The January 2013 Digital Edition of Clinical Oncology News

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • JANUARY 2013 • Vol. 8, No. 1

INSIDE SOLID TUMORS Expert Review: Clinical developments in solid tumors from ASCO . . . . . . . . . . . . . . ......... 18 Dual-targeted therapies in metastatic colorectal cancer . . . . ........ 20 Hope for an Avastin biomarker . . . . . . . . . . . . . . .......... 22 Can 3-D ultrasound detect lymph node metastases? . . . . . . . . . . . .......... 23 Adding mTOR inhibitors fails for metastatic renal cell carcinoma . . . . . . . . ......... 23

ChemotherapyFree Regimen Effective for APL Atlanta—A chemotherapy-free regimen is poised to become the new standard of care in patients with non–highrisk, acute promyelocytic leukemia (APL), according to results from a Phase III trial. The trial, which showed that the combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) improved survival over ATRA and chemotherapy, was reported at the annual meeting of the American Society of Hematology (ASH; abstract 6).

“These results are very important.

This is the first highly effective treatment of APL with acute leukemias without chemotherapy,” said Pierre Fenaux, MD, PhD, a professor of hematology at see APL, page 24

CURRENT PRACTICE Maurie Markman, MD: The catch-22 of surgical oncology trials . . . . . . ............ 3 Ondansetron recalled

by FDA . . . . . . . . . . . . . . . . . . . ......... 20 Clinical Conundrums . . . . . . . . . . . ........ 30

By the NUMBERS

see TAMOXIFEN, N page 4

It takes 10 to 15 years, on average, for an experimental drug to travel from the lab to U.S. patients It costs a company $1.2 billion, including the cost of failures, to get one new medicine from the laboratory to patients

Only one of those five is approved for use

See page 6

xtending treatment with tamoxifen for 10 years, instead of the standard of care of five years, improves survival in women with estrogen receptor (ER)-positive early breast cancer. This news Tamoxifen molecule.. comes from results of the ATLAS (Adjuvant Tamoxi Tamoxifen: Longer Against Shorter) trial, reported at the recent San Antonio Breast Cancer Symposium (abstract S1-2).

“For both recurrence and breast cancer mortality there was little additional benefit during years 5 to 9, but after that there was a very definite effect. We know the carryover effect from tamoxifen persists for quite a long time after treatment,” said Richard

Cancer Drug Development

Only five in 5,000 compounds that enter preclinical testing make it to human testing

The Gastric Cancers: Targeted for Personalized Medicine

10-year tamoxifen affects survival in both fi t and first d second d decades d d post-diagnosis t di i

FOR MORE, see Number of Drugs Under Clinical Development . . . . . . . . . .. 24

Vogl, NY...

ATLAS: Tamoxifen Far Inferior to AIs in Years 6 to 10 Tamoxifen has no benefit until year 11

T

he ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial of five additional years of tamoxifen versus observation was presented at the San Antonio Breast Cancer Symposium on Dec. 5, 2012, and published simultaneously in The Lancett to much notoriety and acclaim.1 The popular press ignored the obvious inferiority of tamoxifen to an aromatase inhibitor

Steven Vogl, MD

when it is given for five years after five years of previous tamoxifen and local therapy for breast cancer. Further, the press ignored the obvious exploratory nature of the statistical analysis, which was conceived after reviewing the data, and the very limited number of women who could potentially benefit. see VOGL, NY, Y page 4

RE VIE WS & COMMENTAR IES

Expert Insights From The US Oncology Network Adjuvant Therapy Fails for High-Risk Soft Tissue Sarcoma . . . . . . . . . . . . . . .... 15 Alex Spira, MD, PhD

Enzalutamide a Major Advance for Prostate Cancer Treatment .............. 26 Mark T. Fleming, MD

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • JANUARY 2013

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer

Charles F. von Gunten, MD University of California, San Diego, CA

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

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 Alabama Birmingham, AL

Oncology Nursing Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

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

Cindy O’Bryant, PharmD

Edward Chu, MD

Mayo Clinic Rochester, MN

University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

University of Colorado Cancer Center Denver, CO

Richard Stone, MD

Sara S. Kim, PharmD

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

The Mount Sinai Medical Center New York, NY

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

Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

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

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

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

Policy and Management

Pharmacy Shaji Kumar, MD

Gastrointestinal Cancer

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

Hematologic Malignancies

Andrew Seidman, MD

Bioethics

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.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Clinical Trials in Surgical Oncology: A Catch-22 T

he recent—and ongoing—intense debate over the role and cost of robotic surgery in the routine management of an increasing number of malignant conditions (e.g., cancers of the prostate, endometrium, ovary) emphasizes a unique and rarely discussed aspect of clinical research within the realm of surgical oncology.1 Consider, for a moment, the process of antineoplastic drug development. Following the completion of Phase I studies focused on toxicity, dose and schedule (but also exploring evidence of clinical benefit within the treated patient population), Phase II, and often randomized Phase III trials will be conducted to determine the efficacy of the strategy. Furthermore, no new antineoplastic drug will be introduced into routine clinical practice until it has satisfied specific FDA-defined criteria.

Clinicians and institutions involved in the process will be required to carefully monitor side effects and follow defined trial protocols (e.g., computed tomography scan of the abdomen or chest every two months until progression is documented). Failure to adhere to the protocol will be considered a minor, or even a major, deviation and situation-specific measures will be undertaken to rectify the deficiencies.

However, during this process you will certainly never hear the claim that individual oncologists involved will need to spend time perfecting their “drug development techniques/skills” before it is possible to evaluate whether this new drug is clinically useful. Rather, efficacy will be defined by the agent’s documented utility ®

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independentt of a physician’s skills or experience with the drug in question. Again, it must be emphasized that the required monitoring and defining of side effects— both incidence and severity—is a critical component of the drug development process, but these skills are not unique to the specific agent in question.

In my opinion, the above description could not be farther from the reality of developing new techniques in cancerrelated surgery. The often quoted, but grossly oversimplified, surgical training paradigm of “see one, do one, teach one” is highly evident in the realm of surgical innovation.

However, once a sufficient number of surgeons are appropriately trained and experienced to theoretically be able to participate in an evidence-based study (or studies), it is highly likely there will be considerable nonrandomized “data” present within the peer-reviewed literature that suggests, or even specifically claims, the superiority of the new technique. And, of course, added to these literature reports there will likely have been presentations of the data at multiple medical meetings, as well as stories in the lay press extolling the virtues of the new approach (e.g., “less morbidity,” “faster return to work,” “reduced

The often quoted, but grossly oversimplified, surgical training paradigm of “see one, do one, teach one” is highly evident in the realm of surgical innovation.

Originators of new surgical techniques will likely spend considerable time, sometimes measured in years, before the claim is made that a new approach is ready for widespread use. Then, others will need to develop their own skills with the strategy before they can be considered fully competent to perform it routinely.

Herein lies the “Catch-22” of innovative surgical research. It is premature to conduct evidence-based randomized trials when only a few surgeons are technically skilled in a procedure and others are still learning. How can one evaluate the “true” efficacy, risks and side-effect profile compared with the “standard of care” under these less than “steadystate” circumstances?

time spent in the hospital,” “lower costs,” etc.).

Finally, even the initial training and early experience by clinicians may demand substantial costs by an institution to purchase a particular machine, device or instrument. As a result, it is understandable that these institutions would have a rational interest in optimizing the financial outcome of their investment.

Individually, and even more so when combined, these factors make any subsequent evidence-based clinical trials difficult, if not realistically impossible in many situations. What patient would want to be randomized to the “old standard” surgical approach when they have been informed (by the treating physician

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

and the media) that the “new approach” offers the advantage of less time in the hospital, less blood loss, a lower risk of infection, and a quicker return to their normal activities of daily living?

I have no intent of suggesting that there is anything inherently wrong with this common paradigm for essential and clinically valid innovation in surgical oncology. Rather, the goal here is to simply acknowledge the reality of the situation and suggest that strategies other than the conduct of randomized trials will be required to objectively evaluate the clinical benefits and cost-effectiveness of proposed improvements in surgical oncology.

Reference 1. Fleming ND, Ramirez PT. Robotic surgery in gynecologic oncology. Curr Opin Oncol.

2012;24:547-553, PMID: 22581356.

Comments or feedback on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor Gabriel Miller at

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JANUARY 2013

TAMOXIFEN continued from page 1

Gray, MSc, of the University of Oxford in the United Kingdom, who presented the study. “After year 10, we found veryy clear, very significant benefit from having continued treatment.”

In the study, 6,846 women with ERpositive breast cancer completed five years of tamoxifen and then were randomized to stop treatment at year 5 or continue for another five years for a total of 10 years of treatment. The risk for recurrence during the period five to 14 years after diagnosis was 21.4% in women allocated 10 years of tamoxifen and 25.1% in women allocated only five years (i.e., to stop at year 5; P=0.002).

Little effect was seen during years 5

VOGL, NY continued from page 1

The study is expected to be practice changing. to 10; the benefit was mainly seen after year 10.

The risk for death from breast cancer during the period five to 14 years after diagnosis was 12.2% in the women who received tamoxifen for 10 years compared with 15% in those who received tamoxifen for five years ((P =0.01).

Again, the greatest benefit was seen 10 to 14 years after diagnosis. Continuing tamoxifen increased the risk for

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

The study is expected to be practice changing. Maura Dickler, MD, an associate attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York City, said the study would change her practice. She will be prescribing tamoxifen for 10 years, “especially for our high-risk, lymph node–positive, premenopausal patients, who typically stop endocrine therapy after five years.”

The ATLAS results were simultaneously published in The Lancet (2012 Dec 5 [Epub ahead of print http://dx.doi. org/10.1016/S0140-6736(12)61963-1]).

—Kate O’Rourke Dr. Gray has no relevant disclosures.

Dr. Dickler has served as a consultant for Genentech.

EDITORIAL BOARD COMMENTARY

Table 1. ATLAS Trial: Effects of Prolonged Tamoxifen on Recurrence and Breast Cancer Death

ATLAS Trial Description ATLAS is an open-label, randomized trial of a second five years of tamoxifen that accrued 12,894 women in 36 countries between 1996 and 2006. Mean follow-up in ATLAS now is 7.6 years from randomization. In 2006, it closed early when the results of the MA.17 trial indicated that prolonged adjuvant therapy with letrozole (an oral aromatase inhibitor [AI]) was clearly effective in the estrogen receptor (ER)-positive patient population given after five years of tamoxifen, with a 48% overall relative reduction in disease recurrences.

The current report was generated when the data were analyzed for the planned Oxford meta-analysis of the benefits of prolonged endocrine therapy in women with known ER-positive tumors. In the entire ATLAS study, only 53% of tumors were known to be ERpositive, with 37% ER status unknown (mainly in Asia). Of those with ER-positive tumors analyzed in the current report, 50% of women were more than 55 years old, 54% were node-negative, 47% had <21 mm tumor diameters, only 15% entered before 2000, only 9% were

developing endometrial cancer. Because endometrial cancer is generally curable, the cu umulative risk for death from endom metrial cancer between five and 14 years after diagnosis was 0.4% compared with 0.2%.

According to Dr. Gray, combining results from previous trials comparing five years of tamoxifen versus none with results from the new trial of 10 years of tamoxifen shows that, in comparison with no tamoxifen, 10 years of the drug reduces breast cancer mortality by one-third during the first decade after diagnosis and by half during the second. Compliance with the random allocation in trials is suboptimal, so actual use of 10 years of tamoxifen could well have a somewhat greater effect.

Observation (%) Tamoxifen (%)

Rate Ratio

10-Year breast cancer recurrence

14.5

13.1

0.90 (years 6-10)

15-Year breast cancer recurrence

25.1

21.4

0.74 (years 11-15)

>15-Year breast cancer recurrence

0.85 (beyond year 15)

10-Year breast cancer death

6.0

5.8

0.97 (years 6-10)

15-Year breast cancer death

15.0

12.2

0.70 (years 11-15)

>15-Year breast cancer death

0.79 (beyond year 15)

ATLAS, Adjuvant Tamoxifen: Longer Against Shorter

still premenopausal when randomized, 32% had only four to 4.9 years of prior tamoxifen, 1% had prior local recurrence, and 2% had prior contralateral breast cancer.

For women with ER-positive tumors, the overall rate of recurrence in years 6-15 was reduced 16%, death rate from breast cancer (attributed locally without review) was reduced 17%, and overall death rate was reduced 12.5%. No benefit was noted for women with known ER-negative tumors. Benefits for those whose tumors’ ER status was unknown were intermediate between those noted for women with ER-positive tumors and the absent benefits for ER-negative tumors.

The authors noted that there was no detectable benefit from tamoxifen for patients during the five years of therapy (i.e., years 6-10), but that considerable benefit emerged later. They reanalyzed the data by five-year periods to make the benefits after year 10 appear

more impressive, since the first analysis suggested that the benefits changed with time, and since a statistical test for heterogeneity was positive (Table 1). This is reasonable and intelligent, but does not test their original hypothesis, and should be considered only an exploratory analysis.

Benefit of Letrozole Switch Huge Compared With Continued Tamoxifen: Letrozole has 48% drop in recurrence and 24% drop in death during years 6 to 10 Table 2 compares the results of 10 years of continued tamoxifen with the results of a switch to letrozole at the start of year 6, as done in MA.17. Letrozole is the obvious winner, although the results are somewhat complicated by the difficulty of correcting for partial crossover of placebo-assigned women to letrozole when the impressive MA.17 results were initially reported. Women

Steven Vogl, MD Medical Oncologist, New York City

who crossed over seemed to have their prognosis substantially improved.2 Thus, using the figures from the ATLAS trial report, of the 6,454 women who were assigned to prolonged tamoxifen, by year 10 letrozole would have prevented recurrence in 7% (449 women) and death by year 10 of at least 1.4% (93 women). We have no data on how the letrozole patients would do after year 10, but the 7% head start on fewer recurrences will presumably translate to many fewer deaths in years 11 to 15.

Minor Effects That Do Not Nullify The Major Conclusions Compliance is an issue for all prolonged hormonal therapies and their studies: By year 7, only 84% of women in ATLAS were still taking the tamoxifen to which they had been assigned, down to about 70% by year 9. Favoring a stronger effect of continued tamoxifen, if more of them had taken tamoxifen longer, fewer would have had disease recurrences and died. Favoring a stronger effect of letrozole after tamoxifen, lack of compliance probably similarly reduced the apparent efficacy of letrozole in MA.17. Making tamoxifen in ATLAS seem less effective than it really was, the control group of ATLAS had a 4% rate of non-protocol hormonal therapy at year 7 and a rate of about 6% at year 9, making the control group’s results seem a little better than

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Which Women Should Get Another Five Years of Tamoxifen?

The obvious superiority of the aromatase inhibitor switch means that every woman who is postmenopausal after five years of tamoxifen should get an AI for at least five years. they would have been if all the control patients had stayed off hormonal therapy.

The small numbers of enrolled women with prior local recurrence and contralateral primaries made the overall prognosis of women entered on ATLAS somewhat worse. While it is not usual to enter such women into adjuvant trials, their small number means that their adverse prognosis affects the overall results very little.

Which Women Are Not Candidates for an Extra Five Years of Tamoxifen?

The obvious superiority of the AI switch to continued tamoxifen (even though this has not been the subject of a prospective randomized trial) means that every woman who is postmenopausal after five years of tamoxifen should get an AI for at least five years.

Whether AI therapy should go longer is the subject of four studies yet to report results, although three have completed accrual. Of the women in the ATLAS trial, 90.5% were postmenopausal by the start of year 6. Thus, most women on the trial would best have been treated with an AI after the first five years of tamoxifen—hence the trial’s early closure to accrual.

This recommendation for AI switch after 5 years of tamoxifen includes women who were premenopausal at diagnosis who later became postmenopausal, according to a recently published analysis of MA.17.3 In this analysis by Paul Goss, MD, PhD, of Massachusetts General Hospital in Boston, the “switch” to letrozole in those women premenopausal at diagnosis produced a reduction in relapse rate of 74% compared to observation, while the reduction was only 33% for those post-menopausal at diagnosis.

Until the results of the RxPonder (SWOG S1007) trial become available (randomizing node-positive women with ER-positive tumors and lower Oncotype DX recurrence scores to observation versus chemotherapy), I believe the standard therapy for women with positive nodes and positive ER status in the primary breast cancer includes chemotherapy. The chemotherapy will render a large proportion of node-positive premenopausal women at diagnosis postmenopausal by the start of the sixth year, leaving very few for tamoxifen. Because younger women (<35 years) have a poorer prognosis by virtue of their age alone in many studies that correct for other prognostic

factors, many physicians offer these women fairly intensive chemotherapy even when nodes are negative, further reducing the pool of women still menstruating after five years of tamoxifen.

This leaves relatively few candidates for prolonged tamoxifen.

Women who are not candidates for an AI because they still have ovarian endocrine function and have sufficient remaining risk should receive tamoxifen. To help define the risk, the Austrian Breast Cancer Study Group (ABCSG) presented a gene expression assay called EndoPredict in San Antonio in 2012.4 The assay is suitable for use on formalin-fixed paraffin-embedded tumor tissue. This assay compares mRNA levels of three proliferation genes and five

estrogen receptor–dependent genes to mRNA levels of three reference genes (similar to the techniques used in the Oncotype DX). The proliferation genes drive the predictive value of the test during the first 5 years of endocrine therapy, and the estrogen receptordependent genes in the next five years.

Using clinical parameters of tumor size and number of involved nodes plus the EndoPredict score, 64% of women in a large validation cohort could be placed into a very low-risk group with almost no relapses after 5 years. If these results see VOGL, NY, Y page 8

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

oncologyfellowadvisor.com

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ONCOLOGYFellow

Vol. 3, Issue 3

S UPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS

oncologyfellowadvisor.com Fellowship Training

Paths

A DAY IN THE LIFE

We highlight the work of fellowship director Timothy Gilligan, MD. 4 FELLOWSHIP TRAINING

Experts discuss what to expect in 6 the first year of fellowship.

FELLOWSHIP TRAINING

Communication skills are crucial for oncology fellows.

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Mentor Memos

Survey Says

Physician Finance

Top-Tier Centerss Share Tips

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ospitals in the United States are anx xious to be included in the annual US News and World Rep port’s list of top hospitals. To make the 2011 to 2012 cut, cancer centers had to treat at least 254 inpatients with h highlevel expertise in 2007, 2008, and 2009 9.1 The following are the top 10 cancer centerss in US News and World Report, in ascending orrder of quality: University of Texas MD Anderson n Cancer Center, Memorial Sloan-Kettering Cancer Center (MSKCC), Johns Hopkins (JH), Mayo Clinic, Dana Farber Cancer Institute/Brig gham & Women’s Cancer Center, University of Washington Cancer Center in Seattle e, Massachusetts General Hospital, UCSF F Medical Center, Cleveland Clinic, and d Ronald Reagan UCLA Medical Center.1 Oncology Fellow Advisor spoke witth Daniel Spratt, radiation oncology trainee at Memorial Sloan-Kettering (No. 2 on the

Top-Tier page 5

Master Work–Life Balance

T

raining to be an oncologist can be rough. In the face of long hours, sleep deprivation, and patient suffering, young oncologists may sacrifice hobbies, interests, and even relationships. Many fellows find comfort in reminding themselves that better days are ahead but experts say that they may be setting themselves up for disappointment.

Oncologists who cope by looking to the future may miss opportunities in the present to shape their career to meet their needs.1 “Putting aside one’s personal needs or personal wellness can eventually come back in a negative

or unhealthy way that can lead to burnout,” said Charles M. Balch, MD, FACS, professor of surgery in the Division of Surgical Oncology at University of Texas Southwestern Medical School in Dallas, Texas. “A successful medical career at the expense of personal wellbeing is not at all successful.”

One in 3 oncologists will experience significant career burnout— described as emotional exhaustion, depersonalization, and a sense of low personal accomplishment that leads to decreased effectiveness at work.2 Some of its more tragic consequences see, Work–Life page 2

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

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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

The Gastric Cancers: Targeted for Personalized Medicine The blunt instrument of cancer chemotherapy, as wielded against gastric cancer, is likely to get considerably more precise and effective. There are many to thank for this development, not least of which are researchers at NewYork-Presbyterian Hospital, who have advanced our understanding of the family of oncologic disorders whose group name—gastric cancer—belies significant variability. The emerging understanding of gastric cancer as a group of subtypes whose susceptibility to chemotherapeutic intervention is not monolithic is set to have a significant effect on clinical drug trials and cancer therapy.

Additionally, a rising tide of research on biomarkers has begun to differentiate susceptibilities to chemotherapy.

Faculty Manish A. Shah, MD Director of Gastrointestinal Oncology Co-director of Research Center for Advanced Digestive Care NewYork-Presbyterian/Weill Cornell Medical Center Associate Professor of Medicine Weill Cornell Medical College New York, New York

Timothy C. Wang, MD Division Chief, Digestive and Liver Diseases NewYork-Presbyterian/Columbia University Medical Center Silverberg Professor of Medicine Columbia University College of Physicians and Surgeons New York, New York

Introduction The Lauren classification scheme,1 the nearly half century–old system that separates gastric adenocarcinomas into either intestinal or diffuse type based on histopathology, does not adequately reflect the latest understanding of gastric cancer.

Manish A. Shah, MD, Director of Gastrointestinal Oncology at NewYork-Presbyterian/Weill Cornell Medical Center, where he is also Co-director of Research at the Center for Advanced Digestive Care, noted that chemotherapy for gastric cancer has been poorly defined for decades. “Whether the patient had diffuse- or intestinal-type gastric cancer didn’t really matter too much in these studies; the patient would receive the chemotherapy that was available for gastric cancer as a whole.”

Dr. Shah, who is also Associate Professor of Medicine at Weill Cornell Medical College, added, “In clinical trials, a chemotherapy’s effectiveness was reported generally, not broken down into subtypes. The patients had stomach cancer, and this trial showed how well the chemotherapy worked against it. This is how research on gastric cancer has been performed for decades.”

Two major factors have converged to change this. First, there is a greater understanding of the varieties of gastric cancer that exist, as well as the factors that influence them.

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CLINICAL ONCOLOGY NEWS • JANUARY 2013

Mouse Models Timothy C. Wang, MD, Division Chief, Digestive and Liver Diseases, NewYork-Presbyterian/Columbia University Medical Center, who is the Silverberg Professor of Medicine at Columbia University College of Physicians and Surgeons, is a world leader in the creation of mouse models for gastric cancer. The mouse models from Dr. Wang’s laboratory help further understanding of how these cancers develop, including their genetic requisites. The mouse models are crucial because a fuller picture of how these gastric cancers develop will offer the opportunity to intervene at an earlier stage, or perhaps prevent the cancer entirely.

Dr. Wang has extensive experience with mouse models of Helicobacter felis and H. pylorii infection, and his lab was the first to fully describe a murine model of Helicobacterdependent gastric carcinogenesis.2 “What we have been doing over the past several decades is combining Helicobacterr infection with genetic modifications in transgenic mice that overexpress growth factors or cytokines, or with various diets, or with other types of infections. We are trying to determine what are the important cofactors that bring about the induction of stomach cancer. Only about 1% of individuals infected with Helicobacterr go on to develop stomach cancer, so why is that? We are researching genetically determined host factors that predispose to stomach cancer.”

Dr. Wang has found that certain coinfections can accelerate, whereas others can impede, the development of cancer.

Surprisingly, helminth worms slow gastric cancer in those infected with H. pylori,3 a fact that is likely reflected in the low prevalence of these cancers in low-lying, wet areas of Africa where the worm is common, despite the locally high rate of H. pylorii infection.

Dr. Wang has used his mouse models to confirm human observations. A report by El-Omar et al in Nature found that specific genetic polymorphisms in the gene for the cytokine interleukin-1beta (IL-1β) seemed to correlate with the susceptibility of gastric cancer in the presence of infection with H. pylori.4 Dr. Wang’s lab was able to overexpress IL-1β in the stomach of mice, which went on to spontaneously develop stomach cancer. When infected with H. felis, the mice developed stomach cancer very rapidly, suggesting that Helicobacterr infection together with high amounts of IL-1β create

an excellent environmental milieu in which stomach cancer develops. These findings validated the human observations of El-Omar et al.5 “What we have learned from our H. pylorii mouse models is that the particular type of immune response is what drives the development of cancer. But it is clear that other infectious agents or bacteria can modulate the response. In the gut there are trillions of bacteria—in fact, there are more bacteria in the gut of a mammal than there are cells in its body. For that reason this is a complicated question.”

Heterogeneity The more one explores the differences in gastric cancers, the more variations present themselves. Most obvious, perhaps, are the geographical differences in prevalence. In the United States, and in the developed West generally, proximal tumors, cancers of the gastroesophageal (GE) junction, distal esophagus, and cardia tumors are significantly more prevalent than in Korea, where middle and lower gastric cancers predominate.6 Staging at diagnosis differs, too, with earlier staging more likely in Korea, which enjoys higher overall survival. Gastric cancer is most common in China and Japan, where intestinal-type cancer predominates.

Epidemiologies vary. Cardia and GE junction cancers, more common in the industrialized West, are 5 times more likely in men than women and twice as likely in blacks than whites. Distal noncardia cancers are twice as likely in men than women and 4 times more likely in blacks than whites.

The main risk factors for gastric cancers are H. pylori, tobacco use, and genetic predisposition. But the relationships are not straightforward. “Stomach cancer is in part disappearing because of the decline in H. pylori, but there is a disconnect between its prevalence in some countries and the rate of cancer. For one thing, it seems that there are differences in bacteria strains, so researchers talk about the African, Asian, and European strains, for example,” Dr. Wang said. “Stomach cancer is most common per case of H. pylorii infection in Japan, so it might be that the Japan strain is the most virulent. There are regions in China and Korea that nearly match Japan in terms of virulence.” Diet may be another factor, although dietary studies have been difficult to replicate.

The role of H. pylorii varies among subtypes of gastric cancer. The pathogenesis of noncardia gastric cancer is initiated by chronic inflammation (eg, from H. pylori), progressing from chronic gastritis, intestinal metaplasia, to dysplasia.7-9 And yet the presence of H. pylorii gastritis may be protective against proximal adenocarcinomas.10,11 Thus, as H. pylori infection has decreased in the industrialized West, a “proximal shift” has been noted, with more proximal GE junction tumors, as well as esophageal cancers, occurring. “There is this idea that gastric cancers are decreasing when, in fact, if you look at individual subtypes, you see quite a lot of variation,” Dr. Shah said.

These geographic differences affect clinical trials. “If you look at a clinical trial done in Europe or North America, perhaps 25% of the patients with stomach cancer will have GE

Supported by

A

B

microtubules (the drug target) may be subtype-dependent (Figure). This finding is now being pursued in a prospective clinical trial in gastric cancer.

In the future, oncologists treating patients with gastric cancer will note the subtype of gastric cancer and treat accordingly, using a drug or drugs that are specifically effective for that group. “By doing this we will be able to increase survival for the whole group of gastric cancers,” Dr. Shah said. “It is still a very deadly disease. This type of research will improve patient outcomes.”

References 1. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma: an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31-49, PMID: 14320675.

2. Wang TC, Dangler CA, Chen D, et al. Synergistic interaction between hypergastrinemia and Helicobacterr infection in a mouse model of gastric cancer. Gastroenterology. 2000;118:36-47, PMID: 10611152.

3. Fox JG, Beck P, Dangler CA, Whary MT, Wang TC, Shi HN, Anderson CN. Concurrent enteric helminth infection modulates inflammation, gastric immune responses, and reduces Helicobacter-induced gastric atrophy.

Nat Med. 2000;6:536-542, PMID: 10802709.

Figure. Drug-target engagement in gastric cancer.

Intestinal-type (A) and diffuse-type (B) gastric cancer cell lines following treatment with docetaxel. Arrows (A) show presence of mitotic arrest, whereas B shows no abnormalities of the microtubule network.

junction tumors, maybe 30% will have diffuse cancers, and the rest will be intestinal antral tumors,” Dr. Shah explained.

“If you did the same clinical trial in Japan, 5% would have GE junction tumors, and the rest would be evenly split between diffuse and intestinal antral tumors.

“And the question is,” Dr. Shah added, “does that matter?”

Tomorrow’s Therapy Increasingly, as targeted pharmacologic intervention for gastric cancer is tested in clinical trials, the heterogeneity of gastric cancer will indeed matter. “There are many new drugs for gastric cancer being tested now or that will be soon,” Dr. Shah said. “There are MET inhibitors, antiangiogenic agents, EGFR [epidermal growth factor receptor] inhibitors, and others. The more targeted the drug and specific the effect, the greater the chance the drug is subtype-specific.”

Dr. Shah offered an example. “Trastuzumab (Herceptin, Genentech) is approved for HER2-positive gastric cancer, for instance, but diffuse gastric cancer is rarely HER2-positive, GE junction tumors are HER2-positive about 30% of the time, and distal intestinal gastric cancers are HER2-positive about 20% of the time. So the target differs among subtypes,” thereby demonstrating their relevance.

Dr. Shah and his colleagues participated in a trial of bevacizumab (Avastin, Genentech/Roche) when added to capecitabine plus cisplatin for first-line treatment of gastric cancer; the primary end point was overall survival.12 Results showed that bevacizumab, while increasing progressionfree survival and overall response rate, did not improve overall survival. A follow-up study evaluated the efficacy of bevacizumab using a comprehensive prospective biomarker analysis, and found that baseline plasma levels of vascular endothelial growth factor A (VEGF-A) and tumor expression of neuropilin-1 are candidate biomarkers of efficacy.13 It also was noted that plasma VEGF-A levels were predictive of efficacy in non-Asian patients.

In a separate study, Dr. Shah and his colleagues found that when bevacizumab was added to chemotherapy in patients with metastatic GE adenocarcinoma, intriguing differences according to gastric cancer subtype were revealed.14 The response rate was 85% in patients with proximal/GE junction tumors, 56% in patients with distal/intestinal tumors, and only 38% in patients with diffuse tumors. Dr. Shah and his colleagues are now examining the influence of gastric cancer subtype on taxane sensitivity, with preliminary data suggesting that the ability of the drug to engage with

4. El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404: 398-402, PMID: 10746728.

5. Tu S, Bhagat G, Cui G, Takaishi S, et al. Overexpression of interleukin1beta induces gastric inflammation and cancer and mobilizes myeloidderived suppressor cells in mice. Cancer Cell. 2008;14:408-419, PMID: 18977329.

6. Strong VE, Song KY, Park CH, et al. Comparison of gastric cancer survival following R0 resection in the United States and Korea using an internationally validated nomogram. Ann Surg. 2010;251:640-646, PMID: 20224369.

7. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylorii infection and the development of gastric cancer. N Engl J Med. 2001;345:784-789, PMID: 11556297.

8. Correa P, Shiao YH. Phenotypic and genotypic events in gastric carcinogenesis. Cancer Res. 1994;54(suppl):1941s-1943s, PMID: 8137316.

9. Shah MA, Ajani JA. Gastric cancer—an enigmatic and heterogeneous disease. JAMA. 2010;303:1753-1754, PMID: 20442394.

10. Kamangar F, Dawsey SM, Blaser MJ, et al. Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter Pylori seropositivity. J Natl Cancer Inst. 2006;98:1445-1452, PMID: 17047193.

11. Abbrederis K, Bassermann F, Schuhmacher C, et al. Erythropoietin-alfa during neoadjuvant chemotherapy for locally advanced esophagogastric adenocarcinoma. Ann Thorac Surg. 2006;82:293-297, PMID: 16798232.

12. Ohtsu A, Shah M, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol.

2011;29:3968-3976, PMID: 21844504.

13. Van Cutsem E, de Haas S, Kang Y-K, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial.

J Clin Oncol. 2012;30:2119-2127, PMID: 22565005.

14. Shah MA, Jhawer M, Ilson DH, et al. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011;29:868-874, PMID: 21189380.

Disclosures: Dr. Shah reported that he has received research funding from Genentech and Sanofi. Dr. Wang reported no relevant disclosures.

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, NewYork-Presbyterian Hospital, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

BB132

Copyright © 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

CLINICAL ONCOLOGY NEWS • JANUARY 2013

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CLINICAL ONCOLOGY NEWS • JANUARY 2013

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are validated, then the EndoPredict score would help spare many women long years of therapy they do not need.

Women considered for a second 5 years of tamoxifen also should not desire pregnancy, since tamoxifen is not established as safe for the embryo and fetus, and they should have tolerated the five years of treatment well.

The ATLAS analysis makes much of the benefits of the first five years of tamoxifen after it is stopped.

Alternative therapies for these women include ovarian suppression and an AI plus ovarian suppression, neither of which has been adequately studied in this setting. Of note is the slightly inferior activity, especially in more obese women, of anastrozole plus ovarian suppression compared with tamoxifen plus ovarian suppression in the ABCSG–12 trial that also looked at adjuvant zoledronic acid.5 Tamoxifen for the second five years is a reasonable alternative for women who cannot tolerate any of the available AIs, although the benefits seem to be much less. The ATLAS trial demonstrates the safety of continued tamoxifen, with an excess incidence of endometrial cancer of only 1.74%, and only an 0.2% increased mortality from endometrial cancer to year 15. Almost none of this risk is for premenopausal women, who

constitute the vast majority of patients who should consider prolonged tamoxifen based on currently available data.

Table 2. Prolonged Tamoxifen Versus Switch to Letrozole: ATLAS Versus MA.171

What Is the Nature of the Tamoxifen “Carry-Over” Effect?

The ATLAS analysis makes much of the benefits of the first five years of tamoxifen after it is stopped. The risk per year for relapse in years 6 to 10 after five years of tamoxifen is 69% of the risk after five years of placebo. The mechanism of this effect is unclear: Perhaps an active metabolite is slowly released from pools in body fat, or perhaps there is an endocrine effect on prolonging tumor dormancy that persists beyond administration of the drug.

The point should be made, contrary to the ATLAS analysis, that the continued benefit from the first five years of tamoxifen does not preclude further benefit from hormonal therapy, since this is clearly evident in MA.17 and other AI crossover trials. It was also evident in trials of continued tamoxifen beyond one and two years of therapy, in which two and five years of tamoxifen produced immediate reductions in relapse rates.

Where Do We Go From Here?

The time beyond 10 years from diagnosis is now open for therapeutic intervention, since ATLAS showed a substantial benefit. The TAM-02 trial from France showed that delayed adjuvant tamoxifen (median of five years from diagnosis) improves disease-free and overall survival in ER-positive populations who were naive to both tamoxifen and AIs.6 This was a study of delayed tamoxifen in women who should have started earlier, but, for some reason, did not. It makes sense to study tamoxifen

Rate Ratio: Tamoxifen

Rate Ratio: Letrozole

10-Year breast cancer recurrence (years 6-10)

0.90

0.52

10-Year breast cancer distant recurrence (years 6-10)

0.90

0.51

10-Year death from any cause (years 6-10)

0.871

0.76

ATLAS, Adjuvant Tamoxifen Longer Against Shorter 1. Figure for total death rate reduction with median follow-up of 12.6 years.

after an AI, the latter given for five years either as primary hormonal therapy or after a switch from five years of tamoxifen. Shorter versions of this switch to tamoxifen were as good as continued letrozole in BIG 1-98.

Should Any Woman Get Tamoxifen Now in Years 11 to 15?

Absent any clinical trial results, I would only consider very late tamoxifen for women with ER-positive tumors at very high risk (many positive nodes) who desire the most aggressive therapeutic posture—those who want “everything done”—and who have finished five years of an AI or cannot tolerate additional AI therapy. One would hope that the switch back to tamoxifen after an AI in years 6 to 10 and tamoxifen in years 1 to 5 would yield immediate benefits, unlike the much-delayed benefits seen in the ATLAS trial. We have no data in hand to support this hypothesis.

References 1. Davies C, Pan H, Godwin J, et al. Longterm effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years

after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2012 Dec 4. pii: S01406736(12)61963-1, PMID: 23219286.

2. Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012;30:718-721, PMID: 22042967.

3. Goss PE, Ingle JN, Martino S, et al. Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann Oncol.

2012 Oct 1. [Epub ahead of print], PMID: 23028039.

4. Dubsky P, Brase JC, Fisch K, et al. The EndoPredict score identifies late distant metastases in ER+/HER2– breast cancer patients. Cancer Res. 2012;72(24 Suppl):Abstract nr S4-3.

5. Pfeiler G, Königsberg R, Fesl C, et al.

Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol. 2011;29:2653-2659, PMID: 21555684.

6. Delozier T, Switsers O, Génot JY, et al.

Delayed adjuvant tamoxifen: ten-year results of a collaborative randomized controlled trial in early breast cancer (TAM-02 trial). Ann Oncol. 2000;11:515-519, PMID: 10907942.

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Independent News for the Oncologist and Hematologist/Oncologist

Consider starting your new patients on ZOMETA today, as they may be able to continue on generic zoledronic acid after the ZOMETA patent expires in March 2013

Indication ZOMETA® (zoledronic acid) 4 mg/5 mL Injection is indicated for the treatment of hypercalcemia of malignancy (HCM) and patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Safe and efficacious use of ZOMETA has not been established for use in hyperparathyroidism or non-tumor-related hypercalcemia.

Highlights from the Important Safety Information • There have been reports of renal toxicity with ZOMETA. Renal toxicity may be greater in patients with renal impairment. Treatment in patients with severe renal impairment is not recommended. Do not use doses greater than 4 mg and monitor serum creatinine before each dose • Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient • Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including ZOMETA. Patients may experience hip, thigh, or groin pain before presenting with a completed femoral fracture. Causality with bisphosphonates has not been established Please see additional Important Safety Information and brief summary of full Prescribing Information on adjacent pages.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2012 Novartis

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ZOM-1052241

Indication • ZOMETA (zoledronic acid) 4 mg/5 mL Injection is indicated for the treatment of hypercalcemia of malignancy (HCM) and patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Safe and effi ficacious use of ZOMETA has not been established for use in hyperparathyroidism or non-tumorrelated hypercalcemia. ®

Important Safety Information • ZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported. Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient.

• Patients with HCM must be adequately rehydrated prior to use of ZOMETA and loop diuretics (if applicable). Loop diuretics should be used with caution in combination with ZOMETA to avoid hypocalcemia. ZOMETA should be used with caution with other nephrotoxic drugs. Carefully monitor serum calcium, phosphate, magnesium, and serum creatinine following initiation of ZOMETA. Short-term supplemental therapy may be necessary.

• In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. Consider individual patient risk/benefit fi profi file before starting ZOMETA therapy in HCM patients with severe renal impairment. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment.

Preexisting renal insufficiency fi and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose.

• Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fi fitting dentures). Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible, as recovery may be prolonged. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefi fit/risk assessment.

• ZOMETA should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant or plans to breastfeed while taking this drug, the patient should be apprised of the potential harm to the fetus or baby.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

• In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including ZOMETA. Discontinue use if severe symptoms develop, as a subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. There have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates.

• Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including ZOMETA. These fractures may occur with minimal or no trauma. A number of case reports noted that patients were also receiving treatment with glucocorticoids at time of fracture.

Causality with bisphosphonates has not been established. Any patient with a history of bisphosphonate exposure who presents with hip, thigh, or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated.

Drug discontinuation in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit/risk fi assessment.

• Insufficient fi data exist on how to safely use ZOMETA in HCM patients with hepatic impairment.

• Acute-phase reaction symptoms can occur in HCM patients, with fever most commonly reported (44% with ZOMETA vs. 33% with pamidronate). Patients may occasionally experience fl flu-like syndrome (fever, chills, flushing, bone pain and/or arthralgias and myalgias). The most common adverse events (≥10%) in HCM clinical trials, regardless of causality, with ZOMETA 4 mg (n=86) were as follows: fever (44%), nausea (29%), constipation (27%), anemia (22%), dyspnea (22%), diarrhea (17%), abdominal pain (16%), progression of cancer (16%), insomnia (15%), vomiting (14%), anxiety (14%), urinary tract infection (14%), hypophosphatemia (13%), confusion (13%), agitation (13%), moniliasis (12%), hypokalemia (12%), coughing (12%), skeletal pain (12%), hypotension (11%), and hypomagnesemia (11%). In controlled HCM clinical trials, adverse events (5-10% frequency) occurring in greater incidence with ZOMETA than pamidronate include: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, non-specific fi infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Injection site reactions (redness, swelling) have been infrequently reported.

• The most common adverse events (≥15%) in bone metastases clinical trials, regardless of causality, with ZOMETA 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lower-limb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%), and paresthesia (15%). Patients should also be made aware of the potential for abdominal pain.

• Ocular adverse events may occur with bisphosphonates, including ZOMETA. Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation fl including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

• Caution is advised when bisphosphonates, including ZOMETA, are administered with aminoglycosides, loop diuretics, and potentially nephrotoxic drugs.

• Patients with multiple myeloma and bone metastases due to solid tumors should be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.

Please see brief summary of full Prescribing Information on adjacent pages.

© 2012 Novartis

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ZOM-1052241

Zometa® (zoledronic acid) Injection Ready-to-Use Solution for Intravenous Infusion (For Single Use) Concentrate for Intravenous Infusion Initial U.S. Approval: 2001 BRIEF SUMMARY: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin (g/dL)).

1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established.

4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2))].

5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient or in the Same Drug Class Zometa contains the same active ingredient as found in Reclast® (zoledronic acid).

Patients being treated with Zometa should not be treated with Reclast or other bisphosphonates.

5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs.

Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary.

5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1))]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa.

Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible.

Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine greater than 400 μmol/L or greater than 4.5 mg/dL were excluded.

Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine greater than 265 μmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information].

5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis.

Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment

reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2))].

5.5 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2))].

5.6 Atypical subtrochanteric and diaphyseal femoral fractures Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Zometa. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma.

Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of Zometa therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.

5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates.

5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients.

5.9 Use in Pregnancy Bisphosphonates, such as Zometa, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy.

Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1))].

6 ADVERSE REACTIONS 6.1 Clinical Studies 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.

Hypercalcemia yp of Malignancy g y The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.

Renal Toxicityy Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information].

The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 4).

Table 4 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials.

Adverse events are listed regardless of presumed causality to study drug.

Table 4: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

Patients Studied Total No. of Patients Studied Total No. of Patients with any AE Body as a Whole Fever Progression of Cancer Cardiovascular Hypotension Digestive Nausea Constipation Diarrhea Abdominal Pain Vomiting Anorexia Hemic and Lymphatic System Anemia Infections Moniliasis Laboratory Abnormalities Hypophosphatemia Hypokalemia Hypomagnesemia Musculoskeletal Skeletal Pain Nervous Insomnia Anxiety Confusion Agitation Respiratory Dyspnea Coughing Urogenital Urinary Tract Infection

Grade 4 Laboratory Parameter

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

86 (100) 81 (94)

103 (100) 95 (92)

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

0/86 0/86 1/70 0/71

— — (1%) —

1/100 0/100 4/81 1/84

(1%) — (5%) (1%)

1Grade

3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) 2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L)

38 14

(44) (16)

34 21

(33) (20)

9

(11)

2

(2)

25 23 15 14 12 8

(29) (27) (17) (16) (14) (9)

28 13 17 13 17 14

(27) (13) (17) (13) (17) (14)

19

(22)

18

(18)

10

(12)

4

(4)

11 10 9

(13) (12) (11)

2 16 5

(2) (16) (5)

10

(12)

10

(10)

13 12 11 11

(15) (14) (13) (13)

10 8 13 8

(10) (8) (13) (8)

19 10

(22) (12)

20 12

(19) (12)

Table 7: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System

12

(14)

15

(15)

Zometa 4 mg n (%)

The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence.

Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa.

Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias.

Mineral and Electrolyte y Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use.

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 5 and 6.

Table 5: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Table 6: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

2/86 1/86 36/70 0/71

(2%) (1%) (51%) —

3/100 2/100 27/81 0/84

(3%) (2%) (33%) —

Injection j Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.

Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2))].

Multiple p Myeloma y and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors.

Table 7 describes adverse events that were reported by 10% or more of patients.

Adverse events are listed regardless of presumed causality to study drug.

Patients Studied Total No. of Patients 1031 (100) Total No. of Patients with any AE 1015 (98) Blood and Lymphatic Anemia 344 (33) Neutropenia 124 (12) Thrombocytopenia 102 (10) Gastrointestinal Nausea 476 (46) Vomiting 333 (32) Constipation 320 (31) Diarrhea 249 (24) Abdominal Pain 143 (14) Dyspepsia 105 (10) Stomatitis 86 (8) Sore Throat 82 (8) General Disorders and Administration Site Fatigue 398 (39) Pyrexia 328 (32) Weakness 252 (24) Edema Lower Limb 215 (21) Rigors 112 (11) Infections Urinary Tract Infection 124 (12) Upper Respiratory Tract Infection 101 (10) Metabolism Anorexia 231 (22) Weight Decreased 164 (16) Dehydration 145 (14) Appetite Decreased 130 (13)

Pamidronate 90 mg n (%)

Placebo

556 (100) 548 (99)

455 (100) 445 (98)

175 83 53

(32) (15) (10)

128 35 20

(28) (8) (4)

266 183 162 162 81 74 65 61

(48) (33) (29) (29) (15) (13) (12) (11)

171 122 174 83 48 31 14 17

(38) (27) (38) (18) (11) (7) (3) (4)

240 172 108 126 62

(43) (31) (19) (23) (11)

130 89 114 84 28

(29) (20) (25) (19) (6)

50 82

(9) (15)

41 30

(9) (7)

81 50 60 48

(15) (9) (11) (9)

n (%)

105 (23) 61 (13) 59 (13) 45 (10) (continued)

Table 7: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%) Musculoskeletal Bone Pain Myalgia Arthralgia Back Pain Pain in Limb Neoplasms Malignant Neoplasm Aggravated Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia Psychiatric Depression Anxiety Confusion Respiratory Dyspnea Cough Skin Alopecia Dermatitis

Pamidronate 90 mg n (%)

Placebo n (%)

569 239 216 156 143

(55) (23) (21) (15) (14)

316 143 131 106 84

(57) (26) (24) (19) (15)

284 74 73 40 52

(62) (16) (16) (9) (11)

205

(20)

97

(17)

89

(20)

191 180 166 149 127

(19) (18) (16) (15) (12)

149 91 111 85 65

(27) (16) (20) (15) (12)

50 58 73 35 43

(11) (13) (16) (8) (10)

146 112 74

(14) (11) (7)

95 73 39

(17) (13) (7)

49 37 47

(11) (8) (10)

282 224

(27) (22)

155 129

(28) (23)

107 65

(24) (14)

125 114

(12) (11)

80 74

(14) (13)

36 38

(8) (8)

Table 8: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Zometa 4 mg n/N

(%)

7/529 (1%) 6/973 (<1%) 115/973 (12%) 19/971 (2%) 1/971 (<1%)

Pamidronate 90 mg n/N

(%)

4/268 (2%) 4/536 (<1%) 38/537 (7%) 2/535 (<1%) 0/535 —

Placebo n/N

(%)

4/241 (2%) 0/415 — 14/415 (3%) 8/415 (2%) 1/415 (<1%)

1Grade

3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) 5Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L) Table 9: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 4 Laboratory Parameter

Creatinine1*

Serum Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5 1Grade

Renal Toxicityy In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (less than 1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (greater than or equal to 1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 10).

Table 10: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer Normal Abnormal Total

Zometa 4 mg

Pamidronate 90 mg

Normal Abnormal Total Prostate Cancer Normal Abnormal Total

Grade 3

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear.

Solid Tumors

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 8 and 9.

Laboratory Parameter

Among the less frequently occurring adverse events (less than 15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group.

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

2/529 7/973 5/973 0/971 2/971

(<1%) (<1%) (<1%) — (<1%)

1/268 3/536 0/537 0/535 1/535

(<1%) (<1%) — — (<1%)

0/241 2/415 1/415 2/415 0/415

— (<1%) (<1%) (<1%) —

3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) 5Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

27/246 2/26 29/272

(11%) (8%) (11%)

23/246 2/22 25/268

(9%) (9%) (9%)

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

17/154 1/11 18/165

(11%) (9%) (11%)

10/143 1/20 11/163

(7%) (5%) (7%)

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

12/82 4/10 16/92

(15%) (40%) (17%)

8/68 2/10 10/78

(12%) (20%) (13%)

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes.

The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate.

In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose.

6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa.

Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5))].

Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5))].

Atypical yp subtrochanteric and diaphyseal p y femoral fractures Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including Zometa [see Warnings and Precautions (5.6))].

Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Hypersensitivity yp y Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported.

Additional adverse reactions reported in postmarketing use include: CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: Increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia.

7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug.

7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials.

7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia.

7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs.

7.4 Thalidomide No dose adjustment for Zometa 4 mg is needed when co-administered with thalidomide.

In a pharmacokinetic study of 24 patients with multiple myeloma, Zometa 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of thalidomide with Zometa did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precaution (5.9)] There are no adequate and well-controlled studies of Zometa in pregnant women.

Zometa may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as Zometa, are incorporated into the bone matrix and are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. If this drug is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus.

In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect.

In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study.

In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were

observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.

8.3 Nursing Mothers It is not known whether zoledronic acid is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zometa, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Zoledronic acid binds to bone long term and may be released over weeks to years.

8.4 Pediatric Use Zometa is not indicated for use in children.

The safety and effectiveness of zoledronic acid was studied in a one-year activecontrolled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7).

At one year, increases in BMD were observed in the zoledronic acid treatment group.

However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk.

Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC((0-last)) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose.

8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.

10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose.

A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known.

In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information].

16 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Manufactured by Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2012-66 March 2012

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Expert Insights From The US Oncology Network

Adjuvant Therapy Fails for High-Risk Soft Tissue Sarcoma From Lancet Oncology

A

recent Phase III trial has concluded that adjuvant therapy with doxorubicin and ifosfamide yields no benefit in relapse-free (RFS) or overall survival (OS) in patients with highrisk soft tissue sarcomas (STS) who have undergone resection. Results were published in the October issue of Lancet Oncology (2012;13:1045-1054, PMID: 22954508).

The multicenter, European-based trial randomized 351 patients with macroscopically resected (within four weeks of surgery) Trojani grade II or III STS

who had no metastases and a performance status lower than 2—a patient group at higher risk for relapse and, perhaps as a result, more in need of some form of adjuvant chemotherapy. All of the enrolled patients in the study (European Organisation for Research and Treatment of Cancer [EORTC] 62931) were between 16 and 70 years of age.

Randomization was stratified by hospital, site of primary tumor, tumor size, planned radiotherapy and isolated limb perfusion therapy. The patients were randomly assigned to receive adjuvant chemotherapy (n=175) with five cycles of doxorubicin 75 mg/m2, ifosfamide

EXPERT INSIGHT Alex Spira, MD, PhD Medical Oncologist and Hematologist, Virginia Cancer Specialists Director, Virginia Cancer Specialists Clinical Research Program, US Oncology Network

S

TS are one of the notoriously difficult malignancies to study due to their heterogeneity and rarity. In this study, Woll et al from the EORTC found no benefit to adjuvant chemotherapy (five cycles of ifosfamide and doxorubicin) given to patients with resected Trojani grade II-III STS. Due to the rarity of these tumors, studies regarding adjuvant therapy have been difficult to accrue to and analyze. The largest meta-analysis, which was reported in 1997, did demonstrate that adjuvant chemotherapy had a survival benefit,1 but this analysis was limited by the relatively poor quality of many of the included studies and their heterogeneity and small size. One other large trial using adjuvant “modern” STS chemotherapy did initially show a survival benefit that did not hold up to rigorous analysis at four years, although the proverbial subgroup “analysis” did show a benefit.2,3 Inherent in all of these studies is the difficulty in studying rare, heterogeneous malignancies. Sarcomas are notoriously large at presentation; patients can routinely present with a

15- to 20-cm mass in their leg, whereas breast medical oncologists remark that a 3- to 4-cm tumor is huge. It took eight years (1995-2003) to accrue this European cooperative group study of 351 patients over 36 sites. The difficulty in making an accurate pathologic diagnosis also is noted in this study; in fact, 6% of patients had low-grade tumors that were ineligible for the study; there was about an 11% discordance rate between local and central review of tumors classified as undifferentiated pleomorphic sarcoma; another 1% were ineligible as gastrointestinal stromal tumors or non-sarcomas. Although not all of these differences would be expected to affect study outcomes, a nearly 20% misclassification rate in lung or breast cancer adjuvant studies would be laughed at, whereas in sarcomas it is expected.

Practically, based on risk for relapse, the two most important factors are grade and size. In terms of recommending adjuvant chemotherapy, most physicians focus on those tumors that are greater than 10 cm or are grade III. There was a nonstatistically

5 g/m2 and lenograstim (Granocyte, Hospira) every three weeks, or no chemotherapy (n=176; control group). In all, 258 patients (129 in each group) with recurrent tumors or marginal resection received radiotherapy.

OS, the trial’s primary end point, did not differ significantly between the two groups ((P=0.72). Median OS was 11.2 years for the chemotherapy group and 12.4 years for the control group. The five-year OS rate was 66.5% in the chemotherapy group and 67.8% in the control group. Moreover, RFS did not differ between the two arms (median 7.55 years for the chemotherapy group and

6.50 years for the control group; P=0.51).

The five-year RFS rate was 54.9% for the chemotherapy group and 52.9% for the control group. The authors noted that patients who underwent isolated limb perfusion therapy “tended to have better relapse-free and overall survival”; however, the number of patients in this subgroup (14) was “too low to draw any conclusions.”

On the positive side, chemotherapy was well tolerated. In all, 130 of 163 patients who started the regimen completed all five cycles. Only 16 had grade 3/4 fever or infection, and there were no deaths due to toxic effects.

This is a negative study, but given the limitations and the general feeling of sarcoma medical oncologists, most of us still will likely recommend adjuvant therapy to those patients with large, high-grade tumors. significant trend toward benefit in these patients in the study by Woll et al, but the numbers of these patients were simply too small to have a statistically significant benefit. Inherent in treating patients with sarcomas is not having clinicians even agree on the doses to use. This study used the “European style” of 5 g/m2 of ifosfamide given over 24 hours one day every three weeks (with a standard dose of doxorubicin). There clearly is a dose response of ifosfamide in sarcomas (as well as some advantages of bolus dosing typically given in the United States over continuous infusion dosing), with most U.S. oncologists giving 10 g/m2 bolus dosing over four days for young, healthy patients.

In most oncology patients, one can get cyclophosphamide-doxorubicin or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) anywhere in the world the same way, but in STS, there still is no standard method of administration.

That being said, this is a negative study, but given the limitations and the general feeling of sarcoma medical oncologists, most of us still will

likely recommend adjuvant therapy to those patients with large, high-grade tumors, after a careful discussion with our patients. Clearly, we must try to do better and get beyond looking at simple adjuvant studies. We must focus more on molecular typing of these tumors to better characterize and study them, as well as develop new drugs that would make studying adjuvant anthracycline and ifosfamide for the umpteenth time a distant (bad) memory.

References 1. Sarcoma Meta-analysis Collaboration.

Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet.

1997;350:1647-1654, PMID: 9400508.

2. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol.

2001;19:1238-1247, PMID: 11230464.

3. Frustaci S, De Paoli A, Bidoli E, et al.

Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology. 2003;65(suppl 2):80-84, PMID: 14586155.

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

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REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Bruton TKI Ibrutinib Shows Activity in B-Cell Malignancies From the Journal of Clinical Oncology

A

Phase I open-label, dose-escalation trial designed to determine the dose, safety profile, pharmacokinetics, pharmacodynamics and antitumor effects of ibrutinib (PCI-32765, Pharmacyclics)—a novel, small-molecule, irreversible inhibitor of Bruton tyrosine kinase (BTK)—has concluded that the drug appears to be well tolerated and demonstrates significant activity across B-cell malignancies, including non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).

Ibrutinib is already showing promising results in Phase II trials, and Phase III trials are under way.

The study, headed by Ranjana Advani, MD, and published online in the Journal of Clinical Oncologyy (2012 Oct 22. [Epub ahead of print], PMID: 23045577), assessed 56 patients with relapsed or refractory B-cell lymphoma, CLL or Waldenstrom macroglobulinemia (over seven cohorts) who had failed at least one previous therapy. Each patient received escalating oral doses of ibrutinib on two different schedules: 1.25, 2.5, 5, 8.3 or 12.5 mg/kg per day on a 28 days

EXPERT INSIGHT Jeff Sharman, MD Medical Oncologist, Willamette Valley Cancer Institute and Research Center Member, The US Oncology Network Hematologic Malignancies Research Committee

I

n contrast to chronic myelogenous leukemia, where pathogenesis is driven by the abnormal BCR-Abl protein, B-cell neoplasms lack a singular abnormality responsible for the disease, in most cases. CLL has a comparatively simple genome with few mutations present early in the disease. Most B-cell lymphomas also lack pathognomonicdriving mutations appropriate for therapeutic intervention.

Instead of driving mutations, CLL and several NHLs appear to be driven in part by abnormal B-cell receptor (BCR) pathway activation. (Note: BCR can mean either breakpoint cluster region or B-cell receptor, which are distinct from one another). The etiology of this stimulus varies across different malignancies but actual mutations account for only some cases.

The BCR signaling pathway is central

to B-cell survival. In laboratory conditions where B-cell signaling could be genetically eliminated, B cells disappeared.1 Pharmacologic intervention in downstream signaling pathway proteins intuitively followed, and inhibition of the proximal signaling enzyme spleen tyrosine kinase (Syk) by fostamatinib was initially proposed in only 2007.2 Since that time, numerous clinical investigations have validated the importance of inhibition of BCR signaling. After Syk activation, BTK propagates the signal leading to downstream activation of phosphoinositide-3 kinase. These latter two proteins are inhibited by ibrutinib and CAL-101 (subsequently GS-1101, now idelalisib), respectively. Following the initial clinical reports of fostamatinib activity,3 the present paper by Advani et al represents the first published report of

on, 7 days off schedule (five cohorts) or continuous daily dosing of 8.3 mg/ kg or 560 mg (two cohorts). The dose escalation proceeded until either the maximum tolerated dose was achieved or until therapy was three dose levels above full BTK occupancy by ibrutinib (occupancy was monitored using a fluorescent affinity probe). Patients were administered therapy until disease progression, unacceptable toxicity, or patient or investigator decision to end therapy.

After a median of five cycles of therapy, most of the adverse events observed

were grade 1 or 2 in severity; only two dose-limiting toxicities occurred and the maximum tolerated dose was not reached. The authors reported that full occupancy of the BTK active site occurred at a dose of 2.5 mg/kg per day.

Pharmacokinetic data indicated rapid absorption and elimination of the study drug; however, BTK occupancy was maintained for at least 24 hours.

The objective response rate with ibrutinib therapy (in 50 evaluable patients) was 60% and the complete response rate was 16%. Median progression-free survival in all patients was 13.6 months.

These drugs will alter the clinical management landscape of patients with B-cell malignancies in the near future and practicing clinicians will need to be aware of this emerging class of therapies. the clinical activity of ibrutinib.

In CLL, virtually all patients experience a rapid reduction in lymph node size and disease-related cytokines concurrently with a rapid rise in white blood cells (WBCs) as cells redistribute from their protective niches in nodes and marrow into the circulation.

Over time, WBCs fall, nodes remain reduced, and improvement in marrow function is common, even in highrisk refractory disease. Different NHLs have been observed to respond as well.

Some cases of diffuse large B-cell lymphomas may respond in dramatic fashion, although prospective identification of these patients is an area of intense interest. Patients with mantle cell lymphoma have enjoyed durable disease control with ibrutinib. Follicular lymphoma appears to respond to both ibrutinib and idelalisib, yet the clinical significance in this more indolent population requires further study.

Investigators and patients alike are

excited because these oral drugs provide unique activity while being well tolerated in most cases. These drugs will alter the clinical management landscape of patients with B-cell malignancies in the near future and practicing clinicians will need to be aware of this emerging class of therapies.

References 1. Kraus M, Alimzhanov M, Rajewski N, et al.

Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/ beta heterodimer. Cell. 2004;117:787-800, PMID: 15186779.

2. Sharman J, Irish J, Coffee G. Targeting syk kinase for the treatment of b-cell lymphoma. J Clin Oncol. 2007;25(18s):Abstract 3600.

3. Friedberg J, Sharman J, Sweetenham J. Inhibition of Syk with fostamatinib disodium has significant clinical activity in nonHodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115:2578-2585, PMID: 19965662.

Dr. Sharman reported no relevant financial disclosures.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Vitamin D Metabolite Has Role in Bladder Cancer Pathogenesis From the Journal of the National Cancer Institute

A

team of researchers has, for the first time, identified a potential role for 25-hydroxyvitamin D3 (25[OH]D3), an active vitamin D metabolite, in the pathogenesis of urothelial bladder cancer (UBC). A summary of findings from the Spanish researchers was published online in October by the Journal of the National Cancer Institute (JNCI ( I; 2012 Oct 29. [Epub ahead of print], PMID: 23108201).

Previous studies have demonstrated

that vitamin D insufficiency, or low levels of 25(OH)D3, is associated with an increased risk for breast and colorectal cancers; however, the role of vitamin D in bladder cancers has remained undefined. The JNCII study, which was funded in part by the World Cancer Research Fund, was therefore designed to assess the degree of association between 25(OH)D3 plasma levels and overall risk for UBC, according to stage and FGFR3 molecular subphenotypes. Earlier research had shown that, in vitro, FGFR3 expression in UBC cell lines with low levels of wild-type FGFR3 is

EXPERT INSIGHT Lina Asmar, PhD Director of Biostatistics & Medical Writing, US Oncology Network Research

T

he most common risk factors for UBC are smoking, occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons, and high levels of arsenic intake. Recently, increasing evidence suggests a significant influence of genetic predisposition on incidence. 1α,25(OH)2D3 is a vitamin D metabolite and can regulate proliferation, apoptosis and cell adhesion at the tumor cell level. Epidemiologic studies show that vitamin D insufficiency is associated with an increased risk for colorectal and breast

cancers, but little is known about the contribution of vitamin D to UBC. Amaral et al assessed the association between plasma 25(OH)D3 levels and risk for UBC in the Spanish Bladder Cancer/EPICURO study, and explored the molecular mechanisms involved with experimental procedures in vitro. They analyzed the association of plasma 25(OH)D3 levels with different UBC tumor invasiveness and grades and FGFR3 mutational and expression status.

Their results showed that the lowest

upregulated by 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3).

The researchers analyzed the 25(OH)D3 plasma concentrations in 1,125 patients with UBC and 1,028 control subjects using chemiluminescence immunoassay. Participants also were stratified by tumor invasiveness and grade, FGFR3 expression and smoking status.

The researchers found a statistically significantly increased risk for UBC among participants presenting the lowest concentrations of 25(OH) D3 (adjusted odds ratio [OR], 1.83;

P=0.006). The association was stronger for patients with muscle-invasive tumors, especially among lowFGFR3 expressers (adjusted OR, 5.94; P=0.005), meaning that individuals with low levels of plasma 25(OH)D3 are potentially at higher risk for more aggressive forms of the cancer. These findings are particularly relevant in Spain, according to the authors of the JNCII study, because incidence rates of UBC there are among the highest in the world and the prevalence of vitamin D deficiency and insufficiency within the country are well documented.

concentration of 25(OH)D3 was statistically significantly associated with the increased risk for UBS (adjusted OR, 1.83; P<0.01) among cases and controls. A dose–response effect also was observed in their study, and an adjusted odds ratio of 5.94 ((P<0.01) was observed

deficiency and insufficiency of vitamin D in the population may be associated with the development of UBC, and 25(OH)D3 levels are associated with FGFR3 expression in the tumor.

These findings also suggest that levels of plasma 25(OH)D3 may poten-

Their findings indicate that the deficiency and insufficiency of vitamin D in the population may be associated with the development of UBC, and 25(OH)D3 levels are associated with FGFR3 expression in the tumor. for patients with muscle-invasive tumors with low-FGFR3 expressers.

Their findings also were supported by the experimental results in vitro that FGFR3 expression was upregulated by 1α,25(OH)D3 in UBC cell lines with low levels of the wild-type FGFR3 gene.

Their findings indicate that the

tially be able, as biomarkers, to predict an individual’s UBC risks and aggressive forms of UBC, but this needs to be replicated in different populations in future studies.

Dr. Asmar reported no relevant financial disclosures.

Let Us Visit Your Practice Please consider inviting the staff of Clinical Oncology News s to visit your practice.

We want to meet you and your colleagues, listen to your concerns and observe the physical site of your practice.

You can help us improve Clinical Oncology News s and fulfill our mission—to provide evidence-based, clinically relevant information that you can use to benefit your patients and practice.

If you are interested, please contact managing editor Gabriel Miller at (212) 957-5300 ext. 265 or via email at gmiller@mcmahonmed.com

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Key Findings: HPV Cancers, Lung Cancer Diagnosis Experts highlight key solid tumor findings over the past year Chicago—A sharp rise in the incidence of human papillomavirus (HPV)–associated cancer of the oropharynx—in stark contrast to steady declines in HPV-unrelated oropharyngeal cancer due to decreases in smoking—virtually guarantees that clinicians will soon begin to see patients with this disease in their practices, according to Ezra Cohen, MD, a head and neck cancer specialist at the University of Chicago speaking about recent developments in squamous cell cancer of the head and neck (SCCHN).

“HPV-positive oropharynx is going to be, in the very near term, the most common virally associated cancer that we see,” Dr. Cohen said. “It is a disease that I have no doubt you will see in your clin-

patients had significantly better overall survival (OS) rates than patients with HPV-negative tumors (82.4% and 57.1%, respectively) and a 58% reduction in the risk for death (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.27-0.66).

The data also revealed an “intermediate” group of HPV-positive patients with a history of smoking who did not fare as well as their HPV-positive nonsmoking counterparts, but who did better than patients with HPV-negative tumors. Overall three-year survival rates based on risk category were 93% for those with low-risk oropharyngeal squamous cell carcinoma, 70.8% for those with intermediate risk, and 46.2% for those at high risk.

Several differences between HPV-pos-

advanced SCCHN—present in 50% to 60% of tumors—and provided the first evidence that as many as 50% of tumors involve mutations in the Notch signaling pathway, Dr. Cohen said.

“These are inactivating mutations, suggesting … that there is a block in the differentiation of these squamous cells that allows somehow the second and perhaps the third hit to lead to the carcinogenic process. We’re still trying to find out exactly when these Notch alterations in the pathway occur,” he said.

Dr. Cohen and his colleagues at the University of Chicago have taken these findings one step further by linking genetic profiles of SCCHN tumors with outcomes. Sequencing on 130 primarily stage IV tumors homogeneously treat-

‘HPV-positive oropharynx is going to be, in the very near term, the most common virally associated cancer that we see. It is a disease that I have no doubt you will see in your clinics.

We are on the cusp of this epidemic.’

—Ezra Cohen, MD

ics. We are on the cusp of this epidemic.”

Dr. Cohen was speaking at the CTCA Review: Advances and Controversies symposium sponsored by Cancer Treatment Centers of America, where experts from different institutions discussed the clinical implications of key studies presented at the 2011 American Society of Hematology and 2012 American Society of Clinical Oncology meetings.

Epidemiologic data indicate that the number of cases will increase dramatically over the next decade and overtake all other HPV-related cancers in this country, Dr. Cohen said, with the most dramatic increase among men aged 55 to 64 years.

The positive aspect of the disease is that it is more curable than HPV-negative oropharyngeal cancers, he said. “These patients actually do very well.”

Dr. Cohen highlighted exome sequencing reports on the mutational landscape of SCCHN that revealed a striking difference between HPV-positive and HPVnegative cancers (Science ( 2011;333:11571160, PMID: 21798893). “HPV-positive cancers, quite simply, have a less disturbed genome than their tobacco-associated HPV-negative counterparts. That belies the reason that they have likely a better prognosis,” Dr. Cohen said.

In a Phase III trial of two radiation-cisplatin regimens for head and neck carcinomas, RTOG 0129, 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors ((N Engl J Med 2010;363:24-35, PMID: 20530316). These

itive and HPV-negative SCCHN have contributed to recognition of the disease as two distinct entities, said Dr. Cohen.

HPV-positive SCCHN occurs primarily at the tonsil and base of the tongue and in patients who are approximately a decade younger and of higher socioeconomic status than HPV-negative patients. “Men somehow appear to be more prone to getting HPV-positive oropharynx cancer [than women] and we really don’t know why,” Dr. Cohen said, noting that the disease occurs in a 3:1 male-to-female ratio.

Overall, head and neck cancer ranks as only the fifth most common malignancy in the world and the fifth most common cause of cancer mortality, but it merits increased attention because of the rise in HPV-associated disease and because “it dramatically affects function. … We do so much above the clavicles that makes us human,” Dr. Cohen said. Fortunately, curative treatment can now be considered in 90% of patients who present with

ed with chemotherapy and including a mix of HPV-positive and HPV-negative tumors revealed five subgroups: hypoxic, basal, classical, HPV-a and HPV-b.

“With the clinical annotation, what we were able to see is that the HPV-positive cancers begin to separate out into HPV-a, which is a very good performing group in terms of outcome, and HPV-b, which is a poorer performing group and is very similar to the basal type of the HPV-negative cancers,” he said.

Avoid FDG-PET as Treatment Planning Tool in Lung Cancer Do not rely on fluorodeoxyglucose positron emission tomography (FDG-PET) as a basis for changes in lung cancer therapy. This was a key take-home message from a review of advances and controversies in lung cancer presented by Ramaswamy Govindan, MD, a professor of medicine at Washington University School of Medicine in St. Louis.

‘In my [lung cancer] practice, I never use PET scans for follow-up of response to therapy. I only use CT scans.’

—Ramaswamy Govindan, MD a local tumor or a local tumor with lymph node metastasis, he said.

Recent studies on the mutational landscape of SCCHN confirmed p53 as the most common mutation in locally

“The PET scan is a wonderful scan, but like many things in life, it’s good but not great. There are limitations,” Dr. Govindan said.

He noted findings from the ACOSOG

Z4031 trial of the accuracy of FDG-PET in diagnosing non-small cell lung cancer (NSCLC; J Clin Oncoll 2012;suppl:abstr 7008). The study, which enrolled patients at 51 sites in 39 cities, revealed an overall accuracy rate of only 73%, an accuracy rate of less than 50% for lesions 2 cm or smaller, and sensitivity and specificity rates of only 82% and 31%, respectively.

The study counters previous meta-analyses showing high sensitivity and specificity with FDG-PET, at 94% and 83%, respectively.

Expanding on these results with his own recommendations, Dr. Govindan advised clinicians also not to use FDGPET as a basis for treatment decisions.

“As a person practicing in a tertiary care center, I see a number of patients getting PET scans over time, and the chemotherapy decisions are made based on the PET scan results,” Dr. Govindan said. “Quite often it’s distressing to see that the chemotherapy was changed or something was altered because SUVs [standardized uptake values] went from 4 to 5. Keep in mind … that so many things can affect SUV. “Of course, if it is a new lesion … and is really suspicious of cancer, that’s a different thing,” he said. “But please don’t change your therapy based on SUV changes.”

He also recommended against using FDG-PET to assess responses to therapy and following chemotherapy and radiation. “In my practice, I never use PET scans for follow-up of response to therapy. I only use CT [computed tomography] scans,” he said.

Research is exploring whether posttherapy PET scans can predict outcomes, but “unless we learn more from that [study], I would advise you not to use PET scans following chemotherapy and radiation treatment,” he added.

Benchmark for Anal Cancer Treatment Response Time; New Standard for Metastatic CRC Don’t evaluate patients too soon to make a decision about whether they are failing chemotherapy and radiation treatment for anal cancer and should be referred for salvage surgery, David H. Ilson, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City, said in a presentation on gastrointestinal cancers.

Dr. Ilson reviewed findings from ACT (Anal Cancer Trial) II, presented at the American Society of Clinical Oncology meeting (abstract 2004), which looked at the optimal timing of response assessment in patients with squamous cell carcinoma of the anus. The study was done

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JANUARY 2013

in the context of a randomized trial of mitomycin versus cisplatin during radiation for anal cancer with or without maintenance chemotherapy. No differences were found between the two agents, and maintenance therapy added no benefit.

But the study provided some new guidance for clinicians on when to assess complete response to treatment. Patients were evaluated at 11, 18 and 26 weeks following chemotherapy and radiation. Complete responses were found in 65.2%, 75.4% and 84.1% of patients at the three intervals, respectively. “What this tells us is that we shouldn’t jump the gun in these patients. We shouldn’t really evaluate too soon to make a decision about whether they’re failing treatment,” Dr. Ilson said. “I think this establishes a benchmark in clinical practice for when we should make the decision about referring patients for surgery or just observing them.”

Dr. Ilson also reviewed findings from the VELOUR trial (ESMO/WCGC 2011; abstract O-0024) which establishes a new standard in second-line treatment for metastatic colorectal cancer (mCRC).

Ziv-aflibercept improved tumor response in second-line treatment for mCRC, particularly in bevacizumab-naive patients, and received FDA approval in August.

“Based on these data, we now have an improved drug for up-front resistance to FOLFOX [5-fluorouracil, leucovorin, oxaliplatin and bevacizumab] and FOLFIRI [fluorouracil, leucovorin and irinotecan] and aflibercept and FOLFIRI is now an option for patients in second-line treatment,” Dr. Ilson said.

In VELOUR, patients who had failed front-line treatment were randomized to second-line treatment with FOLFIRI with or without ziv-aflibercept. Median OS and progression-free survival (PFS) were 13.5 and 6.9 months, respectively, in the ziv-aflibercept group and 12.1 and 4.7 months for patients who received placebo (HR, 0.817; P=0.0032; and HR, 0.758; P=0.00007, respectively).

The study also found that prior bevacizumab exposure did not mitigate the potential benefit from ziv-aflibercept.

Response rates were 11.7% in patients who did and 23.3% in patients who did not receive prior bevacizumab (compared with 8.4% and 12.4% in the respective placebo groups).

Overall, adverse events that led to discontinuation of treatment were about 15% higher in the aflibercept arm, but most of the toxicities were manageable, Dr. Ilson said.

Dr. Ilson also highlighted a randomized Phase II trial of ECX (epirubicin, cisplatin and capecitabine) chemotherapy with or without rilotumumab in firstline treatment for patients with unresectable, locally advanced or metastatic gastric or gastroesophageal cancer (Clinicaltrials.gov identifier: NCT00719550).

Rilotumumab is a monoclonal antibody that targets the hepatocyte growth factor

‘What this tells us is that we shouldn’t jump the gun in [anal cancer] patients.

We shouldn’t really evaluate too soon to make a decision about whether they’re failing treatment.’

—David Ilson, MD, PhD ligand that activates the MET pathway.

Patients were randomized to receive two different dose levels of rilotumumab plus ECX versus placebo plus ECX. The addition of rilotumumab improved median PFS from 4.2 to 5.6 months (HR, 0.64; 80% CI, 0.48-0.85) and median OS from 8.9 to 11.1 months (HR, 0.73, 80% CI,

0.53-1.01). Response rates were 38% and 21% in the two groups, respectively. The trial favored the lower dose as superior, Dr. Ilson said.

The benefit for PFS and OS in this study was limited to the c-MET high expressers, he said, noting that about 40% of gastroesophageal cancers

overexpress the c-MET pathway.

Based on this trial, Amgen plans to conduct a Phase III trial in c-MET high expressers of ECX chemotherapy with and without rilotumumab, he said.

—Susan Birk Dr. Ilson is an investigator at Bayer and Roche. Dr. Cohen is a consultant/advisory board member for Biocon and Vascular Biogenics. Dr. Govindan is a consultant/ advisory board member for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Genentech, GlaxoSmithKline and Pfizer.

RESEARCH Advancing the knowledge of gastric cancers.

Creating more precise and effective treatments.

Targeted for Personalized Medicine nyp.org 877 NYP-WELL (877-697-9355)

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Dual-Targeted Therapies Beneficial in Metastatic CRC Adding erlotinib to bevacizumab improves PFS in colorectal cancer Chicago—Adding the tyrosine kinase inhibitor erlotinib to bevacizumab as maintenance after first-line chemotherapy for unresectable metastatic colorectal cancer (mCRC) significantly increased progression-free survival, according to results of a Phase III study presented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA3500).

Patients who received both targeted therapies reported a substantial increase in diarrhea and skin toxicity; however, the combination was otherwise well tolerated, investigators said.

“These results suggest that erlotinib is active in mCRC and they provide a rationale for double inhibition of VEGF [vascular endothelial growth factor] and EGFR [epidermal growth factor receptor],” principal investigator Christophe Tournigand, MD, of the Hôpital SaintAntoine in Paris, said. The overall survival data from this study, called DREAM (Double inhibition Reintroduction Erlotinib Avastin in Metastatic Colorectal Cancer), is not yet mature.

In this study, mCRC patients who received bevacizumab with one of the commonly used induction therapies for first-line treatment were eligible to participate in the trial of dual-targeted therapies during second-line treatment. The induction regimens included FOLFOX (folinic acid, 5-fluorouracil [5-FU] and oxaliplatin), XELOX (capecitabine and oxaliplatin), and FOLFIRI (folinic acid, 5-FU and irinotecan). The 446 participating patients were randomized to bevacizumab alone or bevacizumab plus erlotinib. Bevacizumab, already considered a standard in first-line mCRC, is a monoclonal antibody (mAb) that targets the VEGF receptor. Erlotinib blocks the EGFR pathway of cell proliferation.

After a median of six maintenance cycles and a median follow-up of 31 months, the hazard ratio (HR) for progression-free survival (PFS) was reduced by 27% (HR, 0.73; 95% confidence interval, 0.59-0.91; P=0.005) with the dualtargeted therapy maintenance versus bevacizumab alone. In absolute terms, the PFS rate was increased by one month (10.2 vs. 9.2 months). Grade 3 or 4 diarrhea was reported by 9% of those on the dual-targeted therapy regimen compared with less than 1% of those on bevacizumab alone. Grade 3 or greater skin toxicity was reported by 19% versus none for bevacizumab alone (Table).

The scientific rationale for the combination of bevacizumab (Avastin, Genentech/Roche) and erlotinib (Tarceva, Genentech/OSI Pharmaceuticals) is that VEGF and EGFR have significant crosstalk, suggesting a potential benefit from dual inhibition. Although a previous study combining bevacizumab with cetuximab (Erbitux, Bristol-Myers Squibb/Eli Lilly), a mAb that targets EGFR, did not produce added benefit but did increase toxicity in first-line mCRC, the new data suggests a small molecular inhibitor may have advantages. At ASCO, Chris Garrett, MD, an associate

Table. The DREAM Trial of Previously Untreated and Unresectable Metastatic Colorectal Cancer Bevacizumab-based induction with FOLFOX or XELOX or FOLFIRI (n=446) Maintenance Bevacizumab Maintenance Bevacizumab Alone (n=224) Plus Erlotinib (n=222) Median progression- 4.6 months free survival

5.8 months

Grade 3-4 diarrhea

<1%

9%

Grade 3 skin toxicity

0%

19%

Number of serious treatment-related adverse events

6

7

The study provides a proof-of-concept for dualtargeted therapies in metastatic colorectal cancer; however, it does not establish a new standard of care. professor of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center in Houston, suggested that this study provides a “proof-of-concept” for combining two

AT A GLANCE Erlotinib Maintenance in mCRC Study suggests synergism with VEGF and EGFR maintenance inhibition Progression-free survival improved with a considerable increase in diarrhea and skin toxicity

targeted therapies in maintenance.

“However, these results do not change clinical practice because there is as yet no demonstrated survival benefit,” Dr. Garrett said. Demonstrating a survival benefit may be difficult to show, however, because of the likelihood that second-line therapies, such as the anti-EGFR mAbs cetuximab and panitumumab, given to the group that did not receive maintenance erlotinib, will obscure differences in the long-term outcomes. Quality-of-life studies may help put the PFS benefit into a more relevant clinical perspective.

—Ted Bosworth

Overall survival data is not yet mature Dr. Tournigand has received honoraria from Roche. Dr. Garrett has nothing to disclose.

CURRENT PRACTICE

Ondansetron Recalled by FDA 32-mg IV dose increases cardiac risks

T

he FDA announced in December that the 32-mg IV dose of the antiemetic ondansetron hydrochloride (Zofran, GlaxoSmithKline) has been removed from the drug’s label due to the potential for serious cardiac risks.

In a Drug Safety Communication issued in June, the FDA stated that this regimen should be avoided due to the risk for QT

interval prolongation, a type of irregular heart rhythm that can lead to torsades de pointes, which is potentially fatal.

The single, 32-mg dose had been used to prevent chemotherapy-induced nausea and vomiting (CINV) and was sold in premixed solutions of either dextrose or sodium chloride, in plastic containers.

The FDA does not anticipate that the

removal of the 32-mg single dose will contribute to a drug shortage of IV ondansetron, as it accounted for less than 1% of the product’s IV sales (e.g., vials and bags) to retail and nonretail channels between June 2011 and June 2012.

Removal of the 32-mg IV dose will be completed by early 2013. Currently, there is not enough information available for the FDA to recommend an alternative single IV dose regimen; however, the agency continues to recommend the IV ondansetron regimen of 0.15 mg/kg administered every four hours, for three

doses. If the calculated weight-based dose exceeds 16 mg, the potential for prolonged QT interval increases, therefore the FDA stipulates that no single IV dose should exceed 16 mg.

Oral dosing of ondansetron as a regimen to prevent CINV has not been affected by the FDA’s announcement, nor does it change the recommended lower dose of IV ondansetron to prevent postoperative nausea and vomiting, which is the other indication for the drug.

—Maureen Sullivan

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Perspectives in Non-Hodgkin’s Lymphoma: Evolving Treatment Paradigms MM111 Release Date: August 22, 2012 Expiration Date: August 22, 2013 The goal of this activity is to provide hematologists-oncologists, medical oncologists, specialty nurses, and other relevant health care professionals with up-to-date, clinically useful information on the management of non-Hodgkin’s lymphoma.

FACULTY • Julie M. Vose, MD, MBA, Nebraska Medical Center • John P. Leonard, MD, Weill Medical College of Cornell University • Jonathan W. Friedberg, MD, University of Rochester Medical Center

MM112 Release Date: October 22, 2012 Expiration Date: October 22, 2013 The goal of this activity is to educate community oncologists on recent evidence in the individualized management of metastatic breast cancer.

FACULTY • • •

Linda T. Vahdat, MD, Weill Cornell Medical Center Adam Brufsky, MD, PhD, University of Pittsburgh Cancer Institute William J. Gradishar, MD, Northwestern University

Perspectives on Breast and Ovarian Cancers: Integrating Data, Improving Outcomes MN122 Release Date: October 31, 2012 Expiration Date: October 31, 2013 The goal of this activity is to provide general oncologists with a concise summary of the most clinically important findings in breast and ovarian cancer research in the previous year.

FACULTY • Stefan Glück, MD, PhD, FRCPS, University of Miami • Ruth O’Regan, MD, Emory University • Robert A. Burger, MD, Fox Chase Cancer Center • Samer I. Schuman, MD, FACS, FACOG, University of Miami

22

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Hope for an Avastin Biomarker Anti-angiogenic therapy may be more beneficial in ER-negative subset; data very limited Chicago—An exploratory analysis of patients in the Eastern Cooperative Oncology Group 2100 trial has shown that a 13-gene signature may help identify breast cancer patients who will gain a survival advantage from bevacizumab. Investigators caution that the study is an underpowered analysis of a subset of patients in the trial and additional studies are needed. The molecular signature is not ready to be used in clinical practice.

“The search for biomarkers continues, as we try to resurrect anti-angiogenic therapy for breast cancer out of the ashes. It’s not dead yet,” said Hope S. Rugo, MD, a professor of medicine at San Francisco’s Helen Diller Family Comprehensive Cancer Center at the University of California, who was not involved with the study.

The FDA originally approved bevacizumab (Avastin, Genentech) for HER2negative metastatic breast cancer after E2100 showed that adding bevacizumab to paclitaxel improved progressionfree survival (PFS) by 5.5 months for women with locally recurrent or metastatic breast cancer. Approval was rescinded after follow-up showed no improvement in overall survival, and additional studies showed only a modest benefit in PFS. In the study presented at the 2012 annual meeting of the American Society of Clinical Oncology (abstract 1027), investigators performed a genetic analysis of 122 paraffin-embedded samples from the E2100 trial, 17% of the total. The sum of a 13-gene vascular endothelial growth factor (VEGF) signature was used to divide samples into VEGF signature–high or VEGF signature–low categories using the average from the samples.

When investigators compared outcomes in breast cancer patients receiving bevacizumab, there was no difference in PFS between the low- and high-signature

categories. In contrast, bevacizumab only provided an improvement in overall survival in patients with the high signature compared with patients receiving paclitaxel alone (hazard ratio [HR], 0.57; P=0.015); this was not seen in patients with the low signature (HR, 1.12; P=0.81).

The study also suggested, although with small numbers, that the highVEGF signature was more likely to be found in patients with estrogen receptor (ER)-negative disease and the low signature was more likely to be found in ER-positive disease.

in breast cancer patients ((BMC Med 2009;7:9, PMID: 19291283). The signature suggests that the response to hypoxia includes the ability to promote new blood and lymphatic vessel formation.

Dr. Rugo said the study offers evidence that anti-angiogenic therapy may

‘The search for biomarkers continues, as we try to resurrect anti-angiogenic therapy t for breast cancer out of the ashes. It’s not dead yet.’

—Hope S. Rugo, MD The 13-gene signa-ture, which includ-ed VEGF, ANGPTL4,, ADM and the genee that codes for mono-carboxylic acid trans-porter 4, SLC16A3, previ-ously was shown to be associated with h distant metastases and poor outcomess

AT A GLANCE The search for an Avastin biomarker Researchers have been searching for a bevacizumab biomarker for nearly 10 years The search has included tumor-, plasma-, serum- and DNAbased markers in at least five cancer types There are many underpowered subanalyses, but few large prospective trials with a suitably powered biomarker component The current study also is underpowered; however, the 13-gene signature has been linked previously with distant metastases and poor outcomes in breast cancer patients

be more beneficial in a subset of breast cancer patients with ER-negative disease. Investigators are further exploring the significance of this signature in other bevacizumab trials.

John Finnie, MD, a staff hematologist and medical oncologist at the David C. Pratt Cancer Center at Mercy Hospital in St. Louis, said reviewing past clinical studies for a clear biomarker signal from patient outcomes could be useful, but “prospective data would be ideal.”

“Extrapolating from the KRAS mutation in colon cancer and EGFR/ALK mutations in lung cancer, a biomarker to determine when bevacizumab may have benefit in the metastatic breast cancer setting could be helpful for several reasons,” said Dr. Finnie. “Selecting optimal patients who could derive improved disease outcomes, while excluding those who might simply have detrimental side effects, is the most important attribute of such a clinical tool.”

—Kate O’Rourke Dr. Rugo has received research funding from Genentech. Dr. Finnie has no relevant disclosures.

AJCC Cancer Staging Atlas: A Companion to the Seventh Editions of the AJCC Cancer Staging Manual and Handbook Carolyn C. Compton, David R. Byrd, Julio Garcia-Aguilar, Scott H. Kurtzman, Alexander Olawaiye See page 27

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JANUARY 2013

3-D Ultrasound Accurately Detects Lymph Node Mets San Diego—Researchers are using three-dimensional, high-frequency ultrasound to reliably detect lymph node (LN) metastases in patients with colorectal cancer and breast cancer.

The technology has been demonstrating up to 100% sensitivity with 73.9% specificity for detecting dissected metastatic LNs in colorectal cancer, according to research presented at the College of American Pathologists’ 2012 annual meeting. This method also showed 100% sensitivity for metastatic LNs in breast cancer, but the specificity for this disease was only 43.7%.

Further refinements in the technology will allow faster scanning and real-time, in situ imaging of nodes that could reduce the need for axillary lymph node dissection.

The researchers used a high-frequency ultrasound scanner that was custom made by Riverside Research, in New York City. They acquired ultrasound signals from 140 LNs freshly excised from 77 consecutive colorectal cancer patients and 102 freshly excised LNs from 74 consecutive breast cancer patients. Twentyone of the colorectal cancer LNs contained metastases, as did 16 of the breast cancer LNs. The investigators created 3-D digital images using specialized software that showed the locations of metastases within the LNs. They then used quantitative analyses of ultrasound echo-signal parameters to find which were most useful for determining the likelihood of metastases in the LNs. The researchers also developed sophisticated software to analyze the echo signals, classify them, and create 3-D digital images that depicted the locations and shapes of the metastases. They compared these images

Left: In a thin section of a colorectal cancer patient’s lymph node, high-definition quantitative ultrasound uses color codes to indicate the likelihood of cancer cells. Values in red indicate a higher likelihood.

Right: A hematoxylin and eosin–stained histology photo-micrograph of the same section, showing concurrence of the ultrasound image and the definitive histology from the metastatic cancer.

to the results of hematoxylin and eosin–stained sections, 3 microns thick, obtained at 50-micron intervals over the full node volume (Figure).

The investigators said that the lower specificity for breast cancer LN metastases may be caused by fatty ingrowths in the axillary LNs. They are developing methods to account for differences in tissue.

Scanning a dissected LN currently takes from five to 30 minutes, depending on its size. The investigators said that they anticipate that further refinements will allow faster scanning and real-time, in situ imaging of nodes that could reduce the need for axillary LN dissection.

“We plan to conduct a study in the near future where we use a hand-held, pen-type device in the operating room to scan sentinel lymph nodes of breast cancer patients during surgery,” said Emi Saegusa-Beecroft, MD,

a surgery research fellow at the University of Hawaii in Honolulu. “If the scan is suspicious for metastases, then a touch prep or frozen section will be used to diagnose the suspicious region of the lymph node. We also could use this apparatus to identify suspicious nodes of other cancers, such as those in the abdomen, thorax and neck.”

Dr. Saegusa-Beecroft is working with investigators from the University of Hawaii as well as others in New York, Paris, Chicago and Japan, on the study. It was funded by a grant from the National Institutes of Health to Riverside Research, where the principal investigator is Ernest Feleppa, PhD. —Rosemary Frei, MSc Dr. Saegusa-Beecroft and her collaborators did not have any relevant conflicts to disclose.

Adding mTOR Inhibitors Fails for First-Line mRCC Combining bevacizumab with targeted agents doubles cost with no benefit Vienna—Results from two recent trials have shown that adding bevacizumab (Avastin, Genentech) to an mTORtargeted agent as first-line therapy for metastatic renal cell carcinoma (mRCC) does not improve outcomes. The results, reported at the annual meeting of the European Society for Medical Oncology (ESMO), have quashed some clinicians’ expectations, which were raised by smaller clinical trials.

“ESMO data demonstrates that you should overcome any temptations you may have to combine existing agents,” said Manuela Schmidinger, MD, a senior physician in the Clinical Division of Oncology at the Medical University of Vienna, in Austria, who was not involved with either study. “There are no benefits but you double the cost.”

According to Dr. Schmidinger, current

strategies in the first-line treatment of mRCC can achieve a median progression-free survival (PFS) of roughly 11 months and a median overall survival of 26.4 months ((N Engl J Med d 2007;356:115124, PMID: 17215529; J Clin Oncol 2009;27:3584-3590, PMID: 19487381).

Researchers had hoped that they could extend survival by simultaneously inhibiting different targets. Promising results from small, Phase I and II trials suggested that patient outcomes might be improved by combining the vascular endothelial growth factor inhibitor bevacizumab with an inhibitor of mTOR ((J Clin Oncoll 2011;29[suppl]: abstract 4548; J Clin Oncoll 2010;28[suppl]: abstract 4516).

Researchers thus launched two larger randomized trials: INTORACT (Investigation of Torisel and Avastin Combination Therapy) and RECORD-2 (Renal

‘ESMO data demonstrates that you should overcome any temptations you may have to combine existing agents.’

—Manuela Schmidinger, MD Cell Cancer Treatment with Oral RAD001 Given Daily).

In the Phase III INTORACT trial, involving 791 patients with predominantly clear cell mRCC, researchers compared bevacizumab plus interferon, a standard treatment option, to the combination of temsirolimus (Torisel, Pfizer), an mTOR (mammalian target of rapamycin) inhibitor, and bevacizumab. There was no difference in PFS (hazard ratio [HR], 1.07; P=0.759) or overall survival (HR, 1.04; P=0.639; ESMO abstract LBA21).

In the Phase II RECORD-2 trial,

involving 365 patients, bevacizumab plus the mTOR inhibitor everolimus (Afinitor, Novartis) was pitted against bevacizumab plus interferon in patients with clear cell mRCC. Researchers found no improvement in the primary end point of PFS (9.3 vs. 10.02 months; HR, 0.91; P=0.485; ESMO abstract 7830).

—Kate O’Rourke Dr. Schmidinger disclosed a consultant or advisory role with Astellas, GlaxoSmithKline, Novartis, Pfizer and Roche, and research funding from Pfizer and Roche.

23

24

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JANUARY 2013

intermediate-risk patients, aged 18 to 70 years, with World Health Organization performance status of 2 or less.

Patients in arm A received ATO 0.15 mg/kg plus ATRA 45 mg/m2 daily until a complete response, then ATO five days per week, four weeks on, four weeks off, for a total of four courses; and ATRA two weeks on and two weeks off for a total of seven courses. Patients in arm B received the standard ATRA plus idarubicin induction followed by three cycles of anthracycline-base plus ATRA consolidation and low-dose chemotherapy and ATRA for maintenance. The median follow-up was 34.3 months.

Event-free survival at two years, the primary end point, was improved in patients receiving ATRA plus ATO compared with ATRA plus chemotherapy (97.1% vs. 85.6%; P=0.02; Table). Overall survival was improved in patients receiving the chemotherapy-free regimen (98.7% vs. 91.1%; P=0.02). Diseasefree survival was improved in the ATRA plus ATO arm compared with the ATRA plus chemotherapy arm (97.1% vs. 90.3%; P=0.14). All patients in the ATO arm and

APL continued from page 1

the Hopital Avicenne in Bobigny, France, who was not involved with the study. “It is applicable to the majority of APL. It has limited toxicity and therefore allows treatment in frail patients and in emerging countries. It paves the way for targeted therapies in other acute leukemias.”

Frontline management of APL includes ATRA, a derivative of vitamin A, plus chemotherapy and ATRA plus ATO, but the latter strategy has only demonstrated high efficacy with reduced toxicity in small, single-center studies. To put the ATRA plus ATO regimen to a thorough test, researchers from the Italian GIMEMA (Italian Group for Haematological Diseases in Adults) cooperative group and the German cooperative groups of SAL (Study Alliance Leukemia) and AMLSG (German AML Cooperative Group) randomized 79 patients to ATRA plus ATO and 80 patients to ATRA plus chemotherapy. The study included low- and

by the

Table. Intergroup APL0406 Study: Survival at Two Years1 ATRA ATRA Plus Plus Arsenic ChemoTrioxide therapy Event-free survival

97.1%

85.6%

Overall survival

98.7%

91.1%

ATRA, all-trans retinoic acid 1. P=0.02 for all comparisons.

95% of patients in the chemotherapy arm achieved a complete remission.

Grade 3/4 thrombocytopenia occurring for more than 15 days was more frequent in the chemotherapy arm in both induction therapy (69% vs. 45%; P≤0.0001) and consolidation cycles 1 (13% vs. 4%; P≤0.0001), 2 (46% vs. 4%) and 3 (10% vs.

2%; P≤0.0004). Grade 3/4 neutropenia occurring for more than 15 days was also more common in patients receiving chemotherapy in induction therapy (62% vs.

35%) and consolidation cycles 1 (25% vs.

4%; P=0.0001), 2 (54% vs. 4%; P≤0.0001) and 3 (17% vs. 3%; P=0.0117). Toxicities more common in the ATRA plus ATO arm included QTc prolongation (13% vs.

0%; P=0.0005), grade 3/4 toxicity (57% vs. 5%; P<0.0001) and leukocytosis, greater than 10 x 109/L (47% vs. 24%; P=0.007).

“ATO plus ATRA is at least not inferior to ATRA plus chemotherapy for the twoyear event-free survival in low-/intermediate-risk patients with APL,” said Francesco Lo-Coco, MD, from the University of Tor Vergata in Rome, who presented the study at ASH. “This regimen is associated with less hematologic toxicity and more, yet manageable, hepatic toxicity and QTc prolongation. We think this regimen may become the new standard of care for [patients who are at] low/intermediate risk for acute promyelocytic leukemia.”

—Kate O’Rourke Dr. Fenaux has no relevant disclosures.

Dr. Lo-Coco disclosed being on the speakers’ bureau for Cephalon and advisory committees for Boehringer Ingelheim.

According to a May study by Pharmaceutical Research and Manufacturers of America (PhRMA), there are currently 981 medicines and vaccines to fight cancer in testing by U.S. companies.

Lung cancer, leukemia and lymphoma top the list of diseases targeted.

numbers

Number of Drugs Under Clinical Development in Different Tumor Types Lung cancer

121

Leukemia

120

Lymphoma

Drug Development

117

Breast

The U.S. has perhaps the most rigorous and expensive drug development process in the world.

111

Other cancers

102

Prostate

94

Unspecified cancer

72

Skin cancer

67

Colorectal cancer

66

Ovarian cancer

It takes 10 to 15 years, on average, for an experimental drug to travel from the lab to patients

63

Brain cancer

It costs a company $1.2 billion, including the cost of failures, to get one new medicine from the laboratory to patients

62

Pancreatic cancer

58

Multiple myeloma

57

Liver cancer

Only five in 5,000 compounds that enter preclinical testing make it to human testing

36

Kidney cancer

35

Head/Neck cancer

25

Stomach cancer

Only one of those five is approved for use

23

Sarcoma

21

Bladder cancer

Applications for FDA approval typically run 100,000 pages or more

9

Cervical cancer

8

0

30

60

90

Source: Pharmaceutical Research and Manufacturers of America, 2012, Medicine in Development for Cancer

120

150

Sources: Pharmaceutical Research and Manufacturers of America, 2012, Medicine in Development for Cancer; Tufts Center for the Study of Drug Development

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26

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Enzalutamide a Major Advance for Prostate Cancer Treatment From The New England Journal of Medicine

T

he novel androgen receptor agonist enzalutamide (Xtandi, Astellas Oncology/Medivation) significantly prolongs survival in men with castration-resistant prostate cancer (CRPC) who have undergone chemotherapy, a Phase III, placebo-controlled clinical trial has concluded.

The AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) trial—the results of which were published in the Sept. 27 issue of The New England Journal of Medicine (2012;367:11871197; PMID: 22894553)—stratified

1,199 men with CRPC after chemotherapy based on Eastern Cooperative Oncology Group performance status score and pain intensity. The participants were randomized (in a 2:1 ratio) to receive either oral enzalutamide (160 mg per day; n=800 patients) or placebo (n=399 patients).

The trial’s primary end point was overall survival (OS). The study’s lead author was Howard I. Scher, MD, of Memorial Sloan-Kettering Cancer Center in New York City.

Median OS in the enzalutamide group was 18.4 months compared with 13.6 months in the placebo group (P ( <0.001). Additionally, 54% of the patients in the study drug

EXPERT INSIGHT Mark T. Fleming, MD Medical Oncologist, Virginia Oncology Associates Member, The US Oncology Network Genitourinary Research Committee

T

he emergence of enzalutamide in the treatment of CRPC is a major breakthrough. On the foundation of rational translational science targeting the androgen receptor, the therapy of CRPC has evolved to an era with minimal toxicity while controlling and relieving manifestations of advanced disease and improving survival. Enzalutamide, as demonstrated by the paper from Scher et al in The New England Journal of Medicine, is a case study in the evolution of these treatments for CRPC. Initially responsive to androgen deprivation, prostate cancer progresses to a castration-resistant state. Clinically, the disease evolves from an asymptomatic, rising PSA clinical state to symptomatic, lethal, castration-resistant metastatic disease. This progression is based scientifically in the overexpression of and dependence on the androgen receptor and androgen receptor signaling for growth. Docetaxelbased chemotherapy serves as a paradigm shift in the clinical treatment of

CRPC—treating symptomatic disease and prolonging life. Enzalutamide is another sequential option for CRPC following chemotherapy, demonstrating similar benefits with minimal toxicity.

Enzalutamide is an oral androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. Although previously available anti-androgens also competitively inhibit binding of androgens to androgen receptor, enzalutamide has a greater affinity for the androgen receptor and is without agonist properties. Uniquely, enzalutamide inhibits both nuclear translocation of androgen receptor and androgen receptor–mediated DNA binding. The inherent clinical benefit demonstrated in patients is derived from this scientific basis.

The present paper demonstrated multiple clinically meaningful benefits for CRPC patients by using enzalutamide. The superiority of enzalutamide over placebo was shown in the primary end point, OS (18.4 vs. 13.6 months), and all secondary end points,

group recorded at least a 50% reduction in their prostate-specific antigen (PSA) levels compared with just 2% in the placebo group. The soft tissue response rate was 29% in the enzalutamide group versus 4% in the placebo group (P ( <0.001) and the quality-of-life response rate (defined as a 10-point improvement in the global score on the Functional Assessment of Cancer Therapy-Prostate questionnaire compared with baseline on two consecutive measurements obtained at least three weeks apart) also was significantly higher (43% vs. 18%; P<0.001).

The median time to PSA progression was 8.3 months in the enzalutamide group compared with three months

in the placebo group (P ( <0.001), and median radiographic progression-free survival was 8.3 months in the study drug cohort versus 2.9 months in the placebo group ((P<0.001).

The authors reported that rates of fatigue, diarrhea and hot flashes were higher in the enzalutamide group, and that seizures were reported in five patients receiving enzalutamide. Overall, however, the enzalutamide group had a lower incidence of grade 3 or 4 adverse events (45.3% vs. 53.1%) than the placebo group, and the median time to the first of these adverse events was 12.6 months in the enzalutamide group compared with 4.2 months in the placebo group.

including PSA response of 50% or greater (54% vs. 2%), PSA response of 90% or greater (25% vs. 1%), soft tissue response rate (29% vs. 4%), quality-of-life response rate (43% vs. 18%), time to PSA progression (8.3 vs. three months), radiographic progression-free survival (8.3 vs. 2.9 months) and time to first skeletal-related event (16.7 vs. 13.3 months). Part of the appeal of enzalutamide appears to be its favorable toxicity profile. Interestingly, although reports of all fatigue (34% vs. 6%) were higher in enzalutamide patients, fatigue

enzalutamide with other agents used in prostate cancer are under way, including with docetaxel (NCT01565928), abiraterone (NCT01650194) and versus bicalutamide (NCT01664923).

Unanswered questions remain in the treatment of CRPC. What is the optimal sequencing of the available agents in CRPC? Are there effective biomarkers to target therapy? Given the choices of therapies—such as sipuleucel-T, cabizataxel, abiraterone and potentially Alphradin—these questions remain.

Hopefully, future trials and data will

Unanswered questions remain in the treatment of CRPC. What is the optimal sequencing of the available agents in CRPC? Are there effective biomarkers to target therapy? grade 3 or greater (6% vs. 7%) was higher in placebo patients. The most concerning toxicity demonstrated was seizures, reported in 0.6% of patients.

Moving forward, the use of enzalutamide is already being studied across the broad clinical state spectrum of prostate cancer. For example, a Phase III study of enzalutamide (PREVAIL) for patients prior to the use of chemotherapy has been completed with data forthcoming (Clinicaltrials.gov identifier: NCT01212991). Additionally, several exciting trials comparing enzalutamide with or exploring the combination of

add clarity to these questions. Already data has been presented on the baseline use of corticosteroids and enzalutamide. Toxicity profiles, patient preference, concomitant medications and comorbidities will help guide treatment decisions and provide insight to these questions. Ultimately, the future is brighter for CRPC patients based on the scientific advances of understanding the androgen receptor and the clinical utility of enzalutamide.

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

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AJCC Cancer Staging Atlas: A Companion to the Seventh Editions of the AJCC Cancer Staging Manual and Handbook

Carolyn C. Compton; David R. Byrd; Julio Garcia-Aguilar; Scott H. Kurtzman; Alexander Olawaiye August 9, 2012

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Significantly expanded and expertly illustrated, this book offers more than 600 illustrations created exclusively for this new edition and is fully updated to reflect the concepts discussed in both the AJCC Cancer Staging Manuall and its companion Handbook.

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Cancer in Children: Clinical Management

Michael C.G. Stevens; Hubert N. Caron; Andrea Biondi March 2, 2012 Cancer in Children is an established and highly regarded introduction to pediatric oncology. In a clear and concise way, it covers the etiology, symptoms and treatment of cancer in children, the complications that can arise during treatment and the various outcomes of the illness.

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Doctor’s Eyes Only: Exclusive Financial Strategies for Today’s Doctors and Dentists

Thomas Martin; Paul Larson; Jeffrey Larson March 13, 2012 This book is the missing financial guide that physicians need as a supplement to their ongoing professional training. These pages include basic financial wisdom that could end up saving them millions of dollars throughout their medical careers.

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Gynecologic Oncology: Clinical Practice and 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. This all-in-one evidencebased gynecologic oncology resource offers high-yield coverage of the d sc p e s underlying discipline’s u de y g principles p c p es and a d proven p o e management a age e t strategies. st ateg es

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Hematologic Malignancies Michael Tomblyn; Karen Winkfield; Bouthaina Dabaja

December 12, 2012 Authoritative reviews and updates discuss recent advances in radiation therapy in treatment of Hodgkin’s lymphoma, B-cell nodal and extranodal lymphomas, follicular lymphoma and cutaneous T-cell lymphoma, mantle cell lymphoma and leukemia.

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Lymphomas John Sweetenham; Jame Abraham

September 1, 2012 This book includes discussion of molecular characterization for different disease-specific lymphoma subtypes and the potential for developing personalized treatment. It also reviews the evolving role of conventional chemotherapy, stem cell transplantation and other salvage treatments.

The articles examine a range of lymphoma subtypes, including Hodgkin, T-cell and aggressive B-cell lymphomas.

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Melanoma William H. Sharfman; Jame Abraham

December 12, 2012 This issue of Emerging Cancer Therapeutics s provides a comprehensive review for practitioners on the current status of melanoma treatment.

There is also coverage of the most recent data pertaining to surgical management, staging and prevention of melanoma in children.

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Rare Cancers: An Issue of Hematology/Oncology Clinics of North America

Guy D. Eslick January 11, 2013 Topics in this issue include rare cancers, mast cell leukemia, uveal melanoma, esthesioneuroblastoma, parathyroid carcinoma, thymoma/thymic carcinoma, mesothelioma, gastrointestinal stromal tumor, uterine sarcoma, cancer of the appendix, urethral cancer, anal cancer and merkel ce carcinoma. cell ca c o a CO0113

28

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Continuing EGFR-TKI Therapy Beyond Progression From the Journal of Thoracic Oncology

A

team of researchers from Japan has concluded that continued use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) even after disease progression may improve overall survival compared with cytotoxic chemotherapy in nonsmall cell lung cancer (NSCLC) patients harboring activating EGFR mutations.

Somatic mutations in the EGFR are an important biomarker in predicting clinical outcomes in patients treated with EGFR-TKIs, such as gefitinib (Iressa,

AstraZeneca) and erlotinib (Tarceva, Genentech). Although EGFR-TKIs in general have significantly improved outcomes among patients with NSCLC and activated EGFR mutations (including deletions in exon 19 and L858R in exon 21), the disease eventually develops resistance to these agents, leading to progressive disease. Most current guidelines indicate that patients with progressive disease—even those with EGFR mutations—should be switched to cytotoxic chemotherapy; however, there have been some reports of rapid tumor growth following EGFR-TKI treatment

EXPERT INSIGHT David Smith, MD Hematologist/Medical Oncologist Research Medical Director for Compass Oncology, An Affiliate of The US Oncology Network

N

ot long after the introduction of the TKIs gefitinib and erlotinib for the treatment of NSCLC, it was noted that a minority of patients had dramatic responses and prolonged benefit. Sequencing of the EGFR gene revealed somatic-activating mutations, which have become important biomarkers for predicting benefit from these agents. Similar to chronic myelogenous leukemia and gastrointestinal stromal tumors (GIST), patients harboring these activating mutations represent a unique subset of patients with NSCLC with profound sensitivity to a single-agent TKI, with a response rate greater than 70% and a prolonged OS compared with that of EGFR wildtype. Duration of response has been reported between 10 and 16 months before acquired resistance develops.

Prolonged survival despite progression has been reported. Oxnard et al prospectively enrolled patients with EGFRmutant NSCLC into a rebiopsy protocol for patients with documented progression and found the median OS from the time of progression to be 16 months.1 They found 60% of patients had a resistance mutation (T790M), and this subgroup seemed to have a more indolent progression, with a median survival of 19 months compared with the 12-month median survival of patients who did not have a detectable T790M mutation. Of note, EGFR-TKI therapy was continued in 87% of the entire cohort despite documented progression.

Investigators have previously

reported personal observations of “indolent progression” as well as “flares” of disease—rapid symptomatic progression and death—after abrupt discontinuation of the TKI in EGFR-mutant patients.

Similar flares have been reported in GIST upon discontinuation of imatinib.

Riely et al reported in 2007 a prospective study of discontinuing the TKI in progressing patients who had previously responded, then reinstituting the TKI three weeks later.2 Seven of 10 patients had an increase in symptoms during the three-week discontinuation and two patients met Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression in the three-week period. In a retrospective study, Chaft et al studied the immediate consequences of discontinuation of TKI therapy by identifying patients participating in trials of acquired resistance to TKI that required a washout period of at least seven days.3 Of 61 patients, 14 (23%) included in the analysis had a disease flare defined as hospitalization or death due to disease progression during the washout period, with a median time to flare of eight days. These reports of indolent progression and rapid disease flares have led to caution about abrupt discontinuation of TKI therapy and questions about the role of continuation of the TKI in the face of objective disease progression.

The present study by Nishie et al is a retrospective comparison of continuation of EGFR-TKI therapy beyond progression versus discontinuation in patients with activating EGFR

discontinuation, an indication that continuing treatment for those with EGFR mutations may have some clinical value.

In the present study, published in the November issue of the Journal of Thoracic Oncology (2012;7:1722-1727, PMID: 23059777), the researchers, led by Kenichi Nishie, MD, retrospectively analyzed data from 551 consecutive patients with advanced NSCLC who demonstrated radiologic disease progression following first- or secondline EGFR-TKI therapy. After screening, 186 of these patients were found to have activating EGFR mutations and, of

mutations and acquired resistance to TKI. The authors identified 64 patients with known EGFR mutations who had developed radiographic progression by RECIST criteria. At the discretion of the treating physician, these patients were either continued on TKI therapy with or without chemotherapy or treated with chemotherapy alone. Thirty-nine patients were continued on the TKI and 25 discontinued the TKI before being treated with chemotherapy alone.

The median OS for the group continuing on TKI therapy was significantly longer than those discontinued, 32.2 versus 23 months. A Cox multivariate analysis was performed with only continued EGFRTKI therapy after progressive disease being associated with improved survival.

Although this is a retrospective study, the prolonged survival in the group continuing on with TKI therapy is provocative and the prolonged OS following progression of the entire group is consistent with previous observations.

It is not clear, however, how treating physicians made their decisions about whether or not to continue TKI therapy. In the study by Oxnard et al, patients with the T790M mutation appeared to have more indolent progression and a prolonged survival than those without.1 It is possible that the groups in the present study were “selected” by treating physicians based on clinical characteristics of aggressiveness of progression leading to bias in the continuation group toward those patients with the T790M mutation or another as yet unidentified biologic variable.

The role of continued EGFR-TKI therapy beyond progression remains unclear. Retrospective analyses, anecdotal reports and personal observations all suggest the “flare” phenomenon is real and careful consideration is warranted when contemplating discontinuation of TKI. The best choice for this population may be a clinical trial, although this option also should be

these, 64 (13 men and 51 women; median age 65.5 years) were selected and analyzed—39 continued EGFR-TKI therapy after progressive disease diagnosis and 25 were switched to cytotoxic chemotherapy alone. Among them, 31 patients had deletions in exon 19 and 33 had point mutations of L858R in exon 21.

Among those who continued EGFRTKI therapy, median overall survival (OS) was 32.2 months, compared with 23 months for those who were switched to chemotherapy (P ( =0.005). Further Cox analysis revealed that continuous EGFRTKI therapy following disease progression was associated with improved survival (hazard ratio, 0.42; P=0.013).

approached with caution if there is a long window of no treatment required for enrollment. Chaft et al urge reconsideration of the standard washout periods of no treatment when patients enroll in clinical trials after progression on a TKI, and suggest that a 24- to 48-hour period should be sufficient.3 Prospective, randomized trials of continued TKI or not, such as ASPIRATION, described by Park et al, are needed.4 Several recent studies have shown the safety and tolerance of adding chemotherapy to continued TKI therapy and now need to be studied in a prospective randomized trial as well.

For now, in the absence of an available clinical trial, decisions about continuation of TKI after progression will need to be made individually, with only limited data and the experience of the treating physician for guidance.

References 1. Oxnard GR, Arcila ME, Sima CS, et al.

Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17:1616-1622; PMID: 21135146.

2. Riely GJ, Kris MG, Zhao B, et al. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res. 2007;13:5150-5155, PMID: 17785570.

3. Chaft JE, Oxnard GR, Sima CS, et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFRmutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res. 2011;17:6298-6303, PMID: 21856766.

4. Park K, Tsai C-M, Ahn M-J, et al. ASPIRATION: Phase II study of continued erlotinib beyond RECIST progression in Asian patients (pts) with epidermal growth factor receptor (EGFR ( ) mutation-positive non-small cell lung cancer (NSCLC).

J Clin Oncol. 2012;30:abstr TPS7614.

Dr. Smith reported no relevant financial disclosures.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JANUARY 2013

Trimodality Therapy With Bladder Preservation an Option From Urology

T

rimodality therapy, including either neoadjuvant chemotherapy followed by radiotherapy (RT) or weekly cisplatin and RT concurrently with bladder preservation, represents a real alternative to radical cystectomy in patients with muscle-invasive bladder cancer, a new study has concluded.

Published in the November issue of the journal Urology (2012;80:10561062, PMID: 22999456), the study enrolled 80 patients with T2-T4 bladder cancer in two successive bladder-sparing protocols: 41 of the

participants received three cycles of neoadjuvant MCV (methotrexate, cisplatin and vinblastine) chemotherapy followed by RT (60 Gy; in complete responders) and 39 were treated with weekly cisplatin (20 mg/m2 per day, 30-minute IV infusion, two days per week) concurrent with RT (64.8 Gy).

The median follow-up was 72 months and patients were closely monitored with cystoscopy reevaluation, biopsy of the tumor site and of all suspected areas, and urine cytology.

The five- and 10-year cumulative overall survival (OS) rates for both protocols were 73% and 60%,

EXPERT INSIGHT Vivek Kavadi, MD Radiation Oncologist, Texas Oncology Medical Director of Radiation Oncology, The US Oncology Network

R

adical cystectomy with urinary diversion has been the mainstay of therapy for patients with muscle-invasive bladder cancer. This standard of care has been so well established that many physicians have taken the opinion that a nonsurgical approach to the care of these patients would deny most of them a chance at cure of their disease. Radical cystectomy, although it is an effective treatment for the cancer, is associated with significant compromises in quality of life. The long-term effects on urinary and sexual function, as well as on body image, cannot be ignored. Over the past 30 years, investigators at several institutions have devised multimodality treatment strategies to offer patients the opportunity for curative treatment with the possibility of bladder preservation. Most of these approaches involve maximal debulking of the tumor via transurethral resection followed by radiation and chemotherapy. The patient is then reevaluated cystoscopically, and those who have had a complete response continue with further chemoradiation therapy, whereas those with residual disease undergo radical cystectomy.

Various chemotherapy regimens, different radiation schedules and sequential versus concurrent chemoradiation approaches have been used.

Zapatero and colleagues present their experience over two decades with two different prospective bladder-sparing trimodality approaches for invasive bladder cancer. From 1990 to 1999, 41

respectively. Bladders were preserved in 83% of the participants. The authors noted that although there were no significant differences in OS (P ( =0.820), cancer-specific survival (P ( =0.688) and distant metastasis ((P=0.417) between protocols, the complete response rates (P ( =0.003) and disease-free survival rates ((P=0.031) were significantly higher among patients who received cisplatin concurrent with RT. Using criteria from the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer, the researchers also evaluated the rates and severity of late

genitourinary and gastrointestinal (GI) toxicity among the 72 patients who survived more than one year from the start of treatment with an intact bladder. They found that the incidence of grade 2 or higher genitourinary and/or GI toxicities was 22% and 6%, respectively. In all, four patients had a reduced bladder capacity (grade 3) and one patient underwent cystectomy because of a shrinking bladder.

The authors reported no GI complications requiring surgical intervention, and the incidence of grade 3 GI complications was 2%.

achieved in 74% overall; 71% in P1 and 80% in P2. Of the 80 patients, 72 completed RT and chemotherapy, suggesting that some who were not evaluated after initial treatment and some who had residual disease still received definitive chemoradiation rather than radical cystectomy, as per protocol design. Eight patients underwent primary radical cystectomy, four on each protocol. Nine of the 72 patients who completed chemoradiation underwent salvage radical cystectomy for recurrent disease. The five- and 10-year OS rate was reported to be 73% and 60%, and the corresponding cancer-specific survival was 82% and 80%, respectively. Additionally, 83% of all surviving patients maintained their own bladder. The group reported that complete

bladder-conserving approaches for muscle-invasive bladder cancer. One group at the forefront of this research has been from Massachusetts General Hospital (MGH). Efstathiou et al recently reported on the MGH experience, treating 348 patients with cT2T4a disease between 1986 and 2006.1 The patients were treated on successive prospective protocols. Of these patients, 72% had a complete response to induction therapy. The five- and 10-year disease-specific survival in the MGH series was 64% and 59%, respectively. The results from this 20-year experience on a large group of patients are consistent with that reported in the current series by Zapatero et al.

In summary, trimodality therapy with bladder-sparing intent is a viable and proven alternative for selected patients with muscle-invasive bladder cancer. Organ-preservation treatment approaches have provided excellent cancer control with enhanced quality of life in many malignancies. Studies such as these hopefully will continue to add evidence in the advocacy for this treatment for appropriately selected patients with muscle-invasive bladder cancer.

Organ-preservation treatment approaches have provided excellent cancer control with enhanced quality of life in many malignancies. patients were treated on protocol 1 (P1) with neoadjuvant MCV chemotherapy.

Complete responders underwent consolidation RT to 60 Gy. From 2000 to 2010, 39 patients were treated on protocol 2 (P2) with concurrent cisplatin chemotherapy and RT. Accelerated hyperfractionated RT was used in 24 patients and standard fractionated RT was used in 15 patients. The total dose to the bladder was 64.8 Gy. Of the 80 patients, 66 were evaluable for response after induction treatment and complete response (R0) was

response rates were higher in the concurrent chemoradiation group. This can be explained by the fact that there was a higher percentage of T2 tumors in the P2 group and also because of study design. In P1, cystoscopy to assess response was performed after MCV chemotherapy alone, whereas in P2, the cystoscopic evaluation took place after chemoradiation. It would be expected that RT would contribute to a higher response rate over chemotherapy alone.

This study is yet another in a growing set of experience with

Reference 1. Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol. 2012;61:705711, PMID: 22101114.

Dr. Kavadi reported no relevant financial disclosures.

29

30

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JANUARY 2013

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Clinical Hematologic Review: Highlights from ASH and NEJM, JCO and Blood QUESTIONS

1. True or False. Carmine Marchi-

oli, MD, on behalf of the Cytoreductive Therapy in Polycythemia Vera (CYTOPV) Collaborative Group reported in The New England Journal of Medicine that among patients with polycythemia vera (PV), maintaining a hematocrit target of less than 45%, compared with a target of 45% to 50%, was associated with a significantly lower rate of thrombotic complications without an increase in serious treatment complications.

2. True or False. Hartmut Döhner,

MD, from the University of Ulm in Ulm, Germany, presented reassuring preliminary Phase II data that demonstrates significantly improved response rates and a trend toward an event-free survival (EFS) benefit with a combination of volasertib (BI 6727, Boehringer Ingelheim) and low-dose cytarabine (LDAC) compared with LDAC alone in patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive treatment.

3. True or False. On behalf of the Eastern Cooperative Oncology Group (ECOG), Justin M. Watts, MD, of Memorial Sloan-Kettering Cancer Center in

ANSWERS

1. True. According to an accompany-

ing editorial by Jerry L. Spivak, MD, of Johns Hopkins University School of Medicine in Baltimore, this study resolves a half-century of debate about the role of phlebotomy in PV and has ramifications for diagnosis and management. From a diagnostic perspective, the data from the study by Marchioli et al confirm the inaccuracy of the World Health Organization criteria with respect to hematocrit for the diagnosis of PV. These criteria have been shown to have a falsenegative rate as high as 64%, a finding that indicates that the diagnosis of PV is being missed in some patients with JAK2 (V617F) mutation who have an apparently normal hematocrit. It is important to acknowledge that the hematocrit target described by Marchioli et al is adequate for men but inadequate for women, who on the basis of other studies should have a target hematocrit of less than 42%.

Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2012 Dec 8. [Epub ahead of print], PMID: 23216616.

Spivak JL. Polycythemia vera, the hematocrit,

6. True or False. Mark

New York City, presented long-term data on 784 young AML patients and showed continued late relapses without transplantation.

J. Levis, MD, PhD, of Johns Hopkins University in Baltimore, presented final results of a Phase II monotherapy trial of quizartinib that demonstrated CRc rates of 44% and 34% in FLT3-ITD mutated and unmutated patients aged 18 years and older with AML relapsed or refractory to secondline, salvage chemotherapy or relapsed after hematopoietic cell transplant (HCT), respectively.

4. True

or False.

Francesco Lo-Coco, MD, from the University of Tor Vergata in Rome, presented results of the multicenter APL0406 trial that demonstrat- Primum non nocere. ed superior EFS with (First, do no harm.) all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) True or False. A study published in compared with conventional ATRA plus chemotherapy in all risk groups The New England Journal of Medicine on of patients with newly diagnosed acute behalf of Marcos de Lima, MD, of MD Anderson Cancer Center in Houston, promyelocytic leukemia (APL). and his colleagues did not show engraftTrue or False. Jorge E. Cortes, ment benefit from manipulated (ex vivo MD, of the University of Texas MD in co-cultures with allogeneic mesenAnderson Cancer Center in Hous- chymal stromal cells) cord blood transton, presented final results of a Phase plantation compared with unmanipulatII monotherapy trial of quizartinib ed cord blood transplantation in adult (AC220, Ambit Biosciences) that dem- patients with hematologic cancers. onstrated composite CR (CRc) rates of 54% and 32% in FLT3-ITD mutated and True or False. In a randomized unmutated elderly relapsed/refractory controlled trial, addition of low-dose AML patients, respectively. gemtuzumab ozogamicin (GO; Mylotarg,

7.

5.

8.

and blood-volume physiology. N Engl J Med. 2012 Dec 8. [Epub ahead of print], PMID: 23216617.

Cassinat B, Laguillier C, Gardin C, et al. Classification of myeloproliferative disorders in the JAK2 era: is there a role for red cell mass? Leukemia.

2008;22:452-453, PMID: 1771354.

Pearson TC, Weatherly-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet. 1978;2:12191222, PMID: 82733.

2. True. In this open-label study, eligi-

ble patients were randomized to receive volasertib (V; 350 mg for one hour IV, days 1 and 15, every four weeks) and LDAC (20 mg twice daily subcutaneously, days 1-10, every four weeks), or LDAC alone until progression/relapse or intolerance. A trend for longer median EFS was observed in patients who received V + LDAC compared with those who received LDAC alone (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.351.05; P=0.0725). Follow-up for overall survival was ongoing at the time of this analysis. Volasertib is a first-in-class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting polo-like kinases (Plks).

Maertens J, Lübbert M, Fiedler W, et al. Phase I/II study of volasertib (BI 6727), an intravenous

polo-like kinase (Plk) inhibitor, in patients with acute myeloid leukemia (AML): results from the randomized Phase II part for volasertib in combination with low-dose cytarabine (LDAC) versus LDAC monotherapy in patients with previously untreated AML ineligible for intensive treatment.

ASH Annual Meeting Abstracts. Blood. 2012;120:411.

3. False. Detailed analyses of four

ECOG studies revealed low, 1.4% (n=11) rates of late (≥3 years) relapses; of these, two were treated on E3483, one on PC486, five on E3489 and three on E1900. Interestingly, recurrent AML was extremely rare after five years or more of remission (<0.2%); the risk for therapy-related AML from contemporary induction and postremission strategies, including autologous transplantation (30% of patients), appears to be minimal.

Watts JM, Zickl L, Litzow MR, et al. Practically all patients with acute myeloid leukemia (AML) in continuous complete remission for 3 years or more are cured of their disease: the ECOG experience. ASH Annual Meeting Abstracts. Blood.

2012;120:132.

4. False. The combination of ATRA plus ATO was not inferior to ATRA plus chemotherapy in terms of twoyear EFS for patients with low- and

Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

Wyeth) to induction chemotherapy reduced relapse risk and improved survival with little added toxicity in elderly patients with AML.

9.

True or False. On Dec. 14, 2012, the FDA granted accelerated approval to ponatinib (Iclusig, Ariad) for the treatment of adult patients with chronic phase, accelerated phase or blast phase chronic myeloid leukemia (CML) who are resistant to or intolerant of prior tyrosine kinase inhibitor therapy, or with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) who are resistant to or intolerant of prior tyrosine kinase inhibitor therapy.

10. True or False. Investigators

from MD Anderson Cancer Center presented encouraging Phase II data showing ibrutinib (PCI-32765, Janssen) in combination with rituximab to be safe and well tolerated with very high early response rates for patients with high-risk chronic lymphocytic leukemia (CLL).

intermediate-risk APL. Patient with highrisk disease were excluded in this multicenter Phase III trial. After a median follow-up of 31 months, the two-year EFS was 97.1% in the ATRA plus ATO treatment arm versus 85.6% in the ATRA plus chemotherapy arm. Overall survival was 98.7% versus 91.1%, respectively.

Lo-Coco F, Avvisati G, Orlando SM, et al. ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non–highrisk acute promyelocytic leukemia (APL): results of the Phase III, prospective, randomized, intergroup APL0406 study by the Italian-German cooperative groups GIMEMA-SAL-AMLSG. ASH Annual Meeting Abstracts. Blood.2012;120:6.

5.

True. Quizartinib, an oral FLT3 receptor tyrosine kinase inhibitor (TKI), is active against both ITD mutated and unmutated FLT3, although higher activity is detected among FLT3-mutated patients.

Median duration of response for mutated and unmutated FLT3-ITD was 12.7 and 22.1 weeks, respectively. It is important to acknowledge that 8% of patients in this study were able to transition from quizartinib to a hematopoietic cell transplant (HCT). These data represent the highest level of single-agent activity observed to date for FLT3-targeted therapy in elderly

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JANUARY 2013

patients with relapsed/refractory FLT3ITD mutated AML. Further Phase I and II studies investigating lower doses of quizartinib as monotherapy and in combination with other agents in FLT3-ITD mutated and FLT3-ITD unmutated AML are needed.

Cortes JE, Perl AE, Dombret H, et al. Final results of a Phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥60 years of age with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. ASH Annual Meeting Abstracts. Blood.

2012;120:48.

6. True. In patients refractory to their

last AML therapy, 47% and 31% achieved a CRc with quizartinib in mutated and unmutated FLT3-ITD groups, respectively. Of clinical significance in this heavily pretreated population, approximately one-third of patients were successfully bridged to potentially curative HCT, and many patients who were refractory to prior therapy responded to quizartinib. Toxicity findings were manageable, primarily myelosuppression and QT prolongation that was mitigated with dose modifications.

Levis MJ, Perl AE, Hombret H, et al. Final results of a Phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. ASH Annual Meeting Abstracts. Blood.

2012;120:673.

7.

False. Cord blood transplantation expanded ex vivo in co-cultures with allogeneic mesenchymal stromal cells in combination with second unmanipulated cord blood units significantly improved engraftment milestones. The median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, compared with 24 days in controls who received unmanipulated cord blood ( <0.001); the median time to platelet (P engraftment was 42 and 49 days, respectively (P ( =0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion ((P<0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively ((P<0.001). de Lima M, McNiece I, Robinson SN, et al. Cordblood engraftment with ex vivo mesenchymalcell coculture. N Engl J Med. 2012;367:2305-2315, PMID: 23234514.

8. True. In the prospective, random-

ized AML-16 (Acute Myeloid Leukaemia and High Risk Myelodysplastic Syndrome) trial, a single dose of GO (3 mg/ m2) at the beginning of induction chemotherapy was associated with clinically meaningful and statistically significant improvement in the cumulative incidence of relapse, relapse-free survival and overall survival.

Burnett AK, Russell NH, Hills RK, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with

acute myeloid leukemia. J Clin Oncol. 2012;30:39243931, PMID: 22851554.

pain, fatigue, headache, dry skin, constipation, fever, joint pain and nausea.

Neuberg DS. Reprise: gemtuzumab ozogamicin for older patients with acute myeloid leukemia. J Clin Oncol. 2012;30:3905-3906, PMID: 22987082.

Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075-2088, PMID: 23190221.

9. True. The recommended dose and

schedule for ponatinib is 45 mg taken orally once daily with or without food.

Ponatinib is being approved with a boxed warning alerting patients and health care professionals that arterial thrombosis and liver toxicity have occurred in ponatinib-treated patients. The most common side effects reported in the clinical trial include hypertension, rash, abdominal

U.S. Food and Drug Administration. Iclusig label information. December 14, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl. pdf. Accessed December 18, 2012.

10. True. Patients were treated with oral ibrutinib 420 mg daily, in combination with weekly rituximab (375 mg/m2) for weeks 1-4 (cycle 1), then daily ibrutinib plus monthly rituximab until cycle

HALAVEN® (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information.

2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.

Recommended dose delays t Do not administer HALAVEN on Day 1 or Day 8 for any of the following: – ANC <1,000/mm 3 – Platelets <75,000/mm 3 – Grade 3 or 4 non-hematological toxicities. t The Day 8 dose may be delayed for a maximum of 1 week.

– If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.

– If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.

Recommended dose reductions t If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1. t Do not re-escalate HALAVEN dose after it has been reduced.

Table 1 Recommended Dose Reductions Recommended Event Description HALAVEN Dose Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following: ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 1.1 mg/m2 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count.

Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.

Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.

5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

5.3 Embryo-Fetal Toxicity There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.

6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: t /FVUSPQFOJB t 1FSJQIFSBM OFVSPQBUIZ t 25 JOUFSWBM QSPMPOHBUJPO The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).

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

In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).

The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.

Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Blood and Lymphatic System Disordersa Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders 35% 8% 16% 2% Peripheral neuropathyb Headache 19% <1% 12% <1% General disorders and administrative site conditions Asthenia/Fatigue 54% 10% 40% 11% Mucosal inflammation 9% 1% 10% 2% Pyrexia 21% <1% 13% <1% Gastrointestinal disorders Constipation 25% 1% 21% 1% Diarrhea 18% 0 18% 0 Nausea 35% 1% 28% 3% Vomiting 18% 1% 18% 1% Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Investigations Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders Anorexia 20% 1% 13% 1% Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders 10% NAc Alopecia 45% NAc

6, followed by daily single-agent ibrutinib. High-risk disease was defined as patients with del17p or TP53 mutations (treated or untreated), progression-free survival of less than 36 months after front-line chemoimmunotherapy, or relapsed CLL with del 11q.

Burger JA, Keating MJ, Wierda WG, et al. The Btk inhibitor ibrutinib (PCI-32765) in combination with rituximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients. ASH Annual Meeting Abstracts. Blood. 2012;120:187.

Dr. Mohammed Aziz assisted in preparing this column.

Table 2 (cont'd) MedDRA ver 10.0

HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 a Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia).

Cytopenias: y p Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN. Peripheral p Neuropathy: p y In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.

Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVENtreated group: t Eye Disorders: increased lacrimation t Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth t General Disorders and Administration Site Conditions: peripheral edema t Infections and Infestations: upper respiratory tract infection t Metabolism and Nutrition Disorders: hypokalemia t Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness t Nervous System Disorders: dysgeusia, dizziness t Psychiatric Disorders: insomnia, depression t Skin and Subcutaneous Tissue Disorders: rash 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen.

Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses off 0.43 times the recommended human dose.

Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.

8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.

8.6 Hepatic Impairment Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C).

8.7 Renal Impairment For patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min).

10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day.

There is no known antidote for HALAVEN overdose.

12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics Specific Populations Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment.

Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function.

Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that geometric mean dose-normalized systemic exposure is similar for patients with mild renal impairment (CrCl 50-80 mL/min) relative to patients with normal renal function. However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dosenormalized systemic exposure increased 2-fold compared to patients with normal renal function.

12.6 Cardiac Electrophysiology The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with eribulin mesylate.

Eribulin mesylate was not mutagenic in in vitroo bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivoo rat bone marrow micronucleus assay.

The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility mayy be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling t Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination. t Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN. –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2012 Eisai Inc. All rights reserved. Printed in USA / March 2012 ERI 346

31

DISCOVER OVERALL SURVIVAL HALAVEN: The FIRST and ONLY single-agent therapy proven to significantly extend OVERALL SURVIVAL after 2 prior lines of MBC therapy1-9

P R O P O R T I O N O F PAT I E N T S A L I V E

UPDATED OVERALL SURVIVAL (OS) ANALYSIS (UNPLANNED): MEDIAN OS, MONTHS (95% CI)1,10,a

The updated OS analysis was consistent with the primary analysis1 The primary analysis, conducted when ~50% of events (deaths) had been observed, demonstrated a median OS for Halaven vs TPC of 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR*=0.81 (95% CI: 0.66, 0.99) (P=0.041)1,10 Results from an updated, unplanned survival analysis of the Phase III, randomized, open-label, multicenter, multinational EMBRACE† trial of Halaven versus TPC in patients with metastatic breast cancer (MBC) (N=762), conducted when 77% of events (deaths) had been observed. The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxanebased chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy), and 3% hormonal therapy.

Halaven is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety Information Neutropenia

t Monitor complete blood counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days t Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels t Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy t Patients should be monitored closely for signs of peripheral motor and sensory neuropathy t Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less t Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days) t Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

Please see accompanying brief summary of Halaven full Prescribing Information.

To learn more about Halaven, visit www.halaven.com

HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2012 Eisai Inc. All rights reserved.

Printed in USA/August 2012 HALA0042 R1

25% (2.6 month)

(n=508)

13.2

INCREASE

(12.1, 14.4)

IN MEDIAN OS

Deaths=386

Treatment of Physician’s Choice (n=254)

10.6 (9.2, 12.0) Deaths=203

TIME (MONTHS) Number of patients at risk

a

Indication

Halaven

508 254

406 178

274 106

142 61

54 26

11 5

0 Halaven 0 TPC

CI=confidence interval; Treatment of Physician’s Choice (Control arm)=TPC. Conducted in the intent-to-treat (ITT) population.

Pregnancy Category D t Halaven is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks

QT Prolongation t In an uncontrolled ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities t Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment t For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Most Common Adverse Reactions t Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%) t The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%) References: 1. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2012. 2. Saad ED et al. J Clin Oncol.

2010;28(11):1958-1962. 3. Slamon DJ et al. N Engl J Med. 2001;344(11):783-792. 4. Geyer CE et al. N Engl J Med. 2006;355(26):2733-2743. 5. von Minckwitz G et al. J Clin Oncol. 2009;27(12):1999-2006. 6. Miller K et al. N Engl J Med. 2007;357(26):2666-2676. 7. Robert NJ et al. J Clin Oncol. 2011;29(10):1252-1260. 8. Sparano JA et al.

J Clin Oncol. 2010;28(20):3256-3263. 9. Jones SE et al. J Clin Oncol. 2005;23(24):5542-5551. 10. Cortes J et al.

Lancet. 2011;377(9769):914-923.

*HR=hazard ratio. † EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus E7389 (Eribulin).