V mutations, 83 (16%) had G13D mutations, and 325 (61%) had other mutations.

The authors found that patients with G13D-mutant tumors had significant variations in treatment effects for tumor response ((P=0.005) and PFS ( =0.046) compared with those with (P other mutations (including G12V). For patients with G13D-mutant tumors, cetuximab plus chemotherapy versus chemotherapy alone significantly improved PFS (median, 7.4 vs. 6.0 months; P=0.039) and tumor response (40.5% vs. 22.0%; P=0.042) but not OS (median, 15.4 vs. 14.7 months; P=0.68); however, within this study population, patients with G12V and other mutations did not benefit from this

treatment combination. Also, patients with KRAS G13D–mutated tumors receiving chemotherapy alone experienced worse outcomes (response, 22.0% vs. 43.2%; P=0.032) than those with other mutations.

The researchers observed that their findings seem to indicate there may be some similarities between the biology of KRAS G13D–mutant tumors and those with BRAF mutations in metastatic CRC, given that patients with both subtypes exhibit poor prognoses. Based on these observations, they suggested that, in the future, geneexpression profiles, DNA mutations and DNA methylation patterns, as well as information on tumor histologic subtype, may provide predictors of treatment response.

collaborative group), a 2010 analysis of multiple studies in refractory CRC, identified a specific subset of patients, those with KRAS G13D-mutated CRC, who appeared to benefit from these agents, resulting in significantly longer median PFS and OS times compared with those carrying other KRAS mutations.1 The present pooled analysis of the CRYSTAL and OPUS studies adds to the growing evidence of varying outcomes and treatment responses among CRC tumors harboring distinct KRAS mutations. Compared with wild type and other KRAS genotypes, KRAS G13D

was consistently associated with lower response to chemotherapy without antiEGFR monoclonal antibody, along with shorter PFS and OS. Tumor responses and PFS appear to be improved with the use of anti-EGFR therapy.

Thus, should all CRC patients with KRAS G13D be treated with cetuximab or panitumumab? Not quite yet. These results need to be validated further in larger prospective studies since other studies report no consistent associations between KRAS genotype and outcomes. This study, however, highlights the importance of determining not only the presence of a KRAS

mutation, but also the exact genotype.

Genomic and molecular studies to elucidate mechanistic differences among genotypes would be valuable in the development of future therapies for these tumors.

Reference 1. De Roock W, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010;304:1812-1820, PMID: 20978259.

Dr. Tan reported no financial disclosures relevant to this study.

HEMATOLOGIC MALIGNANCIES

Pixantrone for Aggressive Relapsed or Refractory NHL From Lancet Oncology

A

recently completed Phase III trial of the aza anthracenedione pixantrone dimaleate (BBR 2778, Cell Therapeutics) has found the novel agent to be safe and effective in the treatment of aggressive relapsed or refractory nonHodgkin lymphoma (NHL), and that it may be an option for patients who have already failed two or more chemotherapeutic regimens. The results were published in the July issue of the journal Lancet Oncology (13:696-706, PMID: 22652183).

For the trial, an international group of researchers, led by Ruth Pettengell, MD, of St. George’s University of London, randomized 140 patients from 66 hospital centers in Europe, Asia, and

North and South America to receive either pixantrone dimaleate—at a dose of 85 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle, for up to six cycles—or one of a series of comparator drugs—vinorelbine (Navelbine), oxaliplatin (Eloxatin, Sanofi-aventis), ifosfamide (Ifex), etoposide (Vepesid), mitoxantrone (Novantrone), gemcitabine (Gemzar, Lilly) or rituximab (Rituxan, Genentech)—at their standard dosing schedule. All patients had histologically confirmed aggressive NHL, which had relapsed following two or more previous chemotherapy regimens. The trial’s primary end point was the proportion of patients with a complete response (CR) or unconfirmed complete response (CRu) in the intention-to-treat (ITT)

population at the conclusion of treatment. Cell Therapeutics funded the study.

Fourteen of the patients (20%) who received pixantrone dimaleate achieved a CR or a CRu at end of treatment compared with four patients (5.7%) in the comparator group ( =0.021). However, only 36 patients (P completed six cycles of protocol treatment and 104 patients discontinued early, with the most common reason being disease progression or relapse.

Five patients (two in the study drug group and three in the comparator group) dropped out prior to receiving treatment.

In all, twice as many patients in the pixantrone dimaleate group (n=12) as in the comparator group (n=6) had

an overall response lasting at least four months (from first documented response until disease progression, follow-up treatment or death), and time to initial overall response was similar between the two groups (median of 1.9 months for both groups; P=0.304).

The most common grade 3 or 4 adverse events in patients given pixantrone dimaleate were uncomplicated/noncumulative neutropenia (41.2% of patients vs. 19.4% in the comparator group), leukopenia (23.5% vs. 7.5%) and thrombocytopenia (11.8% vs. 10.4%).

The researchers concluded that treatment with pixantrone dimaleate was both efficacious and tolerable, and that the drug may be an option for those who had previously failed two or more treatment regimens.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

Is Thrombosis a Prognostic Factor in Pancreatic Cancer?

From Cancer

A

n analysis of incidence and outcomes associated with thromboembolic events in patients with pancreatic adenocarcinoma is the first to identify a correlation between early thrombosis and poor outcomes in the disease.

In the study, which was published in the June 15 issue of the journal Cancer (2012;118:3053-3061, PMID: 21989534), researchers from Memorial Sloan-Kettering Cancer Center in New York City performed survival analyses related to the development and timing of thromboembolic events in 1,915 patients

EXPERT INSIGHT Joel Picus, MD Staff Physician, Siteman Cancer Center and Barnes-Jewish Hospital, Professor of Medicine, Washington University in St. Louis

T

his paper is a nice example of work that can generate many hypotheses, but unfortunately cannot currently improve our ability to care for our patients.

The coincidental finding of thrombosis (whether venous or arterial) in cancer patients in general, and more specifically in patients with pancreatic cancer,

EXPERT INSIGHT Nina WagnerJohnston, MD Staff Physician, Siteman Cancer Center and Barnes-Jewish Hospital, Assistant Professor of Medicine, Washington University in St. Louis

P

ettengell et al report results of their Phase III study comparing pixantrone dimaleate with an investigator-choice single agent (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone or gemcitabine) in patients with relapsed/refractory aggressive NHL. Early experience with pixantrone, an aza anthracenedione designed to reduce anthracycline-related cardiotoxicity, demonstrated a 27% overall response rate (ORR) with a median progression-free survival (PFS) of 106

undergoing chemotherapy for invasive exocrine pancreatic cancer from 2000 to 2009. Timing relative to various clinical parameters—including laboratory data, erythropoietin-stimulating agent (ESA) use and body mass index (BMI)—also was analyzed.

Overall, the researchers identified thromboembolic events in 690 (36%) of the patients. After adjusting for those patients who underwent pancreatic surgery—which, not surprisingly, improves overall survival (OS) in patients with pancreatic adenocarcinoma—a thromboembolic event in this setting significantly increased the risk for death ((P<0.01); additionally, patients with an early thromboembolic

event (occurring within 1.5 months of diagnosis) also had a significantly higher risk for death than those who developed thromboembolic events later or didn’t have them at all ((P<0.01).

Use of ESAs reduced the time to thrombosis among those in the study population. Although most of the thromboembolic events associated with ESA use occurred in the earlier part of the study, before reports emerged regarding the morbidity and mortality effects of the use of these drugs in this setting, this study echoes earlier published reports indicating that ESAs should be used with caution in those with pancreatic cancer. The analysis also revealed that low BMI

was associated with significantly longer time to thrombosis ((P<0.01).

The authors noted that the timedependent nature of their survival analysis only allows for a comparison between early thromboses and all non-early thromboses (ie, late thromboses as well as patients with no thrombosis); thus, they acknowledge, “juxtaposition of survival of all three of these groups independently is not possible.”

Still, their findings indicate a possible future significant role for newergeneration oral anticoagulants (such as direct thrombin inhibitors and factor Xa inhibitors) for thrombosis treatment and perhaps even thromboprophylaxis in selected cancer patients.

has long been recognized. These authors hypothesize that this finding may represent a prognostic factor when we enroll such patients on trials. A number of limitations are recognized by the authors of this work—which start with the constraints of a retrospective study. Other limitations include the lack of information about oral anticoagulation, and the interaction of the type of chemotherapy used, which may be another risk factor for survival and thrombosis.

Even performance status, which is one of the most important prognostic factors for most survival predictions, was not able to be collected in this retrospective study. Finally, stage information was not obtained for this group of patients, which would be important when looking at prognostic information.

Surprisingly in this study—which included 383 patients among the 1,915 who had a Whipple resection—the 1,915 patients had a median survival in the modern era of only 13.7 months. Importantly, in this cohort, there was a link with the use of ESAs to the development of thrombosis. One limitation not discussed was the use of multiple comparisons, as a number of factors were mentioned as tested in their univariate and multivariate analysis, which should be taken into account as increasing the likelihood of finding a variable that appears statistically significant as more items are analyzed in such a fishing expedition.

If we decide this information is important, we are lacking data in the real world that aggressive anticoagulation or other such treatment of

these patients would alter their outcome. In fact, very few of their patients could have their death directly linked to thrombotic disease (i.e., pulmonary emboli, myocardial infarction or strokes). One may even wonder if the patients diagnosed with thrombotic disease did worse with treatment of this complication. Their data did show that 95% of the patients received lowmolecular-weight heparin and 19% had an inferior vena cava filter, but they did not report whether treatment correlated with survival. Wisely, the authors do call for prospective studies of what may be an important factor as we try to improve the care of these patients.

days.1 In the current study, the primary end point of CR or CRu in the ITT population was achieved in 20% for the pixantrone group compared with 5.7% for the comparator arm ((P=0.021), yet the differences in CR were not significant when the analysis was limited to centrally reviewed confirmed cases of aggressive NHL. ORR was 26% for pixantrone versus a surprisingly low 10% ((P=0.003) in the investigator-choice arm. Forty-five percent of patients received oxaliplatin, which has reported single-agent activity of 40%.2 Treatment with pixantrone led to more hematologic toxicity (41% vs. 19% grade 3/4 neutropenia), as well as an increase in cardiac adverse events (35% vs. 21%), despite a lower median previous doxorubicin dose equivalent in the pixantrone arm.

The study was initiated in 2004, before the global adoption of rituximab. Approximately 45% of patients

received prior rituximab, raising the question of how translatable this data is for patients with aggressive B-cell NHL in current practice. Only 10% of patients had T-cell lymphomas.

The study was designed to have at least 80% power to detect a difference in CR/CRu of 15% versus 5% using a sample size of 160 patients per arm. Due to slow accrual, the study was closed after pathology was confirmed in 100 patients. Of the 140 patients treated, only 36 completed six cycles of treatment. To achieve greater than 80% power with 70 patients per group, the true proportion of patients with CR/CRu would have to have been 22% in the pixantrone group and 5% in the comparator group. Enthusiasm for this agent must be tempered in light of these results.

Although pixantrone may find a treatment niche in aggressive NHL, the present study does not provide convincing evidence for its role. For

better appreciation of pixantrone’s activity, we anticipate results of the ongoing Phase III randomized multicenter study of pixantrone plus rituximab compared with gemcitabine plus rituximab in patients with relapsed/ refractory diffuse large B-cell lymphoma.

Dr. Picus reported no financial disclosures relevant to this study.

References 1. Borchmann P, et al. Phase-II study of the new aza-anthracenedione, BBR 2778, in patients with relapsed aggressive nonHodgkin’s lymphomas. Haematologica.

2003;88:888-894, PMID: 12935976.

2. Germann N, et al. Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin’s lymphoma patients. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 1999;10:351-354, PMID: 10355582.

Dr. Wagner-Johnston reported no financial disclosures relevant to this study.

29

30

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2012

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004

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, 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).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Two-Drug Standard Urged For performance status 2 non-small cell lung cancer Chicago—Adding carboplatin to pemetrexed (Alimta, Eli Lilly) improves median overall survival (OS) by roughly 3.5 months in patients with advanced non-small cell lung cancer (NSCLC) and who have a performance status (PS) of 2, a Phase III trial has shown.

“Given the magnitude of benefit seen in the study, and the immediate applicability of these data to clinical practice, we urge the appropriate organizations to revise their guidelines, which to this date, by and large, recommend singleagent therapy for these patients,” said Rogerio Lilenbaum, MD, an oncologist and the chair of the Cancer Institute at Cleveland Clinic Florida in Weston. He reported the results at the recent annual meeting of the American Society of Clinical Oncology (abstract 7506).

received pemetrexed at a standard dose of 500 mg/m2 for four cycles or pemetrexed plus carboplatin for four cycles (area under the curve of 5 plus same pemetrexed dose).

Patients who received carboplatin had improved median OS (9.1 vs. 5.6 months) and OS at 12 months (43% vs. 18%; hazard ratio [HR], 0.57; P=0.001). A subset analysis that excluded 14 patients with squamous cell cancer showed similar results (median overall survival, 9.3 vs.

5.8; HR, 0.59; P=0.003). (In 2009, the trial protocol was amended to exclude squamous histology, based on data showing the interaction of pemetrexed and histologic subtype, but a handful of patients were already enrolled.)

Subgroup analyses also showed that patients who were elderly and had nev-

Table. Subset Analyses Examining Median OS in Advanced PS 2 NSCLC Pemetrexed, mo

Pemetrexed-carboplatin, mo

P Value

Elderly patients

6.1

8.3

P<0.015

Never-smokers

5.2

9.4

P<0.035

NSCLC, non-small cell lung cancer; OS, overall survival; PS, performance status Lilenbaum R, Zukin M, Pereira JR, et al. A randomized phase III trial of single-agent pemetrexed (P) versus carboplatin and pemetrexed (CP) in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS)) of 2. J Clin Oncol Oncol.. 2012;suppl: 2012;su uppl: abstr 7506.

Gregory Kalemkerian, MD, a professor of medicine at the University of Michigan Comprehensive Cancer Center in Ann Arbor, who was not involved with the trial, agreed the results could change practice. “Two-drug regimens with a lower toxicity, such as the carboplatin plus pemetrexed regimen, are an option in patients with performance status 2, but PS 2 is a very heterogeneous patient population,” he said. “Single-agent therapy remains an option for patients with excessive comorbidities or the very elderly with a performance status of 2, and in those who do not tolerate a two-drug therapy.”

In the late 1980s, a four-armed clinical trial of various combination therapies in metastatic NSCLC concluded that PS 2 patients should be excluded from future Phase III trials, because combination therapies resulted in excessive toxicity and dismal survival ((J Clin Oncol 1986;4:14-22, PMID: 3510278). Since then, single-agent therapy has been the standard of care.

The new study, which involved eight centers in Brazil and one in the United States, enrolled stage IIIB/IV NSCLC patients with an Eastern Cooperative Oncology Group status of 2 who had not received prior chemotherapy and had adequate organ function. Patients

er smoked benefited from the doublet therapy (Table). Similar benefits for the combination therapy also were seen for median progression-free survival (PFS) (5.9 vs. 3.0 months; P<0.001) and PFS at 12 months (18% vs. 4%; P<0.001).

Toxicities were mild, with only a trend toward higher rates of anemia (11.7% vs. 3.9%; P=0.066) and neutropenia (5.8% vs. 1.0%; P=0.119) in patients who received carboplatin. There were, however, four documented treatment-related deaths in the carboplatin arm attributed to renal failure, sepsis, pneumonia and thrombocytopenia.

Dr. Kalemkerian said the study was well designed and representative of realworld patients, but could have benefited from a quality-of-life analysis.

According to Dr. Lilenbaum, the results can be generalized to PS 2 patients with all histologic subtypes. “Although carboplatin-pemetrexed may be a particularly suitable regimen for this population because of its safety profile, we don’t think that these results are unique to this regimen or limited to nonsquamous patients,” said Dr. Lilenbaum.

—Kate O’Rourke Drs. Lilenbaum and Kalemkerian disclosed research funding from Lilly.

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 g y and Wound Healing g Complications p 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 g 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.

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 (14.3).]

1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

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).]

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).]

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%

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. 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).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

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 4198 patients with CRC, non-squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) 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 18-88 years (median 60 years), 43.6% male and 83.8% white. The population included 1783 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 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,

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

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 5, 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).]

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))

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 7 (Occurring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo)

and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

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).]

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 4, 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 5, 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%.

Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7.

The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, 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 7).

[See Warnings and Precautions (5.8).]

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 signficantly 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.

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 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 posttreatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

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

NCI-CTC Grade 3-4 Events Bodyy as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra-Abdominal Thrombosis Syncope Digestive g Diarrhea Constipation Hemic/Lymphatic y p Leukopenia Neutropeniaa a

Arm 1 IFL+ + Placebo (n = 396) 74%

System Organ Class/ IFN-α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations g Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system y disorders Headache 16% Renal and urinaryy disorders Proteinuria 3% Respiratory, p y, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

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%

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) Bodyy as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive g Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic y p Thrombocytopenia Nervous Dizziness Respiratory p y Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages pp g Alopecia Skin Ulcer Special p Senses Taste Disorder Urogenital g 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%

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.

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 4. 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 5 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.

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 7. 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 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).

a

IFN-α α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

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 immunogenicity.

The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay 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.

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 4, 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.

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 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 7, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

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

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990

06/12 AVA0000765902 10127309 Initial U.S.Approval: February 2004 Code Revision Date: May 2012 Avastin® is a registered trademark of Genentech, Inc. © 2012 Genentech, Inc.

To confront the threat of angiogenesis in first-line metastatic non-squamous NSCLC…

Think Avastin

Because survival matters most

Percentage Surviving

Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991 100

1-year survival: 51% vs 44%2

80

2-year survival: 23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

10

20

30

50

OS (Months) Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68– 0.94], P=0.013).1 Clinically meaningful 1- and 2-year survival rates were demonstrated with Avastin plus PC (51% and 23%, respectively, vs 44% and 15% with PC alone).2

Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; OS=overall survival; HR=hazard ratio; CI=confidence interval.

Indication 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.

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, 2.4%) — Proteinuria including 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 Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother 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%) Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

References: 1. Avastin Prescribing Information. Genentech, Inc. September 2011. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

©2011 Genentech USA, Inc.

All rights reserved.

AVA0000400601

Printed in USA.

(11/11)

www.avastin.com

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Evolving Treatment Paradigms in

Non-Small Cell Lung Cancer KATHRYN F. MILEHAM, MD Staff Oncologist

HEATHER D. BROOKS, MD Staff Oncologist

EDWARD S. KIM, MD Chair, Solid Tumor Oncology and Investigational Therapeutics Donald S. Kim Distinguished Chair for Cancer Research Levine Cancer Institute Carolinas HealthCare System Charlotte, North Carolina

L

ung cancer remains the leading cause of cancer-related death in the

United States, accounting for 30% and 26% of all cancer deaths in men and women, respectively, and exceeding the predicted death rates for

breast and colorectal cancers combined.1 The overall 5-year relative survival is

a staggering 15.6%.2 Non-small cell lung cancer (NSCLC) is the most common histologic subtype, accounting for more than 85% of all lung cancer cases.

The evolution of conventional lung cancer treatment and personalized therapy continues. Screening studies finally have established a role for early detection. However, very few patients present with earlystage disease. With the majority of patients presenting with advanced disease, better evaluation and treatment decisions using histology and molecular therapies are desperately needed. Current treatment plans have resulted in an increased median overall survival (OS) from 2 months to more than 12 months.3,4 Still, the need for improved outcomes with reduced treatment

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

toxicity persists in a time when personalized therapy is evolving into a standard.

Conventional Chemotherapy Since 1997, the American Society of Clinical Oncology (ASCO) has recommended the use of cisplatin-based chemotherapy for patients with advanced NSCLC and an adequate performance status. This was based on a meta-analysis of 52 clinical trials with more than 9,000 patients.5 Cisplatin-based chemotherapy showed a 27% reduction in the risk for death at 1 year.6

C L I N I C A L O N CO LO GY N E WS â&#x20AC;˘ S E P T E M B E R 2 0 1 2

1

Subsequent clinical trials focused on increasing efficacy using newer agents and decreasing toxicity by substituting carboplatin for cisplatin. Although the role of platinum-based doublet regimens as a mainstay has been well established, this paradigm is changing dynamically as newer agents are developed and molecular targets are identified.

Two variables must be considered in the choice of a platinum-based doublet: the platinum agent used (cisplatin or carboplatin) and the agent combined with the platinum. Chemotherapeutics approved for use in this setting include paclitaxel, gemcitabine, vinorelbine, docetaxel, and pemetrexed (Alimta, Lilly).

Results from a large trial comparing cisplatin-paclitaxel with 3 other regimens (carboplatin-paclitaxel, cisplatin-docetaxel, and cisplatin-gemcitabine) found no significant difference in OS (median 7.9 months) among the 4 regimens.7 Of note, there were less serious toxicities reported in patients treated with carboplatin-paclitaxel.

More recently, nanoparticle albumin-bound paclitaxel (Abraxane, Celgene) has been shown to be effective as well as tolerable in NSCLC. Preliminary results from a Phase III trial comparing carboplatin-nab-paclitaxel with carboplatin-paclitaxel showed higher response ra tes (RR) in the nab-paclitaxel arm.8 When compared with paclitaxel, nab-paclitaxel was associated with reduced incidence of grade 3 or higher nonhematologic toxicities, specifically neuropathy, myalgia, and arthralgia (3% vs 10%), despite the higher paclitaxel dose delivered.

A Phase III study of 1,725 patients with advanced NSCLC compared front-line treatment with cisplatin-pemetrexed and cisplatin-gemcitabine.9 This trial showed similar overall efficacy between the regimens, and, importantly, demonstrated a benefit difference based on histology. When examined by histology, patients with nonsquamous NSCLC treated with cisplatin-pemetrexed sustained a statistically significant survival advantage over those treated with cisplatingemcitabine (median OS, 11.8 and 10.4 months, respectively), including significantly better survival in those with adenocarcinoma (12.6 vs 10.9 months; hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.710.99; P=0.03). In contrast, patients with squamous cell histology had a shorter median survival when treated with cisplatin-pemetrexed. Identification of specific NSCLC histology has become important in the overall evaluation of patients with lung cancer.

Changing Paradigms The increasing influence of histologic subtype in the choice of agents, the identification of new molecular targets, and the availability of targeted agents is changing the strategy for front-line treatment selection in advanced NSCLC. Molecular testing of lung tumors (eg, epidermal growth factor receptor [EGFR] and anaplastic lymphoma kinase [ALK]) to facilitate treatment selection is readily available and can be

2

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

considered a standard of care, as it is for other solid tumors, including breast and colorectal. This truly allows clinicians to personalize therapy for individual patients.

Bevacizumab (Avastin, Genentech), a humanized monoclonal antibody (mAb) that inhibits vascular endothelial growth factor (VEGF)-A, not only was the first targeted agent proven to extend survival when added to conventional chemotherapy (carboplatin-paclitaxel) in the front-line treatment of advanced NSCLC, but in Eastern Cooperative Oncology Group (ECOG) 4599, it also was the first treatment regimen to demonstrate a median OS greater than 1 year in any Phase III trial of metastatic NSCLC (12.3 vs 10.3 months; HR, 0.79; CI, 0.67-0.92; P=0.003).4 Prudent patient selection is essential with the use of bevacizumab because increased toxicity and patient deaths have been reported.

Somatic mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) gene have been reported in lung cancers (predominantly adenocarcinomas). EGFR mutations are associated with sensitivity to EGFR-targeted therapies.

Erlotinib (Tarceva, Genentech), a reversible tyrosine kinase inhibitor (TKI), acting directly at EGFR, is FDA-approved for the treatment of NSCLC after platinum-failure. More recently, 2 notable trials investigated the use of erlotinib in the front-line management of advanced NSCLC patients with EGFR mutations.

EURTAC (European Erlotinib Versus Chemotherapy) is a prospective, randomized Phase III trial that investigated whether front-line treatment with erlotinib is superior to platinum-based chemotherapy in patients with EGFR mutations.10 At the time of interim analysis, progression-free survival (PFS) in the erlotinib arm was superior to that in the chemotherapy arm (9.4 vs 5.2 months; HR, 0.42; P<0.0001). Median OS was not significantly different (22.9 vs 18.8 months; HR, 0.80; P=0.42). The Phase III OPTIMAL (Erlotinib Versus Gemcitabine/Carboplatin in Chemo-na誰ve State IIIB/IV Non-Small Cell Lung Cancer Patients With Epidermal Growth Factor Receptor Exon 19 or 21 Mutation [ML20981]) trial is evaluating the efficacy of front-line erlotinib versus gemcitabine-carboplatin in 165 patients with advanced NSCLC who harbor EGFR-activating mutations.11 Treatment with erlotinib improved median PFS (primary end point) when compared with chemotherapy (13.1 vs 4.6 months). Common toxicities associated with erlotinib treatment are rash and diarrhea.

Gefitinib (Iressa, AstraZeneca), an inhibitor of the EGFR tyrosine kinase domain, was evaluated in several trials. INTEREST (Iressa Non-small cell lung cancer Trial Evaluating Response and Survival Against Taxotere) compared gefitinib and docetaxel in patients with advanced NSCLC who had received previous platinum-based chemotherapy.12 Results for all 1,433 patients confirmed noninferiority of gefitinib compared with docetaxel for OS (7.6 vs 8 months; HR, 1.020; CI, 0.905-1.150). Patients with EGFR mutations

treated with gefitinib had longer PFS compared with those treated with docetaxel.13 In IPASS (Iressa Pan Asia Study), patients with advanced NSCLC who never smoked or formerly were light smokers received either carboplatin-paclitaxel or gefitinib in the front-line setting. Although median PFS was similar in both arms (5.7 vs 5.8 months), patients treated with gefitinib had a significantly higher PFS at 12 months (24.9% vs 6.7%; HR, 0.74; CI, 0.65-0.85; P<0.0001).14 Other strategies targeting the EGFR pathway have been reported. Cetuximab (Erbitux, Bristol-Myers Squibb) is a chimeric mAb that inhibits EGFR. The FLEX (First-Line Erbitux in Lung Cancer) trial evaluated front-line cisplatin-vinorelbine with or without cetuximab in patients with EGFR-expressing advanced NSCLC.15 Cetuximab was then given as continuation maintenance until progressive disease or intolerable side effects developed. The addition of cetuximab improved OS (11.3 vs 10.1 months; HR, 0.871; CI, 0.7620.996; P=0.044). Interestingly, first-cycle rash (commonly associated with EGFR inhibitors) was associated with improved survival.16 The combination of targeted agents against VEGF and EGFR with platinum-based chemotherapy may result in improved survival benefit. SWOG (Southwestern Oncology Group) 0536 was a Phase II study that combined carboplatin, paclitaxel, cetuximab, and bevacizumab for up to 6 cycles followed by weekly maintenance bevacizumab until disease progression in patients with advanced NSCLC.17 The combination was found to have an adequate safety profile and has led to an ongoing Phase III trial (SWOG 0819) investigating carboplatin-paclitaxel or carboplatin-paclitaxelbevacizumab with or without concurrent cetuximab in advanced NSCLC. The EML (echinoderm microtubule-associated protein-like) 4-ALK fusion oncogene is a new biomarker that has been identified in a small subset of patients with NSCLC (approximately 4%).18 Patients with ALK rearrangements have similar characteristics as those with EGFR mutations (adenocarcinoma, nonsmokers, or light smokers); however they often are young and male.19 Because these patients are resistant to EGFR tyrosine kinase inhibitors (TKIs), identifying patients with ALK rearrangements and customizing therapy to this target has been a focus of research efforts. Fluorescence in situ hybridization (FISH) rather than immunohistochemistry is the diagnostic test of choice to uncover ALK rearrangements.20-22 Crizotinib (Xalkori, Pfizer) is an ALK and MET TKI that recently was approved by the FDA for patients with ALK-positive advanced NSCLC. Of the 82 patients in the seminal Phase I study, 46 had a confirmed partial response and 1 had a confirmed complete response, for an overall RR of 57% (primary end point).23 At the mean treatment duration of 6.4 months, 33% had stable disease with minimal toxicities. Evaluation of an expansion cohort suggests a survival advantage in ALK-positive patients treated with crizotinib versus

crizotinib-naive ALK-positive patients.24 Although crizotinib is a new standard of care for patients with ALKpositive advanced NSCLC, 3 ongoing clinical trials (PROFILE 1007, 1005, and 1014) continue to evaluate the role of this targeted therapy. Chromosomal rearrangements involving the ROS1 receptor, a tyrosine kinase, have recently been described in a subset of NSCLC and appear to be therapeutic targets for ALK therapies (eg, crizotinib). The incidence of ROS1 abnormalities has been reported to be between 1% and 2% and seems to be independent of ALK status.25

Maintenance Therapy Data from multiple trials consistently have shown improvements in survival with maintenance therapy (Table).26-32 Strategies include either continuation of one or more of the initial agents (continuation maintenance), the introduction of an additional agent (switch maintenance), or a combination. Pemetrexed and erlotinib are FDA-approved as maintenance therapy.

Several trials adding targeted agents to chemotherapy have included a continuation maintenance strategy.

In the previously mentioned ECOG 4599 trial, patients receiving bevacizumab with carboplatin-paclitaxel in the experimental arm continued bevacizumab every 3 weeks until progression of disease or intolerable side effects.4 The FLEX trial also examined the role of cetixumab maintenance after front-line treatment. Patients with EGFRexpressing advanced NSCLC who received cetuximab with chemotherapy in the experimental arm continued cetuximab after chemotherapy until progression or intolerable side effects.15 In July 2009, the FDA approved pemetrexed for maintenance treatment of patients with advanced NSCLC with nonsquamous histology who had not progressed after initial chemotherapy. This approval was based on data from a Phase III trial of 664 patients with advanced NSCLC who did not progress on an initial platinum-based doublet (non-pemetrexed based) and then received maintenance pemetrexed or placebo.26 Compared with patients receiving placebo, those who received maintenance pemetrexed had both improved PFS (4.3 vs 2.6 months; HR, 0.50; CI, 0.420.61; P<0.0001) and OS (13.4 vs 10.6 months; HR, 0.79; CI, 0.65-0.95; P=0.012). This provides an example of the efficacy of a switch maintenance strategy.

Preliminary data from the PARAMOUNT trial presented at ASCO 2011 support the use of pemetrexed in a continuation maintenance treatment strategy.27 This Phase III international trial examined 939 patients with advanced nonsquamous NSCLC. Those who did not progress during cisplatin-pemetrexed induction therapy were randomized to receive either maintenance pemetrexed every 3 weeks plus best supportive care (BSC) or placebo plus BSC until evidence of progression.

Patients receiving maintenance pemetrexed sustained an improved PFS (HR 0.64; CI, 0.51-0.81; P=0.00025), with a 36% reduction in risk for progression. The favorable tolerability profile and ease of administration make

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

3

Table. Selected Trials of Maintenance Therapy in Advanced NSCLC Clinical Trial

Treatment Arms

N

PFS, mo

Median OS, mo

Fidias et al29

GC, then immediate docetaxel GC, then delayed docetaxel

309

5.7 (P=0.001)

12.3 (P=0.0853)

2.7

9.7

CT, then E CT, then P

438 451

PFS was significantly prolonged with E versus P in all patients (HR, 0.71; 95% CI, 0.62-0.82; P<0.0001)

12 11

Pemetrexed + BSC P + BSC

441 222

Overall/NSQ/SQ 4.3/4.5/2.8 2.6/2.6/2.6

Overall/NSQ/SQ 13.4/15.5/9.9 10.6/10.3/10.8

Miller et al30 (ATLAS)

CT + B, then B + P CT + B, then B + E

768

3.7 (P=0.0012) 4.8

NA

Paz-Ares et al27 (PARAMOUNT)

Cisplatin + pemetrexed, then pemetrexed + BSC Cisplatin + pemetrexed, then P + BSC

359

3.9

NA

180

2.6

Cisplatin + B + pemetrexed, then B + pemetrexed Cisplatin + B + pemetrexed, then B

128

10.2 (P=0.001)

125

6.6

Carboplatin + B + pemetrexed, then B + pemetrexed Carboplatin + B + paclitaxel, then B

NA

NA

Capuzzo et al28 (SATURN)

Ciuleanu et al26

Barlesi et al31 (AVAPERL)

Patel et al32 (PointBreak)

NA

NA

B, bevacizumab; BSC, best supportive care; CI, confidence interval; CT, first-line platinum-based chemotherapy; E, erlotinib; GC, gemcitabine-carboplatin; HR, hazard ratio; NA, not available; NSQ, nonsquamous; OS, overall survival; P, placebo; PFS, progression-free survival; SQ, squamous

pemetrexed an appealing option for maintenance therapy in advanced NSCLC. The FDA approved erlotinib in April 2010 for maintenance treatment of patients with advanced NSCLC with nonprogressive disease after front-line platinumbased chemotherapy. This approval was based on the large Phase III SATURN (Sequential Tarceva in Unresectable NSCLC) trial.28 This trial was one of the first to evaluate maintenance therapy versus placebo in a prospective fashion. Patients with advanced NSCLC (N=1,949) received erlotinib or placebo after platinumbased doublet chemotherapy. Maintenance erlotinib was associated with a statistically significant improvement in both PFS (HR, 0.71; CI, 0.62-0.82; P<0.0001) and OS (12 vs 11 months). In an exploratory analysis, patients with EGFR mutations sustained an even greater benefit from maintenance erlotinib.

In the Phase III IFCT-GFPC 0502 study, treatmentnaive patients with advanced NSCLC were treated with

4

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

4 cycles of cisplatin-gemcitabine.33 Those who did not progress were randomized to observation, continuation maintenance gemcitabine, or switch-maintenance erlotinib. PFS was significantly prolonged in patients receiving either maintenance with gemcitabine or erlotinib versus observation alone (HR, 0.51; CI, 0.39-0.66 and HR, 0.83; CI, 0.73-0.94, respectively).

Additional strategies for maintenance include a combination of continuation and switch, in which one of the agents from initial therapy is continued, and an additional agent that was not used previously is added. This concept was tested in the ATLAS trial, a Phase III evaluation of bevacizumab with or without erlotinib after completion of chemotherapy with bevacizumab for front-line treatment of advanced NSCLC.30 Patients who were treated with combination maintenance showed a showed significant improvement in PFS (4.8 vs 3.7 months; HR, 0.722; CI, 0.592-0.881; P=0.0012) over those treated only with continuation maintenance.

Squamous

Adenocarcinoma or nonsquamous

Chemotherapy doublet

EGFR-mutation and ALK-translocation testing

ALK-translocation positive

EGFR-mutation negative

Crizotinib

Erlotinib

ALK-translocation negative and EGFR-mutation negative

Bevacizumab eligible

Bevacizumab noneligible

Bevacizumab + chemotherapy doublet

Non-bevacizumab chemotherapy doublet (pemetrexed-based)

Maintenance therapy • Pemetrexed • Bevacizumab • Erlotinib • Docetaxel

Disease progression

• Salvage therapy • Consider clinical trial

Figure. Proposed algorithm for treatment of NSCLC. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer

Final efficacy outcomes of AVAPERL were presented at the 16th ECCO (European CanCer Organisation)— 36th ESMO (European Society for Medical Oncology) Multidisciplinary Cancer Congress in September 2011.

This ongoing Phase III study is evaluating continuation maintenance with bevacizumab with or without pemetrexed following 4 cycles of front-line cisplatin-bevacizumab-pemetrexed in advanced nonsquamous NSCLC.31 Those who had at least stable disease after front-line treatment were randomized to either bevacizumab alone or bevacizumab plus pemetrexed.

The median PFS (primary end point) from the start of induction therapy was 6.6 versus 10.2 months, respectively (HR, 0.50; P<0.001). When evaluated from time of randomization, the median PFS was 3.7 months versus 7.4 months, respectively (HR, 0.48; P<0.001).

These encouraging findings will be further evaluated with large Phase III trials. ECOG 5508 is a Phase III study that will randomize 1,282 patients to

bevacizumab, pemetrexed, or a combination of bevacizumab and pemetrexed after 4 cycles of initial therapy with carboplatin-paclitaxel-bevacizumab in advanced nonsquamous NSCLC. PointBreak is a separate randomized, open-label Phase III study comparing carboplatin-pemetrexed-bevacizumab followed by maintenance pemetrexed-bevacizumab with carboplatin-paclitaxel-bevacizumab followed by maintenance bevacizumab in advanced nonsquamous NSCLC; patients will receive up to 4 cycles of induction treatment followed by maintenance until progression or treatment discontinuation.32 Although observation is still an option in patients with disease control after initial chemotherapy, consideration should be made for maintenance therapy, especially in patients with preserved performance status.

Options for maintenance therapy in advanced NSCLC include continuation of front-line therapy with bevacizumab, cetuximab, pemetrexed, or gemcitabine, or

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

5

switching to pemetrexed for patients with nonsquamous histologies and erlotinib for those with EGFRmutated tumors. Additional considerations can be made for doublet maintenance therapy.

Overcoming Resistance EGFR

AND

ACQUIRED EGFR RESISTANCE

An active area of research centers on mechanisms of resistance to EGFR TKIs, including amplification of the MET oncogene and secondary mutations in EGFR, such as the T790M mutation in exon 20. The T790M mutation is the most common mechanism of acquired resistance, accounting for more than 50% of the cases. Dual EGFRMET inhibition is a potential approach for overcoming MET-mediated resistance to EGFR inhibitors. ARQ 197 is an oral, selective, non-ATP competitive inhibitor of c-MET, a receptor tyrosine kinase implicated in cancer cell migration, invasion, and proliferation. A global randomized, double-blind, placebo-controlled Phase II trial compared erlotinib plus ARQ 197 with erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with advanced NSCLC. Median PFS (primary end point) was prolonged with combined treatment (16.1 vs 9.7 weeks; HR 0.81; CI, 0.57, 1.15; P=0.23). PFS was particularly improved among patients with nonsquamous histology, KRAS mutations, and EGFR wild-type status.34 Another therapy under evaluation is MetMAb, a monovalent mAb that specifically binds the Met receptor.

OAM4558g was a global randomized, double-blind, placebo-controlled Phase II study comparing erlotinib plus MetMAb with erlotinib plus placebo in the second- or third-line management of advanced NSCLC. The addition of MetMAb to erlotinib in these patients significantly improved PFS and OS in patients who had high expression of Met in their tumors, resulting in 3-fold reduction in the risk for death.35 There is increasing interest in irreversible EGFR inhibitors, mainly through the discovery of the oral small-molecule EGFR TKI BIBW 2992 (afatinib). Differing from its predecessors, afatinib binds irreversibly to both EGFR and HER-2 and is active against both wild-type and multiple mutant forms of EGFR. A Phase II trial of afatinib in patients with advanced NSCLC who were previously treated with erlotinib or gefitinib was conducted in Japan. The primary end point was objective tumor response. Afatinib was deemed efficacious based on 69% disease control rate of greater than 8 weeks and median PFS of 4.4 months.36 Additional ongoing studies are investigating the use of afatinib in patients with NSCLC in various treatment settings. One strategy tested combination afatinib with cetuximab in patients with EGFR mutations whose disease has progressed on erlotinib.37 Disease control was observed in all patients enrolled at the recommended Phase II dose of afatinib, with tumor size reduction up to 76%. At the 2012 ASCO annual meeting, Yang et al presented the results of a large-scale Phase III study assessing the activity of front-line afatinib versus cisplatin and pemetrexed

6

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

chemotherapy in patients with tumors harboring EGFR mutations.38 The trial randomized 345 patients and demonstrated significantly prolonged PFS for those treated with afatinib compared with those treated with chemotherapy (median 11.1 vs 6.9 months; HR, 0.58 [0.43-0.78]; P=0.0004). In patients with common mutations (Del19/L858R) (n=308), median PFS was 13.6 months in the afatinib group versus 6.9 months in the chemotherapy group (HR, 0.47 [0.34-0.65]; P<0.0001). The objective response rate also was significantly higher with afatinib versus chemotherapy (56% vs 23%; P<0.0001). This is the first randomized study to demonstrate benefit of an oral targeted therapy versus chemotherapy in a molecularly selected population.

EML4-ALK

AND

CRIZOTINIB RESISTANCE

EML4-ALK is a novel fusion oncogene occurring in about 3% to 7% of NSCLC cases.24 The fusion results from a small inversion within chromosome 2p, leading to expression of a constitutively activated, chimeric tyrosine kinase. EGFR mutations and EML4-ALK rearrangements are generally mutually exclusive.39 Patients tend to respond rapidly to crizotinib, but many develop resistance after about 1 year of therapy, and increased brain metastases have been reported.40 The FDA recently approved crizotinib for patients with advanced NSCLC with ALK-positive rearrangements as demonstrated via the Abbott Vysis test. Second-generation ALK TKIs and heat shock protein 90 inhibitors as strategies to treat crizotinib-resistant tumors are under way.41

Newer Targeted Therapies The recent advances in the treatment of NSCLC have involved the integration of targeted therapeutics and more accurately defining the subset of patients who are most likely to benefit from a given treatment. We have attempted to use clinical factors such as tobacco history, gender, and ethnicity to determine appropriate therapy. However, because 60% of lung cancers carry an identifiable mutation,42 there is movement toward assessing genetic factors more quickly. The Lung Cancer Mutation Consortium (LCMC) has reported the frequencies, characteristics, and therapeutic options for genetic mutations found in lung cancer. Additionally, appropriate patients are offered participation in LCMC-linked clinical trials of agents targeting the identified mutation.

The importance of histology cannot be underestimated. Although targeted therapies have improved outcomes for patients with adenocarcinoma of the lung, patients with squamous cell carcinoma very rarely respond to these same agents. In addition to EGFR, the other promising targets including EML4-ALK, KRAS, and MET also may be limited to adenocarcinoma. Given that squamous cell lung cancers account for about 25% of new lung cancer cases and 40,000 deaths per year in the United States, it is important to identify and understand the genomic alterations that drive this histologic subtype. To date, 3 molecular targets have been

identified in squamous cell carcinomas: Fibroblast growth factor receptor 1 (FGFR1) is amplified in about 20% of squamous cell lung cancer43 and PI3KCA and DDR2 mutations each have been identified in about 3% of squamous cell carcinomas.44 All of these mutations represent promising targets for future therapy, and they are already being considered for clinical trials.

Although studies continue to evaluate therapies based on tumor histologic profiles, the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial tackled personalized treatment based on tumor molecular biomarker profiles.

This was the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized study in patients with heavily pretreated NSCLC. Based on results from core needle biopsy specimens, patients were treated with erlotinib, vandetanib (Caprelsa, AstraZeneca), erlotinib plus bexarotene (Targretin, Eisai), or sorafenib (Nexavar, Bayer).45 Patients with mutant-KRAS tumors benefited from sorafenib. Attention has also been placed on targeting BRAF mutations, especially because most of the identified mutations in NSCLC seem to be mutually exclusive.46 Thus, agents such as vemurafenib (Zelboraf, Genentech) and dasatinib (Sprycel, Bristol-Myers Squibb), which have shown activity in V600E BRAF mutations and DDR2 mutations, respectively,44,47 are being evaluated in these settings.

All of these efforts are substantial steps toward individualized lung cancer therapy.

Conclusion Paradigms in all stages of treatment of advanced NSCLC are evolving toward targeted molecular therapies with better tolerability profiles. Based on recent studies, new standards of management in advanced NSCLC must be considered including maintenance strategies and targeted therapies. To improve our management of lung cancer patients, more tissue should be collected (eg, core biopsies) to evaluate upfront not only histology but also biomarker profiles. The BATTLE trial has already demonstrated the feasibility of this type of approach in advanced NSCLC.45 One day, we hope patients with lung cancer will be treated according to a biomarker tumor profile and not limited by their age or performance status. Unique treatment strategies can then be directed to each patient on a truly individual basis. Finally, broader clinical trial participation should be encouraged to enhance our knowledge of how to continue to improve outcomes in a disease that remains the leading cause of cancer death in the United States.

References 1.

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90, PMID: 21296855. Erratum in: CA Cancer J Clin. 2011;61(2):134.

2. National Cancer Institute. SEER stat facts sheets: lung and bronchus. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed August 6, 2012.

3. Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of

phase III trials for patients with advanced non-small-cell lung cancer: sobering results. J Clin Oncol. 2001;19(6):1734-1742, PMID: 11251004.

4. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550, PMID: 17167137. Erratum in: N Engl J Med. 2007;356(3):318.

5. Douillard JY, Tribodet H, Aubert D, et al. Adjuvant cisplatin and vinorelbine for completely resected non-small cell lung cancer: subgroup analysis of the Lung Adjuvant Cisplatin Evaluation.

J Thorac Oncol. 2010;5(2):220-228; PMID: 20027124.

6. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials.

BMJ. 1995;311(7010):899-909, PMID: 7580546.

7.

Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.

N Engl J Med. 2002;346(2):92-98, PMID: 11784875.

8. Socinski MA, Bondarenko IN, Karaseva NA, et al. Results of a randomized, phase III trial of nab-paclitaxel (nab-P) and carboplatin (C) compared with cremophor-based paclitaxel (P) and carboplatin as first-line therapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(18 suppl): Abstract LBA7511.

9. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551, PMID: 18506025.

10. Rosell R, Gervais R, Vergnenegre A, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. J Clin Oncol.

2011;29(suppl): Abstract 7503.

11. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutationpositive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised phase 3 study. Lancet Oncol.

2011;12(8):735-742, PMID: 21783417.

12. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small cell lung cancer (INTEREST): a randomized phase III trial. Lancet. 2008;372(9652):1809-1818, PMID: 19027483.

13. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol. 2009;28(5):744-752, PMID: 20038723.

14. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957, PMID: 19692680.

15. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet.

2009;373(9674):1525-1531, PMID: 19410716.

16. Pirker R, Rodrigues-Pereira J, Szczesna A, et al. Prognostic factors in advanced NSCLC: experience from the FLEX trial. J Clin Oncol.

2009;27(15 suppl): Abstract 8083.

17. Kim ES, Herbst RS, Moon J, et al. S0536: Carboplatin, paclitaxel, cetuximab and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small cell lung cancer (NSCLC), a SWOG phase II study. PD3.5.5. Presented at: 2009 IASLC World Congress on Lung Cancer; July 31-August 4, 2009; San Francisco, CA. 18. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature.

2007;448(7153):561-566, PMID: 17625570.

19. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27(26):4247-4253, PMID: 19667264.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

7

20. Kim H, Yoo SB, Choe JY, et al. Detection of ALK gene rearrangement in non-small cell lung cancer: a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression. J Thorac Oncol.

2011;6(8):1359-1366, PMID: 21587085.

33. Perol M, Chouaid C, Milleron BJ, et al. Maintenance with either gemcitabine or erlotinib versus observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC: IFCT-GFPC 0502 phase III study. J Clin Oncol. 2010;28(15 suppl): Abstract 7507.

21. Rodig SM, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res. 2009;15(16):5216-5223, PMID: 19671850.

34. Schiller JH, Akerley WL, Brugger W, et al. Results from ARQ 197209: a global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol.

2010;28(18 suppl): Abstract LBA7502.

22. Mino-Kenudson M, Chirieac LR, Law K, et al. A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res. 2010;16(5):1561-1571, PMID: 20179225.

23. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703, PMID: 20979469. Erratum in: N Engl J Med. 2011;364(6):588.

24. Shaw AT, Yeap BY, Solomon BJ, et al. Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls. J Clin Oncol. 2011;29(suppl): Abstract 7507.

25. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecure class of lung cancers. J Clin Oncol.

2012;30(8):863-870, PMID: 22215748.

26. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374(9699):1432-1440, PMID: 19767093.

27. Paz-Ares LG, De Marinis F, Dediu M, et al. PARAMOUNT: Phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo plus BSC immediately following induction treatment with pem plus cisplatin for advanced nonsquamous non-small cell lung cancer (NSCLC). J Clin Oncol. 2011;29(suppl): Abstract CRA7510.

28. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. SATURN: A doubleblind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol.

2009;27(15 suppl): Abstract 8001.

29. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small cell lung cancer. J Clin Oncol. 2009;27(4):591-598, PMID: 19075278.

30. Miller VA, O’Connor P, Soh C, et al. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC).

J Clin Oncol. 2009;27(18 suppl): Abstract LBA8002.

35. Spigel DR, Ervin TJ, Ramlau R, et al. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. J Clin Oncol. 2011;29(suppl): Abstract 7505.

36. Yamamoto N, Katakami N, Atagi S, et al. A phase II trial of afatinib (BIBW 2992) in patients (pts) with advanced non-small cell lung cancer previously treated with erlotinib (E) or gefitinib (G).

J Clin Oncol. 2011;29(suppl): Abstract 7524.

37. Janjigian YY, Groen HJ, Horn L, et al. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. J Clin Oncol.

2011;29(suppl): Abstract 7525.

38. Yang, J, Schuler M, Yamamoto N, et al. LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. J Clin Oncol. 2012;(suppl): Abstract LBA7500.

39. Takahashi T, Sonobe M, Kobayashi M, et al. Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol. 2010;17(3):889-897, PMID: 20183914.

40. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363(18):1734-1739, PMID: 20979473.

41. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci USA. 2011;108(18):7535-7540, PMID: 21502504.

42. Kris MG, Johnson BE, Kwiatkowski DJ, et al. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC).

J Clin Oncol. 2011;29(suppl): Abstract CRA7506.

43. Dutt A, Ramos AH, Hammerman PS, et al. Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PloS One. 2011;6(6):e20351, PMID: 21666749.

31. Barlesi F, de Castro J, Dvornichenko V, et al. AVAPERL (MO22089): Final efficacy outcomes for patients (pts) with advanced nonsquamous non-small cell lung cancer (nsNSCLC) randomized to continuation maintenance (mtc) with bevacizumab (bev) or bevacizumab + pemetrexed (pem) after first-line bevacizumabcisplatin (cis)-pem treatment (tx). Eur J Cancer. 2011;47(2 suppl): Abstract LBA34.

44. Hammerman PS, Sos ML, Ramos AH, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011;1(1):78-89, PMID: 22328973.

32. Patel JD, Bonomi P, Socinski MA, et al. Treatment rationale and study design for the pointbreak study: a randomized, open-label phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small cell lung cancer. Clin Lung Cancer. 2009;10(4):252-256, PMID: 19632943.

46. Kobayashi M, Sonobe M, Takahashi T, et al. Clinical significance of BRAF gene mutations in patients with non-small cell lung cancer.

Anticancer Res. 2011;31(12):4619-4623, PMID: 22199339.

8

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

45. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011;1(1):44-53, PMID: 22586319.

47. Johnson FM, Tang X, Tran H, et al. Phase II study of dasatinib in non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27(suppl): Abstract e19015.