TAP Vol 2 Issue 15

Metastatic breast cancer 7

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Maintenance treatment in NSCLC 11

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VOLUME 2, ISSUE 15

Hot chemotherapy debate 41

OCTOBER 15, 2011

ASCOPost.com

Editor-in-Chief, James O. Armitage, MD

2011 Breast Cancer Symposium

Studies Validate Safety of Breast-conserving Surgery in Young Patients with Breast Cancer

Health-care Policy: A Three-act Play

By Caroline Helwick

Y

oung age is not a Breast-conserving Therapy vs Mastectomy reason, in itself, to in Young Women recommend mastectomy for early breast cancer in ■■ In women aged 40 and younger, two studies found no difference in women aged 40 and undisease-free and overall survival between breast-conserving surgery and der, according to two studmastectomy. ies presented at the 2011 ■■ Young age alone is not a reason to recommend mastectomy.

Breast Cancer Symposium in San Francisco.

While younger women have been pegged as that young women who have breast cancer really having more aggressive disease, the results sugneed to have mastectomy,” Dr. Seidman commented. gest that contemporary management—including genetic testing, improved imaging techniques, and Retrospective Review more effective treatment—helps to ameliorate the In the first study, Julliette M. Buckley, MD, adverse factors associated with worse outcomes, a breast surgery fellow at Massachusetts Gensuggested Andrew D. Seidman, eral Hospital, Boston, led a retrospective review MD, of Memorial Sloan-Ketterof 628 patients aged ≤ 40 years (median age, 37) ing Cancer Center, who moderdiagnosed with stage I–III breast cancer between ated a press briefing.

1996 and 2008. Of these women, 71% had breast“This is an important revisitaconserving therapy.1 SEE PAGE 48 tion of the conventional wisdom continued on page 3 European Multidisciplinary Cancer Congress

International Prostate Cancer Studies Report Inroads in Managing Bone Metastases

By Alice Goodman

T

reatment and prevention of bone metastases in patients with prostate cancer is coming of age, according to several studies presented at the European Multidisciplinary Cancer Congress (ECCO/ESMO/ESTRO). Among the most impressive studies reported was an international phase III trial of radium-223, an investigational

radiopharmaceutical, evaluated in men with castration-resistant prostate cancer and symptomatic bone metastases. For the first time, a survival advantage was seen in the treatment arm receiving radium-223 along with delayed time to first skeletalrelated event (Fig. 1 on page 10).1 A separate phase III study demonstrated that denosumab (Prolia, Xgeva) delayed the development of bone metastasis in men with prostate cancer,2 and a third This is the first drug study found that ibandronate was as [radium-223] targeted effective as radiotherapy in treating pain related to bone metastasis in to bone metastases in prostate cancer.3

prostate cancer that has been shown to improve survival.

– Chris Parker, MD

By Richard Boxer, MD, FACS

T

he health of Americans, the economy, the debt crisis, and the action or inaction in Washington are all seriously interrelated. Decades ago, the bank robber Willie Sutton was asked why he robs banks. His famous answer, “Because that’s where the money is,” succinctly describes the approach that Washington has taken toward the health-care economy.

Affordable Care Act The last time Congress and the President balanced the budget, when President Bill Clinton and Speaker Newt Gingrich were in power, the economy was balanced on the back of health care, specifically nursing homes, home health, and reimbursement to hospitals and physicians.

Since physician services account for only 20% of the health-care dollar, all patient services had to be reduced in order to balance the budget. Hospitals, nursing homes, home health devices, and pharmaceuticals were then (and will be again) drastically affected. This new round of debt recontinued on page 2

Dr. Boxer is Professor of Clinical Urology at the University of Miami, and Clinical Professor at the University of Wisconsin, Madison, and the Medical College of Wisconsin.

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 Breast Cancer Symposium ������� 3, 7, 8 European Multidisciplinary Cancer Congress 2011 �������������������������9, 10 Best of ASCO® Annual Meeting ‘11 �� 31–34 Direct from ASCO ��������������������������������������� 22 Letters to the Editor ������������������������������������� 48

Radium-223 “Radium-223 chloride improved survival and time to [skeletal-related events] and was very well tolercontinued on page 9

October is Breast Cancer Awareness Month

A Harborside Press® Publication

The ASCO Post | OCTOBER 15, 2011

PAGE 2

Opinion

Health-care Policy continued from page 1

Editorial Board James O. Armitage, MD Editor-in-Chief

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD National Comprehensive Cancer Network

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University

Harold J. Burstein, MD Dana-Farber Cancer Institute

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Robert W. Carlson, MD Stanford University Medical Center

Lynn D. Wilson, MD Yale University School of Medicine

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Stanley H. Winokur, MD Singer Island, Florida

Jay S. Cooper, MD Maimonides Medical Center

William C. Wood, MD Winship Cancer Institute, Emory University

John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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earning more money than the original subsidy would allow, from $250 to $450, in 2014 and beyond), and flipped it to doctor reimbursement, so that doctors treating Medicare patients would not have a reduction in their compensation.

duction and, in part, the Patient Protection and Affordable Care Act passed in 2010 will also impact services—some positively, some negatively.

As a last ditch effort of the forces that were opposed to it in Congress, that Debt Reduction Act 2010 health-care reform legislation is beThe recently enacted Debt Reduction ing questioned as to its constitutionality.

Act of 2011, which caused such partisan Since the Republiwrangling in the cans could not kill preceding months, American physicians the legislation in increases the strain. either the House With this Act, a will use their...limitless or Senate, and the “super committee” commitment to President signed it, was created to find the third branch of $1.5 trillion in debt excellence to continue the Federal governreduction on top to improve health-care ment, the Judiciary, of the $1.5 trillion is where the focus the legislation allegquality, service, and has shifted. As of this edly reduces. In fact, patient outcomes. writing, two appeals the Debt Reduccourts have ruled tion Act only slows the Affordable Care the increase of the Act is constitutional and one has ruled it debt. The election of 2012 will determine is unconstitutional. The Obama Adminwhether there will be real savings because istration has requested that the Supreme the Act specifically lasts until early 2013.

Court hear this case. Thus, it will likely go Again, Congress has “kicked the can to the Supreme Court. I think the Court down the road.” may rule narrowly, that the portion of the Affordable Care Act requiring purchase of Accumulated Effects insurance does not meet the Commerce Thus, the accumulated effects of the Clause, but regardless of whether the Patient Protection and Affordable Care Court rules for or against that portion of Act (2010), the Sustainable Growth the Act, the remainder of the bill will reRate (1998, with continuing avoidance main the law of the land. The issue will not of the enforcement), and the Debt Rebe resolved until both the Court acts and duction Act (2011) were designed to the results of the 2012 election are deterincrease access, stabilize the economy, mined. and continue to fund Medicare at rates allowing health-care providers to mainBalanced Budget Act tain everyone’s desired service requireAs the Affordable Care Act proments, while reducing the debt. Uncergresses, another issue looms large: the tainty remains, but time will tell.

Balanced Budget Act of 1998 with its What is absolutely certain is that attendant Sustainable Growth Rate.

American physicians will use their enorThis Act provided for an automatic remous human and technologic resources duction in health provider payments if and limitless commitment to excellence to Medicare limits were exceeded (as they continue to improve health-care quality, have been for every year since). It has service, and patient outcomes. The quesnever been fully implemented, and each tion is, can the business model that has year Congress has pushed the enforcebeen the backbone of private solo, partment forward with an accumulated efnership, or group practice be sustained fect of each year increasing the amount with all the financial strains? Clearly, exof reduction to health providers for the penses for physicians’ small businesses are following year. Today, the “fix” for this not reduced by Acts of Congress. In fact, excess in Medicare spending will require they can have the opposite effect. nearly $250 billion. The law calls for docWorking with both Republicans and tors to receive a 30% reduction in annual Democrats—to educate them as to the payments beginning in 2013. However, consequences of their actions or inacCongress will certainly not allow this tions—is the only process by which draconian cut to occur.

American medicine can be maintained Demonstrating a bit of sleight of as it has been practiced for generations. hand, Congress took money from one The market and American leadership are program (the Affordable Care Act subtelling us we need to change the private sidies to families, raising the penalty for practice model. The battle is joined.

■

ASCOPost.com | OCTOBER 15, 2011

PAGE 3

2011 Breast Cancer Symposium continued from page 1

“Studies have shown that young age at diagnosis is an independent risk factor for local recurrence after

Julliette M. Buckley, MD

lumpectomy, and our study determined the risk of locoregional and distant recurrences in the modern era of multimodal treatment,” Dr. Buckley said.

At a median follow-up of 72 months, women who underwent breast-conserving therapy had no higher rates of locoregional or distant recurrences than women treated with mastectomy. For the overall group, the 5-year rate of locoregional recurrence was 5.6%, increasing to 13% at 10 years. Median time to first locoregional recurrence was 38 months.

By type of surgery, the 5- and 10year rates of locoregional recurrence

were 4.6% and 13.3%, respectively, after breast-conserving therapy and 8.5% and 10.8%, respectively, following mastectomy (Fig. 1).

In the overall group, disease-free survival was 82.5% at 5 years and 68.6% at 10 years. Overall survival rates were 93.1% and 87%, respectively.

On multivariate analysis, only tumor size > 2 cm and positive lymph nodes were independent predictors of recurrence. Adjuvant hormonal therapy reduced the risk of disease recurrence, both local and distant, twofold, Dr. Buckley reported.

According to these findings, she concluded, “lumpectomy is indeed a safe option for young women.”

15% Locoregional recurrence

Breast-conserving Surgery in Young Patients

Lumpectomy Mastectomy

10%

5%

Log-rank test: P = .4

0% 0

24

48

akesh Patel, MD, Medical Director of the Targeted Radiation Institute at Western Radiation Oncology, Pleasanton, California, was the invited discussant of the second study. He noted that in spite of well documented equivalent survival rates between the surgical approaches, mastectomy rates are increasing across all ages.

“There are multifactorial reasons for this,” he pointed out, “including improved reconstruction options, use of preoperative MRI, identification of high-risk patients with genetic predispositions, and concerns about long-term radiotherapy impact. And all the factors have a greater influence in younger patients.”

Mastectomy does prevent more locoregional recurrences, he acknowledged, and it is believed that “for every four local recurrences prevented, one life is saved.” But

96

120

Follow-up time (months)

Number at risk Lumpectomy 421

390

289

193

111

54

Mastectomy 162

127

79

53

28

11

Fig. 1: Cumulative incidence of locoregional recurrence by type of surgery. Courtesy of Julliette M. Buckley, MD.

Usama Mahmood, MD

SEER Database Analysis In the second study, researchers analyzed the Surveillance, Epidemiology, and End Results (SEER) database

of 14,764 women ≤ 40 years old diagnosed with early breast cancer (T1-2, N0-1, M0) between 1990 and 2007, 45% of whom underwent breast-conserving therapy.2 The median followup was 5.7 years.

After adjusting for numerous potential confounders, women treated with breast-conserving therapy had no worse

Expert Point of View

R

72

this is only true when the reduction in local recurrence is substantial, which is generally not the case for node-negative early breast cancer in young women.

Complex Decision The choice between breast-conserving therapy and mastectomy can be complex, he emphasized, and should take into account biologic factors, genetic risk, the variable effectiveness of systemic therapy, the need for radiation therapy postmastectomy, the potential for long-term side effects, and quality of life.

Commenting during the press conference, Andrew D. Seidman, MD, of Memorial Sloan-Kettering Cancer Center, agreed. “We are starting to look beyond the usual prognostic factors such as tumor size, grade, and

Andrew D. Seidman, MD

Rakesh Patel, MD

lymph node, estrogen receptor, and HER2 status, and are moving into biologic subtyping to obtain additional information regarding the risk of relapse.” He said he considers many factors when recommending a surgical approach. One reason mastectomy has become more palatable, he added, is the recognition that young women are immediately referred for a breast reconstruction consultation.

■

Disclosure: Drs. Patel and Seidman reported no potential conflicts of interest.

outcomes than women treated with mastectomy in terms of overall survival or breast cancer-specific survival, reported Usama Mahmood, MD, of The University of Texas MD Anderson Cancer Center in Houston. In a matched-pair analysis of 4,644 of these women, conducted when Dr. Mahmood was at the University of Maryland, 10-year overall survival was 83% and 10-year cause-specific survival was 86% in each treatment group.

“While a series of studies have compared breast-conserving therapy to mastectomy and found equivalent survival in early-stage breast cancer, there has nonetheless been reluctance to apply the findings to young women.

Our study suggests that young women should be counseled appropriately regarding their treatment options and should not choose a mastectomy based on an assumption of improved survival,” Dr. Mahmood concluded.

■

Disclosure: Drs. Buckley, Seidman, and Mahmood reported no potential conflicts of interest.

References 1. Buckley JM, Coopey S, Samphao S, et al: Recurrence rates and long-term survival in women diagnosed with breast cancer at age 40 and younger. 2011 Breast Cancer Symposium. Abstract 70. Presented September 8, 2011.

2. Mahmood U, Morris CG, Neuner GA, et al: Equivalent survival with breast conservation therapy or mastectomy in the management of young women with earlystage breast cancer. 2011 Breast Cancer Symposium. Abstract 85. Presented September 8, 2011.

The ASCO Post | OCTOBER 15, 2011

PAGE 4

Expert’s Corner

Can Bayesian Design Streamline Our Sluggish Clinical Trial System?

By Ronald Piana

Donald A. Berry, PhD

T

he randomized controlled clinical trial has long been the gold standard for new cancer drugs to demonstrate worthiness of FDA approval; however, many experts contend that that our method of bringing drugs to the market is plagued by undue costs, long delays, and overregulation. According to Donald A. Berry, PhD, Professor, Department of Biostatistics, The University of Texas MD Anderson Cancer Center, we could streamline drug approval by using the Bayesian approach to design more efficient trials. Dr. Berry published an editorial in the Journal of Clinical Oncology about “Adaptive Clinical Trials: The Promise and the Caution,”1,2 and recently spoke about the subject with The ASCO Post.

Trial Design What’s the major difference between traditional trial design and Bayesian adaptive design.

That is difficult to answer because traditional trial designs are, in fact, adaptive. The recent push toward adaptive design is actually one of

degree. Traditional designs are generally simple, with fixed randomization ratio, fixed treatment arms (usually two), and fixed sample size. The main adaptive aspects of traditional phase III clinical trials are interim analyses, which allow for stopping the trial early and announcing the results.

Traditional cancer trials address a single question, whereas “more adaptive” clinical trials address many questions. These questions may include: Which treatment is best among a set of possibilities, allowing for combination therapies? What doses and schedules?

For which patients? Thus, the promise of adaptive clinical trials is that they answer more questions and faster.

Traditional phase III trials tend to be large, and they are getting larger all the time. Think of them as aircraft carriers, while adaptive designs are more like PT boats.

I-SPY 2 Can you share an example of an adaptive trial that you helped design?

Yes, I am coordinating the I-SPY 2 trial (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) with Laura Esserman, MD, MBA, Director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco (see sidebar).

It’s a phase II drug screening trial in neoadjuvant therapy for breast cancer. At any time there are as many as six arms, including a standard therapy control arm. Using Bayesian predic-

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Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

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A Snapshot of I-SPY 2

W

ith principal investigator Laura Esserman, MD, MBA, of the University of California, San Francisco, and co–principal investigator Donald Berry, PhD, of MD Anderson Cancer Center, I-SPY 2 will screen up to 12 different drugs in neoadjuvant therapy for breast cancer over the course of the trial. In order to do this, the trial designers received a master Investigational New Drug (IND) approval from the FDA—which allows them to graduate, drop, and add drugs seamlessly, without having to stop the trial to write a new protocol, dramatically reducing the time it takes to move from one drug to another. The simple device of having a common control arm is a major efficiency.

The focus of the trial is to match experimental drugs with tumor biomarker signatures. The trial is a prototype of personalized medicine. It is sponsored by the Cancer Biomarkers Consortium, which is a public-private partnership managed by the Foundation for the National Institutes of Health. The trial demonstrates the willingness and, indeed, the enthusiasm of pharmaceutical companies to work together to improve the speed and efficiency of cancer drug development.

Three new investigational agents currently in development have already been selected for testing as part of the first phase of the trial. These agents include: ■■ ABT-888 (veliparib), a PARP inhibitor ■■ AMG 386, an angiogenesis inhibitor ■■ HKI-272 (neratinib), a pan ErbB inhibitor

■

tors of success in a small, focused phase III trial, the arms are replaced as they graduate to phase III or are dropped because of futility. The ultimate goal is to provide information about which drugs benefit which patients, leading to smaller phase III trials that involve patients who respond to the experimental therapy.

Cautionary Note What should we be cautious about as we move further into this new trial design?

Biases can creep into adaptive trials. For example, if the investigators and others know the adaptations, then such knowledge reveals trial results. This could affect the conduct of the trial and therefore the trial’s credibility.

Caution is indeed appropriate, as the FDA points out in a draft guidance on adaptive designs. Much of the territory is unexplored. It took many years for medical researchers to learn how to properly build and conduct continued on page 6

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The ASCO Post | OCTOBER 15, 2011

PAGE 6

Expert’s Corner

Bayesian Design and the Clinical Trial System continued from page 4

seemingly simple randomized trials.

Adaptive trials are usually much more complicated and therefore more challenging.

And some adaptive trial designs are just plain dumb.

Outcome-adaptive randomization seems intuitive. What are the practical obstacles that this model faces in cancer drug development?

Naysayers defending the status quo.

Speed and Efficiency The Institute of Medicine (IOM) has issued a report to improve speed and efficiency of clinical trial development and activation.3 Does the adaptive clinical trial model help accomplish that goal?

Yes, it does. Indeed, a principal focus of chapter 2 of the IOM report is adaptive clinical trials, and Bayesian adaptive trials, in particular. This excerpt from chapter 2 of the IOM report addresses your question: [T]he current explosion of biological knowledge demands increased attention to developing trial designs that can take advantage of this knowledge more fully…many clinical trialists are developing approaches to clinical trials that involve multiple stages or otherwise permit increased flexibility by SEE PAGE 48 allowing for changes

to be made during the trial, based on emerging results. Such design innovations have potential for decreasing the time to study conclusions and improving the likelihood of offering effective treatment to a greater proportion of trial participants.

Endpoints Where do endpoints factor in when designing adaptive clinical trials?

In one sense the issue is independent of one’s approach to trial design: In an adaptive approach, one adapts

long in coming. There may be information available about how each patient is doing over time, and this information can be used to model the primary endpoint.

One simple example is disease progression. A patient whose disease has not progressed usually lives longer than one whose disease has progressed. More generally, we may be able to use imaging or other longitudinal biomarkers to assess tumor burden in anticipation of the primary endpoint.

The randomized controlled trial has taken medical research to a high scientific plateau. But it is more than 60 years old and has changed little over that period. We cannot be satisfied with the status quo. to the endpoint. But the timing of the endpoint can affect the usefulness of an adaptive approach. Suppose the endpoint becomes known 2 years after treatment and the trial’s accrual period is shorter than 2 years. Information starts to accrue only after all the patients are treated and therefore no adaptations are possible. In some cancers, overall survival is long (happily so!) and so it is difficult to adapt…unless accrual is very slow.

In many ways cancer has lagged behind other therapeutic areas in being adaptive. But in one way it excels, and that is when the primary endpoint is

Looking Ahead Another major issue in our trial system is the waste of intellectual energy and precious resources associated with the extremely high failure rate of clinical trials.

Do adaptive trials offer relief from this syndrome?

Of course there are going to be failures; however, with adaptive design, trials involving agents that are not effective in any subset of the disease fail early, saving substantial costs and enabling drug developers to move into more promising directions.

Any last thoughts on the landscape of U.S. clinical cancer trials?

Visit The ASCO Post website at:

Atlanta after Sherman’s armies marched through comes to mind.

Only one out of three phase III cancer trials is successful. This is the worst of all therapeutic areas, with cardiovascular phase III trials a distant second worst at 46%. One result is the burgeoning cost of cancer therapies. More important is the consequent slow pace of cancer drug development.

Finally, I want to stress that I am enormously respectful of randomization in clinical trials. The randomized controlled trial has taken medical research to a high scientific plateau. But it is more than 60 years old and has changed little over that period. We cannot be satisfied with the status quo. We must explore ever-higher plateaus. There are dangers along the way but the climb is inevitable. And it will help speed the cures for cancer.

■

Disclosure: Dr. Berry is co-owner of Berry Consultants, LLC. Berry Consultants designs adaptive clinical trials—including some in oncology—for pharmaceutical companies, medical companies, and NIH cooperative groups.

References 1. Berry DA: Adaptive clinical trials: the promise and the caution. J Clin Oncol 29:606-609, 2011.

2. Korn EL, Freidlin B: Outcome-adaptive randomization: Is it useful? J Clin Oncol 29:771-776, 2011.

3. Institute of Medicine: A national cancer clinical trials system for the 21st century: Reinvigorating the NCI Cooperative Group Program. http:// books.nap.edu/openbook.php?record_ id=12879

ASCOPost.com

ASCOPost.com | OCTOBER 15, 2011

PAGE 7

2011 Breast Cancer Symposium No Value for Axillary Dissection in Patients with Breast Cancer and Occult Nodal Metastases

By Caroline Helwick

I

n a subanalysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 study, nearly 16% of clinically node-negative patients were found to have occult metastases upon more detailed assessment of the sentinel lymph nodes. While a slight difference in outcomes was found among this group, there were no differences according to whether the patients underwent sentinel node dissection or axillary lymph node dissection, Thomas Julian, MD, of Allegheny General Hospital, Pittsburgh, reported at the 2011 Breast Cancer Symposium in San Francisco.1

1.2% for mortality and 2.8% for diseasefree survival. At 5 years, overall survival was excellent in both groups: 94.6% in

those with occult metastases and 95.8% among those without occult metastases.

“So our question was, if there is a dif-

ference according to the presence of occult metastases, did the addition of axilcontinued on page 8

Now Enrolling A Randomized Phase 3 Trial

Thomas Julian, MD

Clinical Importance Questionable “The clinical importance of immunohistochemistry-detected occult metastases is questionable,” said Dr. Julian.

The NSABP B-32 investigators had previously reported small but statistically significant differences in outcomes for patients found to have occult metastases.2 Patients with occult metastases had a 40% increase in mortality (P = .03) and a 30% increase in distant disease (P = .02), compared with patients with no occult metastases. However, the absolute differences were only

R A N D O M I Z E D

Placebo Q2W + Gemcitabine Ganitumab 12 mg/kg Q2W + Gemcitabine Ganitumab 20 mg/kg Q2W + Gemcitabine

KEY INCLUSION CRITERIA:

■■ Of 3,986 patients with breast

• Previously untreated with chemotherapy or radiation

■■ Disease-free and overall survival were slightly worse among patients with occult metastases.

■■ Axillary nodal dissection

Primary endpoint

Ganitumab (AMG 479) is an investigational IGF1R inhibitor that has not been approved by the FDA.

Occult Metastases in Breast Cancer cancer in NSABP B-32 who had negative sentinel nodes, 15.9% had occult metastases on deeper examination.

OS

• Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas (AJCC Stage IV) • ECOG Performance Status 0 or 1 For Additional Information: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com (20060540) • www.ClinicalTrials.gov (NCT01231347)

Oncology

provided no additional benefit over sentinel node dissection alone.

ASCO 2011 Journal Ad_AMG479_090611.indd 1

9/6/2011 5:08:17 PM

The ASCO Post | OCTOBER 15, 2011

PAGE 8

2011 Breast Cancer Symposium continued from page 7

lary dissection factor into this?” Dr. Julian said, “but we found no effect of treatment on overall and disease-free survival.”

Key Data The pathology research team, led by Donald L. Weaver, MD, performed a more detailed assessment of the sentinel nodes, involving deeper sectioning and immunohistochemistry staining. Among the 3,986 patients with clinically and H&E-negative sentinel nodes, occult metastases were identified in 616 patients: 316 in the axillary lymph node dissection arm and 300 in the sentinel node dissection arm (for 51 per arm, occult metastases status remained unknown).

Among patients with occult nodal metastases, complete axillary lymph node dissection did not significantly improve overall survival (HR = 0.89; P = .62; Fig. 1) or disease-free survival (HR = 0.79; P = .16), Dr. Julian reported.

The overlooked metastases were mostly isolated tumor cell clusters (11.1%) or micrometastases SEE PAGE 48 (4.4%). However, 0.4% of patients thought to have negative sentinel nodes actually had macrometastases > 2.0 mm. Axillary lymph node dissection identified 23 patients (7%) with additional nodal metastases beyond the

sentinel nodes.

The actual differences in outcomes were less than 3%.

Therefore, systemic therapy in these patients would add little benefit while conveying toxicity. No benefit in overall or disease-free survival was seen when axillary lymph node dissection to detect the presence of occult metastases was added, especially since only 23 patients had additional positive nonsentinel nodes, Dr. Julian concluded.

Similar Findings in Other Study

100% 80% Percentage alive

Occult Metastases in Breast Cancer

60% 40%

Group

N

SNR+AD 316 SNR 300

20%

Deaths 37 31

HR

P

0.89 .62

0% 0

2

4

6

8

The results are congruent Years after randomization with previous findings from the American College of 1: Overall survival of patients with sentinel node–negative breast cancer and occult metastases in the NSABP B-32 Surgeons Oncology Group Fig. study. HR and P value adjusted for age, clinical tumor size, and planned type of surgery. AD = axillary dissection; SNR = (ACOSOG) Z11 study, sentinel node resection. Courtesy of Thomas Julian, MD. which found no survival Cancer Symposium. Abstract 80. Presentbenefit from complete axillary lymph noted. “We as surgeons affect survival ed September 8, 2011. node dissection compared with sentinel by achieving local-regional control, 2. Weaver DL, Ashikaga T, Krag DN, et node dissection only (P = .008 for nonand both approaches did that. There al: Effect of occult metastases on survival inferiority).3 In Z11, more extensive diswas no difference in survival.” in node-negative breast cancer. N Engl J Disclosure: Drs. Julian, Weaver, and Giuliano section revealed that 27% of patients had Med 364:412-421, 2011. reported no potential conflicts of interest. positive nodes beyond the sentinel nodes, 3. Guiliano AE, McCall LM, Beitsch PD, et al: ACOSOG Z0011: A randomsaid Armando E. Giuliano, MD, of Ceized trial of axillary node dissection in dars-Sinai Medical Center, Los Angeles, References women with clinical T1-2 N0M0 breast 1. Julian TB, Anderson SJ, Mamounas who also spoke at the symposium. cancer who have a positive sentinel node.

EP, et al: Effect of axillary dissection for “About 27% of patients with senti2010 ASCO Annual Meeting. Abstract occult detected sentinel nodes metastases nel node dissection only had unresectCRA506.

Presented June 7, 2010. on survival: NSABP B-32. 2011 Breast ed cancer remaining in the axilla,” he

■

Expert Point of View wo breast cancer studies presented at the 2011 Breast Cancer Symposium—NSABP B‑32 and ACOSOG Z11—suggest that aggressive approaches to surgically remove occult metastases are not necessary.

Armando E. Giuliano, MD, of Cedars-Sinai Medical Center, Los Angeles, and principal investigator of ACOSOG Z11, said that based on the latest data, complete axillary lymph node dissection does not improve outcomes for most women with sentinel node metastases. As a surgeon, he commented, “Most of us believe removing tumors is always a good thing.” But, he added, “We cannot ignore biology and results of prospective randomized studies. It seems that lymph node metastases often lack the ability to metastasize to other sites. Metastatic sites might be tumor-

specific, and removal of axillary lymph nodes in patients with limited metastases is not beneficial.”

He added that contemporary trials show that axillary recurrences are extremely rare.

In ACOSOG Z11, the difference in regional recurrence between axillary Armando E. Giuliano, MD dissections and sentinel node biopsy alone was only 0.4%. At worst, this could predict for just a 0.1% survival advantage at 15 years. Based on these data, he reserves axillary lymph node dissection for patients with clinically palpable nodes only.

Donald L. Weaver, MD, of the Uni-

versity of Vermont College of Medicine, Burlington, who served as the B-32 protocol pathologist, agreed the two studies have important implications—namely, they argue against intensively looking for small metastases that will not make a difference in outcome.

Donald L. Weaver, MD “ The more you look, the more you find,” Dr. Weaver acknowledged, but this results in diminishing returns and additional work, and is of questionable value to the patient, he suggested.

“Occult metastases are not discriminatory predictors of outcome!”

Raj Chawla/UVM Medical Photography

T

he emphasized. Regional and distant recurrences in B-32 occurred in 3.6% of the sentinel node–negative population, including 21.7% of patients in this subgroup with occult metastases and 78.3% without, he pointed out.

“If additional treatment was given based exclusively on the presence of occult metastases, 90% of these patients would be overtreated,” he said.

He calculated that this amounts to $44.8 million in health-care dollars spent per year to account for a 1.2% difference in outcome.

Dr. Weaver’s recommendation is that pathologists should continue to section sentinel lymph nodes no thicker than 2 mm and examine one microscopic section from each block, without requiring additional levels or immunohistochemistry.

■

Disclosure: Drs. Giuliano and Weaver reported no potential conflicts of interest.

ASCOPost.com | OCTOBER 15, 2011

PAGE 9

European Multidisciplinary Cancer Congress 2011 Prostate Cancer and Bone Metastases continued from page 1

ated. If approved, this drug is likely to become standard of care,” said Chris Parker, MD, Royal Marsden Hospital, London. “This is the first drug targeted to bone metastases in

Expert Point of View

“R

adium-223 chloride is an effective, well tolerated, and convenient treatment, and it has a survival benefit. These favorable characteristics may well promote its use in clinical practice,” said formal discussant of this abstract, Wim J.G. Oyen, MD, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Wim J.G. Oyen, MD

“An alpha-emitting radiopharmaceutical appears to have more advantages than beta-emitters,” he said. “Beta-emitters aim at palliation of pain, but they have frequent adverse events and no survival advantage,” Dr. Oyen said, adding that hematologic toxicity is common.

“ALSYMPCA demonstrated a remarkable survival advantage for radium-223, with limited, if any, toxicity,” Dr. Oyen said.

“Put in perspective with other trials of newer treatments for prostate cancer, radium-223 achieved a gain of 2.8 months in overall survival, very similar to other new treatment options such as abiraterone (Zytiga), which gained 3.9 months, and sipuleucil-T (Provenge), which produced a survival gain of 4 months.

Dr. Oyen said that in order to explore further patient benefits, radium-223 should be studied in combination with other therapies and should be explored in the adjuvant setting for high-risk patients.

■

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

prostate cancer that has been shown to improve survival. Other drugs targeted to the bone treat symptoms,” he added.

The ALSYMPCA international phase III trial (ALpharadin [radium-223] in SYMptomatic Prostate Cancer) was selected as a Late-

Breaking Abstract for the Presidential Session at the European Congress.

Injectable radium-223 targets areas of new bone formation, such as cancer metastasis, and emits highly damaging short-range alpha particles.

This kills the tumor cells but spares the more distant cells in the bone

marrow, Dr. Parker explained.

“Only a few hits are required with radium-223, whereas with beta radiation [used in other radiopharmaceuticals], thousands of hits are needed, and there is damage to the surrounding tissue,” Dr. Parker said. continued on page 10

The ASCO Post | OCTOBER 15, 2011

PAGE 10

European Multidisciplinary Cancer Congress 2011 Prostate Cancer and Bone Metastases continued from page 9

Treatment with radium-223 takes 5 minutes and is performed on an outpatient basis.

Randomized Study Design The ALSYMPCA international trial enrolled 922 men from 19 countries with hormone-refractory prostate cancer and multiple symptomatic bone metastases. Patients were randomized 2:1 to either 6 injections of radium-223 given 1 out of every 4 weeks or sham placebo injections; all patients also received current standard of care.

Median overall survival was 14 months in the radium-223 arm vs 11.2 months in placebo patients (P= .000185). Median time to first skeletal-related event was 13.6 months vs 8.4 months, respectively (P = .00046), representing a 39% improvement with the alpha-emitting agent.

Other findings were normalization of alkaline phosphatase in 33% of men treated with radium-223 versus 1% of placebo patients, and a 49% improvement in time to PSA progression (P = .00015).

Dr. Parker said that radium-223 was well tolerated. “This is one of the very few trials with more adverse events reported in the placebo group,” he said.

Grades 3 and 4 hematologic toxicities were: anemia, 11% with radium-223 vs 12% with placebo; neutropenia, 2% vs 1%, respectively; and thrombocytopenia, 4% vs 2%, respectively. The most common nonhematologic adverse events in both groups were bone pain,

nausea, diarrhea, constipation, and vomiting.

Quality-of-life data were collected and will be analyzed at a future time, Dr. Parker said.

Denosumab Denosumab delayed the onset of bone metastasis by 4 months compared with placebo in men with castration resistant prostate cancer in a separate international, double-blind, randomized trial.2 The main results were reported at the May 2011 meeting of the American Urological Association. Stephane Oudard, MD, George Pompidou Hospital, Paris, France, reported subgroup analyses at the European Congress showing that denosumab’s effects were consistent across all prespecified subgroups.

Managing Bone Metastasis in Prostate Cancer ■■ For the first time, a treatment for bone metastasis has shown a survival advantage in men with prostate cancer.

■■ Radium-223, an alpha-emitting radiopharmaceutical, prolonged survival by about 3 months and delayed the time to skeletal-related events by about 5 months compared with placebo.

■■ Denosumab delayed the development of bone metastasis by about 4

months compared with placebo in men with castration-resistant prostate cancer, but did not impact survival.

■■ A single dose of ibandronate was as effective as a single dose of

radiotherapy in improving bone pain in men with metastatic prostate cancer, but 50% of patients in both treatment arms did not achieve pain relief.

rent data, overall survival was identical compared with placebo. This may not meet regulatory muster. The FDA may not consider bone scan changes an important endpoint,” stated Oliver Sartor, MD, Director of the Prostate Program at Tulane Cancer Center in New Orleans.

Ibandronate

A late-breaking abstract presented at the European Congress showed that single-dose ibandronate was no better than a single dose of radiation therapy Oliver Sartor, MD for localized metastatic bone pain in the multicenter randomized RIB trial.3 “This is the first demonstration That study included 407 men with that targeting the bone environment prostate cancer and metastatic bone prevents bone metastasis,” said J. Bellpain who were randomized to either munt, MD, Hospital del Mar, Barcetreatment with ibandronate or radialona, Spain, formal discussant of the tion therapy; crossover was allowed subgroup analyses. at 4 weeks if pain relief was insuffi“A caveat for this trial is that overcient. Overall survival was no differall progression-free survival was not ent between the two treatment arms. altered by denosumab. Based on curThe study was presented by Peter J. Hoskin, MD, Mt. Vernon Cancer Center, Northwood, Middlesex, UK. Discussant of this ab100% HR = 0.695; 95% CI, 0.552–0.875 stract, Daniel Zips, MD, 90% P = .00185 Technische Universität, 80% Dresden, Germany, said, 70% “This is the first large 60% randomized controlled Radium-223, n = 541 trial to compare radio50% Median OS: 14.0 months therapy vs bisphospho40% nates in the treatment 30% of metastatic bone pain.

Placebo, n = 268 20% The major finding was Median OS: 11.2 months equivalence for pain re10% lief. However, with both 0% treatments, 50% of paMonth 0 3 6 9 12 15 18 21 24 27 tients don’t have a good response. We need better Radium-223 541 3 0 450 330 213 120 72 30 15 therapies for bone pain.”

Placebo 268 218 147 89 49 28 15 7 3 0 Dr. Zips said that in his view, radiotherapy will reFig. 1: Overall survival (OS) in ALSYMPCA trial. Courtesy of Chris Parker, MD.1 main the standard of care

for metastatic bone pain. “However, ibandronate remains an effective treatment option for patients who can’t tolerate radiotherapy,” Dr. Zips added.

■

Disclosure: Dr. Parker has received honoraria from Bayer for advisory boards. Dr. Sartor has been a consultant to Amgen.

References 1. Parker C, Heinrich D, O’Sullivan JM, et al: Overall survival benefit of radium-223 chloride (Alpharadin) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer: A phase III randomized trial (ALSYMPCA). Eur J Cancer 47 (suppl 2): 3 , 2011 (Abstract 1LBA).

2. Oudard S, Smith M, Karsh L, et al: Denosumab and bone metastasis-free survival in men with castrate-resistant prostate cancer: Subgroup analyses from an international, double-blind, randomized, phase 3 trial. Eur J Cancer 47 (suppl 1): S484, 2011 (Abstract 7003).

3. Hoskin P, Sundar S, Reczko K, et al: A multicenter randomized trial of ibandronate compared to single dose radiotherapy for localized metastatic bone pain in prostate cancer (RIB). Eur J Cancer 47 (suppl 2): 6, 2011 (Abstract 7LBA).

FDA Update

I

n September 2011, FDA approved denosumab (Prolia) as a treatment to increase bone mass in patients at high risk of fracture from androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer.

Denosumab, also marketed under the brand name Xgeva, was approved by FDA in November 2010 for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

See FDA Update on page 13 for more information on this recent approval.

■

ASCOPost.com | OCTOBER 15, 2011

PAGE 11

JCO Spotlight Thoracic Oncology

New ASCO Focused Update Recommendation on Maintenance Treatment of Stage IV Non–Small Cell Lung Cancer

By Matthew Stenger

A

focused update to the 2009 ASCO Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer reflects new evidence on maintenance therapy in patients with response or stable disease after four cycles of first-line cytotoxic chemotherapy.1 The 2009 update recommendation (recommendation A6) stated that cytotoxic chemotherapy should be stopped at progression or after four cycles in patients without response and evidence that did not support (1) continuation of cytotoxic chemotherapy until disease progression or (2) initiation of a different chemotherapy before disease progression in patients with stable disease or response to first-line SEE PAGE 48 therapy.2

New 2011 Recommendation The 2011 focused update states that for patients with stable disease or response after four cycles, “immediate treatment with an alternative, singleagent chemotherapy such as pemetrexed in patients with nonsquamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered [italics added].” The recommendation also states that because of limitations of the data in this area, a break from cytotoxic chemotherapy in patients with response or stable disease after a fixed course of first-line therapy is also an acceptable option, with second-line treatment being delayed until disease progression.

It continues to be recommended that first-line cytotoxic chemotherapy

be stopped at disease progression or after four cycles in patients not responding and that two-drug cytotoxic combinations be given for no more than six cycles.

‘Switch Maintenance’ Trials The focused update is based on review of data from seven phase III trials involving immediate non–cross-resistant alternative therapy (“switch maintenance”) in patients with response or stable disease after first-line treatment.

The trials using docetaxel, pemetrexed (Alimta, in patients with non–squamous cell carcinoma), erlotinib (Tarceva), gefitinib (Iressa), and gemcitabine as switch maintenance therapy showed increased progression-free survival with maintenance therapy, with one of the two trials using erlotinib and the trial using pemetrexed also showing statistically significant increases in overall survival. These gains were accompanied by acceptable toxicity.

Key findings from these trials included the following: ■■ Immediate docetaxel showed an increase in progression-free survival vs delayed docetaxel (5.7 vs 2.7 months; P < .001) and a trend toward increased overall survival (12.3 vs 9.7 months; P = .0853).

■■ Pemetrexed showed prolonged progression-free survival (4.3 vs 2.6 months; HR = 0.502; P < .001) and overall survival (13.4 vs 10.6 months; HR = 0.79; P = .012) vs placebo, with benefit limited to patients with nonsquamous histology.

■■ Erlotinib significantly increased progression-free survival, though

Recommendation on Maintenance Treatment of Stage IV NSCLC ■■ First-line cytotoxic chemotherapy should be stopped at disease

progression or after four cycles in patients whose disease is stable but not responding to treatment.

■■ First-line two-drug cytotoxic combinations should not be given for more than six cycles.

■■ In patients with response or stable disease after four cycles of first-

line cytotoxic chemotherapy, immediate switching to single-agent maintenance therapy with pemetrexed in patients with nonsquamous histology, or docetaxel in unselected patients, or erlotinib in unselected patients, may be considered.

■■ A break from cytotoxic chemotherapy in such patients is also acceptable, with initiation of second-line therapy at disease progression.

The March of Progress in Lung Cancer Treatment

By Christopher G. Azzoli, MD

B

efore the discovery of predictive molecular tests (eg, EGFR mutation and ALK rearrangement), each chemotherapy drug for stage IV non–small cell lung cancer had about the same chance of success. Progress was made as more drugs were discovered. Patients lived longer with second- and third-line therapies, and studies were launched to improve the sequence and timing of drug selection.

The studies considered in this guideline update Christopher G. Azzoli, MD showed that second-line drugs given immediately after completion of first-line therapy (so-called “switch maintenance” therapy) improve survival. The studies that showed an improvement in overall survival did not mandate second-line therapy, and stopped therapy at four cycles in patients responding to first-line therapy. This leaves doubt as to how much survival gain was due to better treatment with switch maintenance, or undertreatment in the control arm.

Also, these studies were launched before the advent of molecular tests, which have since revolutionized chemotherapy drug selection for this disease.

Still, these studies demand attention because they contribute to a march of progress in which more drugs, more choice, and more opportunities for treatment are leading to better outcomes for our patients.

■

Disclosure: Dr. Azzoli reported receiving research funding from Genentech, sanofi-aventis, and Eli Lilly.

by only 1.2 weeks, vs placebo (12.2 vs 11.1 weeks; HR = 0.71; P < .001). Overall survival was prolonged by 1 month (12 vs 11 months; HR = 0.81; P = .0088) In another trial, erlotinib or placebo was added to continued bevacizumab (Avastin) after four cycles of platinum-based therapy plus bevacizumab. Progressionfree survival was prolonged for erlotinib vs placebo (4.8 vs 3.7 months; HR = 0.72; P = .0012), with no difference in overall survival.

The update committee did not specify erlotinib plus bevacizumab as an acceptable switch maintenance regimen because of lack of data showing an overall survival benefit of either maintenance bevacizumab alone or switch maintenance with erlotinib plus bevacizumab.

■■ No benefit of carboxyaminoimidazole vs placebo was found after 3 to 6 months of chemotherapy in a trial closed due to slow accrual.

■■ Gefitinib vs continued platinum doublet chemotherapy (up to six

cycles) produced a statistically but not clinically significant prolongation in progression-free survival (4.6 vs 4.3 months; HR = 0.68; P < .001), with no difference in overall survival.

■■ Progression-free survival was prolonged with maintenance gemcitabine (3.8 vs 1.9 months; HR = 0.55; P < .001) and maintenance erlotinib (2.9 vs 1.9 months; HR = 0.82; P = .002) vs observation after four cycles of cisplatin/ gemcitabine, with no difference in overall survival based on preliminary findings.

ASCO guidelines indicate that patients with radiologic response after four cycles of first-line cytotoxic chemotherapy may be considered for continuation of treatment for two additional cycles. In line with this recommendation are data on switch maintenance therapy indicating better response with the cytotoxic agents docetaxel and gemcitabine in patients with response vs stable disease after four cycles of platinum-based firstline treatment. continued on page 12

The ASCO Post | OCTOBER 15, 2011

PAGE 12

JCO Spotlight

NSCLC Guidelines Update continued from page 11

Toxicity and Chemotherapy Breaks The ASCO panel notes that the clinical trial data used for establishing the guidelines for duration of firstline chemotherapy involve drugs that are associated with cumulative toxicity and that the advent of new drugs without cumulative toxicity, as well as biomarkers for their effectiveness, will “complicate and perhaps diminish the importance of the question of optimal duration of therapy.”

The panel also notes that it would be of interest to analyze why some of the patients in the control arms of the reviewed studies, whose treatment had resulted in disease control after four cycles of first-line treatment, did not receive second-line treatment. In this regard, the panel states, “Until the time of further [overall survival] benefit shown in studies in which there was sufficient second-line therapy offered to participants in the control arm, and given the limitations of current data, the panel accepts as viable the traditional approach of allowing patients a break from cytotoxic chemotherapy after a fixed course of first-line therapy, with initiation of second-line chemotherapy at disease progression.”

5 and 6 improves PFS. ■■ The focused update recommendation involves only single-agent maintenance therapy. Further, it does not specifically recommend for or against switch maintenance in patients with response or stable disease after 4 cycles of first-line therapy, with the op-

tion of second-line treatment delayed until disease progression.

■

References 1. Azzoli CG, Temin S, Aliff T, et al: 2011 focused update of 2009 American Society of Clinical Oncology clinical practice guideline update on chemotherapy for

stage IV non–small-cell lung cancer. J Clin Oncol. September 6, 2011 (early release online).

2. Azzoli CG, Baker S Jr, Temin S, et al: American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol 27:6251-6266, 2009.

For Locally or Regionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)...

Select ERBITUX + RT

Further Considerations Important considerations in implementing the focused update include the following: ■■ The recommendation regarding switch maintenance generally applies to patients whose fitness is sufficient to tolerate increased adverse events.

■■ The recommendation for pemetrexed does not apply to patients receiving this agent as part of initial treatment, since such patients were not included in the study supporting the recommendation.

■■ Data are insufficient to suggest a best switch maintenance approach in patients receiving bevacizumab or cetuximab in first-line treatment, since such patients were not included in any trial showing OS benefit.

■■ There are no data to guide selection of best treatment for patents still responding to and tolerating platinum-based treatment after 4 cycles. In these patients, the traditional approach has been to continue first-line therapy, since there are data showing that delivery of cycles

ERBITUX Indications ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck ■ ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

ASCOPost.com | OCTOBER 15, 2011

PAGE 13

FDA Update

FDA Approves Denosumab to Increase Bone Mass in Patients with Cancer

D

enosumab (Prolia) recently received FDA approval as a treatment to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant

aromatase inhibitor therapy for breast cancer.

Pivotal Trials The approvals were based on results from two international, ran-

domized, double-blind, placebo-controlled trials in patients receiving androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy

for Increased OVERALL SURVIVAL ERBITUX Is the Only Anti-EGFR MAb With Increased Overall Survival in Combination With RT Survival in Combination With RT*1,2 ERBITUX + RT (n=211)

vs

RT alone (n=213)

Median overall survival 49.0 months

vs

29.3 months

vs

45%

19.7

month improvement

HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year survival rate 55% P=0.05

22%

improvement†

EGFR=epidermal growth factor receptor; MAb=monoclonal antibody; RT=radiation therapy; HR=hazard ratio; CI=confidence interval. * A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 † Relative increase in improvement, from 45% to 55%; ([55-45]/45) x 100=22. Median follow-up=54 months.2

■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

for breast cancer. Trial 20040138 was a 3-year trial that enrolled 1,468 men with prostate cancer (median age 76 years). Men less than 70 years of age were required to have either a baseline continued on page 14

The ASCO Post | OCTOBER 15, 2011

PAGE 14

FDA Update

FDA Approves Denosumab continued from page 13

bone mineral density T-score at the lumbar spine, total hip, or femoral neck between –1.0 and –4.0, or history of osteoporotic fracture. Trial 20040135 was a 2-year trial that enrolled 252 women with breast cancer (median age

59 years). Women had a baseline bone mineral density T-score at the lumbar spine, total hip, or femoral neck between –1.0 and –2.5 and had not experienced fracture after age 25.

Patients were randomized to receive subcutaneous injections of either placebo or 60 mg denosumab, once ev-

ery 6 months, for a total of 6 doses in the prostate cancer trial and for a total of 4 doses in the breast cancer trial.

Study Design and Outcomes The primary outcome measure in each trial was the percent change in lumbar spine bone mineral density, from

baseline to month 24 in men with prostate cancer and from baseline to month 12 in women with breast cancer. A secondary outcome measure in the prostate cancer trial was the incidence of new vertebral fractures through month 36.

In Trial 20040138, randomization was stratified by age (< 70 years vs ≥ 70

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In three patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms.

Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneiform rash occurred in 1-17% of patients — Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

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PAGE 15

FDA Update

years) and duration of androgen deprivation therapy at trial entry (≤ 6 months vs > 6 months). At trial entry 79% of patients received androgen deprivation therapy for more than 6 months.

In Trial 20040135, randomization was stratified by duration of adjuvant aromatase inhibitor therapy at trial

entry (≤ 6 months vs > 6 months). At trial entry 62% received adjuvant aromatase inhibitor therapy for more than 6 months.

Denosumab resulted in a statistically significant effect on bone mineral density as compared to placebo at 24 months in patients with nonmeta-

static prostate (P < .0001) and at 12 months in patients with breast cancer (P < .0001). In men with prostate cancer, denosumab also significantly reduced the incidence of new vertebral fractures at 36 months. The proportion of men with new vertebral fracture at 36 months was 1.5% in men treated

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

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

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2011. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

© 2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US11AB05808

5/11

with denosumab compared to 3.9% in men on the placebo arm ( P = .0125).

Safety and Administration Adverse reactions reported in ≥ 10% of denosumab-treated patients and more frequently than in placebocontinued on page 16

The ASCO Post | OCTOBER 15, 2011

PAGE 16

FDA Update

FDA Approves Denosumab continued from page 15

treated patients were arthralgia and back pain. Pain in extremity and musculoskeletal pain were also noted. Hypocalcemia was observed only in denosumab-treated patients (2.4%) at the month 1 visit.

The recommended dose and schedule for denosumab as a treatment to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer is 60 mg subcutaneously every 6 months.

On June 1, 2010, denosumab (Prolia) at the same dose and schedule was approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture. On November 18, 2010, denosumab (marketed under the tradename Xgeva) was approved for the prevention of skeletal-related

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

WARNING: seRIOUs INFUsION ReACTIONs and CARDIOPULMONARY ARResT Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.]

INDICATIONs AND UsAGe squamous Cell Carcinoma of the Head and Neck (sCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

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

Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONs None.

WARNINGs AND PReCAUTIONs Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.

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

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

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

Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.]

Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneiform rash occurred in 1–17% of patients.

Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]

Use of erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

Hypomagnesemia and electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

events in patients with bone metastases from solid tumors. The dose for this indication is 120 mg subcutaneously every 4 weeks.

Denosumab is a monoclonal antibody that binds to RANKL, a protein involved in the formation, function, and survival of osteoclasts.

■

epidermal Growth Factor Receptor (eGFR) expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

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

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

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

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

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

The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

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

Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

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

The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

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

Table 1:

Incidence of selected Adverse events (≥10%) in Patients with Locoregionally Advanced sCCHN erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) body system Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 Chills1 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 0 9 1 Dyspepsia 14 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 Alanine Transaminase, high3 43 2 21 1 38 1 24 1 Aspartate Transaminase, high3 33 <1 24 0 Alkaline Phosphatase, high3 Respiratory Pharyngitis 26 3 19 4 skin/Appendages 4 87 17 10 1 Acneiform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction.

Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

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

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

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FDA Update

New Biomarker Test Cleared to Evaluate Ovarian Cancer Likelihood

F

ujirebio Diagnostics announced that it has received 510(k) clearance from the FDA to market the company’s HE4 Test in an algorithm called ROMA to aid in assessing whether a premenopausal or postmenopausal

woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy on surgery.

The ROMA (Risk of Ovarian Malignancy Algorithm) test uses the results from simple blood tests, CA-125 and

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2:

Incidence of selected Adverse events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with erbitux Monotherapy erbitux plus bsC bsC alone (n=288) (n=274) body system Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 Infusion Reactions3 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 Mouth Dryness 11 0 4 0 Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.

Adverse events were graded using the NCI CTC, V 2.0.

3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated.

BSC = best supportive care 1 2

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%).

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

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

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

Postmarketing experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

• Aseptic meningitis DRUG INTeRACTIONs A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

HE4, to identify patients presenting with adnexal mass as being at high or low likelihood for finding malignancy on surgery. HE4 has been shown to be elevated in epithelial ovarian cancers but is not elevated in many benign gynecologic

Use IN sPeCIFIC POPULATIONs Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old.

No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.

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

NONCLINICAL TOxICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).

Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIeNT COUNseLING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

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

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

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

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

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

Copyright © 2004–2011 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886A8

ER-B0001A-03-11

Rev March 2011

diseases. Combining physician assessment with the independently validated ROMA algorithm enables physicians to identify patients at high likelihood of malignancy who should have their surgery performed by a gynecologic oncologist.

“This combination test will allow physicians to identify those patients who should be treated by a gynecologic oncologist and equally important allow women with benign disease to stay in their communities with the physician who knows them best. It will change the way doctors diagnose and treat ovarian cancer,” said Richard G. Moore, MD, Associate Professor of Obstetrics and Gynecology at the Alpert School of Medicine at Brown University in Providence, Rhode Island. Dr. Moore is the lead researcher for the team that developed ROMA and author of two multicenter studies investigating the use of HE4 and CA-125 and ROMA.

Published Data A large body of published, multinational, peer-reviewed clinical eviSEE PAGE 48 dence supports the use of the HE4 test in combination with the CA-125 test.

Its utility as a stratification tool is supported by results from a prospective, double-blind, multicenter trial involving 472 women with pelvic mass who were scheduled for surgical intervention.

Data from a study of 472 patients presented at this year’s Annual Meeting of the Society of Gynecologic Oncologists and published in the August 2011 issue of Obstetrics and Gynecology show that ROMA alone was highly accurate in assigning a combined preand postmenopausal patient population to likelihood groups, with 93.8% of epithelial ovarian cancers correctly classified as high likelihood.1 Looking at the postmenopausal group, ROMA had a sensitivity of 92.3%, a specificity of 76.0%, and a negative predictive value of 97.4%. Looking at the premenopausal group, ROMA had a sensitivity of 100%, a specificity of 74.2%, and a negative predictive value of 100%.

■

Reference 1. Moore RG, Miller MC, Disilvestro P, et al: Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol 118(2, Part 1):280-288, 2011.

The ASCO Post | OCTOBER 15, 2011

PAGE 18

Journal Spotlight Genitourinary Oncology

Short-term Androgen Deprivation plus Radiotherapy Improves Outcomes in Intermediate-risk Prostate Cancer

By Alice Goodman

T

he addition of short-term androgen-deprivation therapy to external-beam radiation therapy

improved overall and disease-specific survival in men with nonbulky localized prostate cancer and pros-

tate-specific antigen (PSA) levels up to 20 ng/mL, as reported recently in The New England Journal

of Medicine. 1 The benefit of the addition of short-term androgen-deprivation therapy was seen mainly in men with intermediate-risk disease, not low-risk disease, in this large, randomized, phase III international trial.

A caveat about these findings is that the radiation techniques used in this study were those used in 1994, when the study was initiated.

More sophisticated techniques now in use deliver higher doses than what was possible 17 years ago. The benefit of short-term androgendeprivation therapy has not been proven with the newer techniques, said lead author Christopher Jones, MD, a radiation oncologist at Radiological Associates in Sacramento, California.

What role may MUC1 play in NSCLC Christopher Jones, MD

Current Practice Currently, most patients receive intensity-modulated radiation therapy, and many opt for treatment with brachytherapy (delivered via seeds [low-dose] or catheter [high-dose]).

These newer techniques are associated with improved efficacy, Dr. Jones noted, which raises the question of the value of short-term androgendeprivation therapy when added to modern radiotherapy techniques in intermediate-risk prostate cancer.

“It is not correct to routinely give short-term androgen-deprivation therapy to all patients on high doses of radiation delivered by modern techniques,” Dr. Jones stated.

The ongoing Radiation Therapy Oncology Group (RTOG) 0815 study is designed to answer the question of whether short-term androgen-deprivation therapy should be given with high-dose radiation, he explained. That study is currently accruing over 1,500 intermediate-risk patients who will be randomly as-

It’s well-known that mucins protect healthy cells, but did you know that aberrant overexpression of mucin 1 (MUC1) by tumor cells may play a role in tumor cell survival?1-3 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC.

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Visit www.emdserono.com to learn more about EMD Serono Oncology.

1. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021.

2. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42): 5667-5677. 3. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816.

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003296_emddsa_dsa_tea_fa2.indd 1

7/28/11 4:40 PM

ASCOPost.com | OCTOBER 15, 2011

PAGE 19

Journal Spotlight

signed to high-dose radiation (physician’s choice of technique) with or without short-term androgen-deprivation therapy (6 months in the new study).

NEJM Study Details The study by Jones and colleagues (RTOG 94-08) enrolled 2,028 patients from 212 centers in the United States and Canada with localized prostate cancer (stages T1b, T1c, T2a, or T2b) and PSA levels ≤ 20 ng/mL. About 48% of cancers were T1, and about 52% were T2. About 63% had Gleason score 2 to 6, about 28% were Gleason 7, and about 9% were Gleason 8 to 10; a small percentage—about 2%—had unknown Gleason scores. Participants received no previous treatment for prostate cancer and were randomized to receive short-term androgen-deprivation therapy (2 months before radiotherapy and 2 months during radiotherapy) plus radiotherapy or radiotherapy alone. A total radiation dose of 66 Gy was delivered to the pelvis and prostate.

The addition of short-term androgen-deprivation therapy led to a modest but significant improvement in overall survival at 10 years, from 57% with radiotherapy alone to 62% with short-term androgen-deprivation therapy (P = .03). Ten-year disease-specific mortality was also reduced, from 8% to 4% (P = .001), along with a reduction in the secondary endpoints of biochemical failure (as shown by PSA level), distant metastases, and positive biopsy rate at 2 years.

In a multivariate analysis, a Gleason score of 7 or higher was a negative predictive factor for overall survival, disease-free survival, distant metastases, and biochemical failure.

Other negative prognostic factors

Expert Point of View

C

ommenting on the RTOG 94-08 trial, Michael Zelefsky, MD, Professor of Radiation Oncology and Vice Chair of Clinical Research for the Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center in New York, stated, “This important randomized trial corroborates that even a short course of hormone therapy has an impact on prostate cancer years later. A number of studies have previously shown the benefit of androgen-deprivation

Among intermediate-risk patients, short-term androgen-deprivation therapy improved long-term survival outcomes. therapy—especially of longer duration—in high-risk patients.

But this study is most notable because it showed that even among intermediate-risk patients, shortterm androgen-deprivation therapy improved long-term survival outcomes. The study by Jones et were older age and nonwhite race for overall survival; clinical T2 lesions for disease-specific mortality; and PSA ≥ 4 ng/mL for biochemical failure.

Subgroup Analysis When the data were reanalyzed according to subgroups, the gains

Androgen Deprivation plus Radiotherapy in Localized Prostate Cancer ■■ A large, randomized, controlled trial showed that adding short-course androgen-deprivation therapy to external-beam radiation therapy significantly improved overall survival and disease-specific survival at 10 years in men with intermediate-risk prostate cancer.

■■ Intermediate risk was defined as a Gleason score of 7 or a Gleason score of 6 or less with a PSA level of more than 10 and up to 20 ng/mL or clinical stage T2b.

■■ Given the study’s 1994 initiation, much lower doses of radiation therapy were used than are standard today.

■■ An ongoing study is addressing the use of short-term androgendeprivation therapy with contemporary radiation doses.

al is the largest randomized trial demonstrating the benefits of androgen-deprivation therapy with external-beam radiotherapy for this risk group.”

A major limitation of the study, which dates back to 1994 for its inception, is that the prescribed radiation doses used at that time were significantly lower than currently used doses. Also, more sophisticated targeted radiation techniques are now available and routinely employed.

Retrospective Study While it remains unclear whether hormonal therapy is still critical for intermediate-risk patients when they are treated to higher radiation doses, Dr. Zelefsky noted that recent data from his own institution indicate that there could indeed be a benefit.1 “We have recently noted in a retrospective study comprising over 2,500 patients that even for intermediate-risk patients treated with higher doses of external-beam radiotherapy, reductions in biochemical failures and distant metastases were noted with the addition of a short-course androgen-deprivation therapy,” Dr. Zelefsky said.

Further, Dr. Zelefsky noted, the findings of Jones and colleagues in overall survival and disease-free survival with short-term androgendeprivation therapy were limited mainly to men in the intermediaterisk group (intermediate risk was defined as a Gleason score of 7 or a Gleason score of 6 or less with a PSA level of more than 10 and up to 20 ng/mL or clinical stage T2b).

The 10-year overall survival rate was increased from 54% to 61%, and 10year disease-specific mortality was reduced from 10% to 3% with the addition of short-term androgendeprivation therapy in intermediate-risk men.

The benefits of short-term androgen-deprivation therapy were achieved with minimal toxic effects, including serious cardiovascular effects and long-term gastrointestinal or genitourinary complications of radiotherapy. The addition of shortterm androgen-deprivation therapy

Michael Zelefsky, MD

may not be applicable in the setting of prostate brachytherapy, with or without supplemental intensity-modulated radiotherapy.

“A number of large studies, albeit retrospective, have not shown a clear benefit for hormones in this setting,” he said. “However, the role of short-term androgen-deprivation therapy in brachytherapytreated intermediate-risk patients and in those treated with dose escalation is currently being tested in the RTOG 0815 trial.”

■

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

Reference 1. Zelefsky MJ, Pei X, Chou JF, et al: Dose escalation for prostate cancer radiotherapy: Predictors of long-term biochemical tumor control and distant metastases-free survival outcomes. Eur Urol. August 22, 2011 (early release online).

had a somewhat stronger impact on erectile function than radiotherapy alone; responses SEE PAGE 48 on a Sexual Adjustment Questionnaire showed that although 73% of androgen-deprivation therapy group were able to have erections always, almost always, or sometimes pretreatment, only 44% had this response at 1 year.

In the radiotherapy-alone group, 79% reported good pretreatment erectile function compared with 54% at 1 year.

■

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

Reference 1. Jones C, Hunt D, McGowan DG, et al: Radiotherapy and short-term androgen deprivation for localized prostate cancer.

N Engl J Med 365:107-118, 2011.

In HER2+ breast cancer

If you could inhibit dimerization

could you interrupt oncogenic signaling?

Š 2011 Genentech USA, Inc. All rights reserved. PER0000229700 Printed in USA.

HER receptor dimerization is critical for HER2+ breast cancer Dimerization, or pairing, between multiple HER receptors is a key factor in cancer formation.1 The HER family of receptors is composed of 4 transmembrane receptor tyrosine kinases that must dimerize, or pair, with themselves or with other HER receptors in order to activate downstream signals.2,3

Preventing ligand-induced HER dimerization: a novel therapeutic approach

When HER2 receptors are overexpressed, as in HER2+ breast cancer, excessive dimerization leads to abnormal activation of signaling, which may result in tumor growth.3,4

The HER2:HER3 dimer: the most potent oncogenic receptor pair While HER2 can dimerize with any HER receptor, the HER2:HER3 receptor pair is particularly potent because it potentiates HER2â&#x20AC;&#x2122;s oncogenic ability.5 When a ligand binds to HER3, it causes a change in conformation that allows HER3 to dimerize with HER2.6 HER2 activates the mitogen-activated protein kinase (MAPK) pathway that leads to cell proliferation.2 HER3 can directly activate the phosphatidylinositol 3-kinase (PI3K) cell survival pathway, which blocks apoptosis.2

Available anti-HER2 agents do not block HER2:HER3 dimer formation, and may not fully prevent the PI3K cell survival signaling mediated by HER3.6 Preventing the formation of HER2:HER3 dimers may have the ability to inhibit both the MAPK cell proliferation pathway and the PI3K cell survival pathway.7 As our understanding of the complexities of HER2+ breast cancer continues to evolve, Genentech BioOncology is committed to researching how more comprehensive HER2 receptor inhibition could result in a more complete oncogenic signaling blockade.

To learn more about HER pathways and the potential for dimerization inhibition, please visit www.ResearchHDIs.com.

References: 1. Rosen LS, Ashurst HL, Chap L. Targeting signal transduction pathways in metastatic breast cancer: a comprehensive review. Oncologist. 2010;15:216-235.

2. Holbro T, Civenni G, Hynes NE. The ErbB receptors and their role in cancer progression. Exp Cell Res. 2003;284:99-110. 3. Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer. 2001;8:11-31. 4. Amin DN, Sergina N, Ahuja D, et al. Resiliency and vulnerability in the HER2-HER3 tumorigenic driver. Sci Transl Med. 2010;2:1-9. 5. Campbell MR, Amin D, Moasser MM. HER3 comes of age: new insights into its functions and role in signaling, tumor biology, and cancer therapy. Clin Cancer Res. 2010;16:1373-1383. 6. Koutras AK, Fountzilas G, Kalogeras KT, Starakis I, Iconomou G, Kalofonos HP. The upgraded role of HER3 and HER4 receptors in breast cancer. Crit Rev Oncol Hematol. 2010;74:73-78. 7. MĂŠnard S, Tagliabue E, Campiglio M, Pupa SM. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol. 2000;182:150-162.

The ASCO Post | OCTOBER 15, 2011

PAGE 22

Direct from ASCO

ASCO Study Shows Integrating Nonphysician Providers into Oncology Practices Is a Win for Patients and Providers

I

s the expanded use of nonphysician providers (NPPs) a viable way to help ease the challenges oncology practices could feel if the number of oncologists entering the field does not keep pace with potential growth in the demand for their services?

The ASCO Workforce Advisory Group thought the question had great merit. To collect real-world data to test it, the group asked Oncology Metrics, a division of Altos Solutions, Los Altos, California, to conduct a national survey among U.S. oncology practices. The purpose: to identify the collaborative practice models and services provided by NPPs that have proven most effective among those practices that employ them, and also to find out how patients, physicians, and NPPs feel about working together. NPPs are also known as midlevel or advanced practice providers.

Conducted in 2009–2010, the ASCO Study of Collaborative Practice Arrangements was funded by Susan G. Komen for the Cure®, and the results have just been published in the September issue of the Journal of Oncology Practice.

Satisfaction High for All The results, it turns out, were very illuminating, showing that satisfaction among patients seen in practices with NPPs was high, with virtually all patients recognizing who was an NPP and who was an oncologist.

“That dispelled a couple of myths: that patients didn’t always know they were being treated by an NPP, and also that patients weren’t as comfortable with them since they’re not doctors. Neither of those turned out to be the case,” said Dean F. Bajorin, MD, a Cochair of the Workforce Advisory Group.

The study also showed that physicians and NPPs—usually nurse practitioners or physician assistants—experienced very high satisfaction with the arrangement and reported that productivity increased in their practice after the integration of NPPs. The typical NPP-to-physician ratio was found to be one NPP to two physicians, and the most popular model for employing NPPs was the incidentto-practice model, in which the NPP

routinely sees patients independently of the physician, with the physician always present in the office suite if needed.

distractions that I do; they can go in the exam room with a patient and shut the door for 30 minutes, and the patients really appreciate that,” she commented. “I would personally love to do that but instead need to field physician and hospital calls.”

Huge Oncologist Shortage Projected The time for employing such workplace alternatives is now, said Dr. Bajorin, who is Attending Physician in the Genitourinary Oncology Service at Memorial Sloan-Kettering and Professor of Medicine at Weill Medical College of Cornell University. He pointed to a 2007 ASCO study showing that by 2020 the demand for visits to oncologists is expected to increase 48%, while the number of practicing oncologists will rise by only 14%. The increased demand is due largely to a calculated doubling of the number of Americans who will be older than age 65, and an 81% increase in people living with or surviving cancer. The study projected an alarming shortfall of between 2,550 and 4,080 oncologists by 2020.

“Our system can’t train enough oncologists to respond to that need—it’s simply not possible,” Dr. Bajorin said. “We have to have other ways to meet demand for oncology services while maintaining a high level of excellence. Midlevel practitioners or nonphysician providers provide an opportunity to do that.”

Elaine L. Towle, CMPE

Study coauthor Elaine L. Towle, CMPE, Director of Consulting Services at Oncology Metrics, explained that the first round of surveys yielded 226 responses, from which 33 practices were chosen for more in-depth study. Satisfaction surveys were administered to the physicians, NPPs, and patients in each of the 33 practices. Finally, focus groups or interviews were conducted to go even deeper.

Carolyn B. Hendricks, MD

NPPs: More Time to Spend with Patients The Center for Breast Health in Bethesda, Maryland, was among the 33 practices that had in-depth study.

The Center has used certified nurse practitioners since its inception in 2001, and at the time that it participated in the study, it had two physicians and two nurse practitioners. Medical Director Carolyn B. Hendricks, MD, said the practice uses the incident-topractice model in which nurse practitioners handle most routine patient visits, with the physician nearby. If there are complications or a patient has metastatic cancer, the physicians and nurse practitioners alternate visits, with the patient always getting a headsup about whom they’ll see next time.

Also, so that patients don’t feel in any way cut off from their physician, the nurse practitioners always ask at the end of each visit whether there’s anything the patient would like to talk to the doctor about.

Dr. Hendricks recalled that the study showed that all but two of her 530 patients reported high satisfaction with nurse practitioners. Those two respondents expressed concerns about the experience level of the nurse practitioners. In response to those comments, Hendricks changed her model a bit, now always seeing new patients first and explaining to them that the nurse practitioner is an experienced member of the team whose job is to enhance patient care. From there, she explains how often the patient will see the nurse practitioner.

Dr. Hendricks said that the lion’s share of patients have been very pleased with nurse practitioners because the nurse practitioners can give them far more attention than most physicians can. “They don’t have the same stream of interruptions and

Partnership Model Becoming More Common Shirley Shuster, APRN, BC, OCN, an NPP since 1976, says she’s aware of many oncologists partnering with NPPs to handle patient care these days, rather than the old model of relegating them strictly to administering chemotherapy.

“If employed in the right way, the NPP really saves time; oncologists

Shirley Shuster, APRN, BC, OCN

are starting to recognize that now,” said Ms. Shuster, Director of Clinical Services at Commonwealth Hematology Oncology in Quincy, Massachusetts, which also participated in the study.

Ms. Shuster added that patients seem to appreciate that when oncologists employ NPPs, there is a team of people putting their heads together on their care rather than just a lone doctor. “The patient realizes that the NPP and the physician are communicating about their treatment plan; they understand that we’re talking to each other about their care, collaborating on it— they feel comforted by that,” she said.

Next: More Tailored Education The study—which represents the first in-depth analysis of how oncology practices are using NPPs— makes a very strong case for oncologists who don’t already team up with NPPs to explore doing so as soon as possible. “The integration of nonphy-

ASCOPost.com | OCTOBER 15, 2011

PAGE 23

Direct from ASCO

sician practitioners into oncology practice offers a reliable means to address increased demand for oncology services without adding physicians,” the authors of the study concluded.

Dr. Bajorin said that the Workforce Advisory Group is considering possible next steps, such as helping to formalize oncology training for

Dean F. Bajorin, MD

NPPs, many of whom come into oncology practices with training only in adult medicine and must then get their oncology know-how on the job in apprentice fashion. Dr. Bajorin said ASCO is talking with nursing and physician assistant societies about the possibility of collaborating, as the shortage of oncologists mounts. © 2011. American Society of Clinical Oncology. All rights reserved.

Help Inform ASCO Policy with New Oncology Practice Survey

A

s part of ongoing efforts to respond to a rapidly evolving oncology practice environment, ASCO is conducting a groundbreaking national survey to better understand the challenges facing oncology practices brought on by the current economic, legislative, and regulatory changes.

Under the guidance of ASCO’s Clinical Practice Committee (CPC), and in collaboration with the Center for Workforce Studies at the State University of New York–Albany, the Assessment of the Evolution and Status of Practices Survey (AESOP) is aimed at gaining a deeper understanding of current oncology practice environments.

This study will provide timely and accurate data about oncology practices to help inform ASCO’s policy positions with policymakers, cancer advocates, and health-care consumers.

“Many systemic pressures in the health-care system today stand in the way of the best possible cancer care and

CONQUERING

research. These pressures include the implementation of health-care reform, a flawed sustainable growth rate, the movement toward Accountable Care Organizations, and other new proposed payment models,” said Therese Mulvey, MD, member of the CPC steering subcommittee and AESOP project leader. “In order to continue to effectively advocate on behalf of our members, ASCO needs more detailed information about how member practices are faring in the current environment in order to provide the most accurate, compelling information to lawmakers and regulators.”

Comprehensive Report The AESOP survey will collect critical data on the number of oncology practices in the United States and provide ASCO with an accurate profile and a more in-depth understanding of the types of practices, staffing configurations, and affiliations that practices

have with hospitals, medical centers, and other facilities. AESOP will also provide important insight on issues of critical concern such as the number of practices that have been forced to close, merge and/or reduce staff, salaries, or the patient services they provide.

“ASCO will publish a comprehensive report and fact sheet on the state of oncology practices in the U.S. based on the results of this first-ever national survey. We also anticipate that this project will not be a static, one-time event, but will be an ongoing effort to collect and refine data over time so that we may continue to advocate effectively for our members and their patients for years to come,” said Dr. Mulvey.

To participate in the AESOP survey, please contact practice@ asco.org or visit ASCO in Action at ascoaction.asco.org.

■

© 2011. American Society of Clinical Oncology. All rights reserved.

Cancer.

Together, anything is possible.

The Conquer Cancer Foundation. Our name says a lot. Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supporting the world’s pre-eminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

ConquerCancerFoundation.org

The ASCO Post | OCTOBER 15, 2011

PAGE 24

Direct from ASCO

What’s Hot in

JOP

New Features Added to Cancer.Net’s Popular ‘Find an Oncologist’ Database

W

hen patients need to find an oncologist, Cancer.Net is there to help with the Find an Oncologist database, at www.cancer.net/findanoncologist.

This database is made up of ASCO members who have made their

Top 5 most-accessed articles recently published in Journal of Oncology Practice

contact information public. In addition to location and specialty, patients can now search by gender, language, and type of practice. © 2011. American Society of Clinical Oncology. All rights reserved.

■

Volume 7, Issue 3

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting

By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity?

By Dean H. Gesme, MD, et al

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

What’s Hot in

Barriers to Recruitment of Rural Patients in Cancer Clinical Trials

By Shamsuddin Virani, MB, BS, et al

JCO

Top 10 most-accessed articles recently published in Journal of Clinical Oncology

JCO.org 1. The Era of High-Dose Chemotherapy for Breast Cancer: Revisiting a Troubled Quest Virginia F. Borges, et al 29(24): 3205

6. Adjuvant Chemotherapy in Colon Cancer: Ageism or Appropriate Care?

Joleen Hubbard, et al 29(24): 3209

2. Art of Oncology: New Voices Wanted David P. Steensma 29(25): 3343

7. Personalized Tamoxifen: What Is the Best Way Forward?

James M. Rae 29(24): 3206

3. It Is Time to Include Patients With Brain Tumors in Phase I Trials in Oncology Patrick Y. Wen, et al 29(24): 3211

8. Targeted Therapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Can There Be Too Many Active Drugs?

Sarat Chandarlapaty, et al 29(23): 3111

4. Chemotherapy, Trastuzumab, and Pathological Complete Response: When Shall We Three Meet Again?

David A. Cameron 29(25): 3344 5. Ongoing Challenge of Stage II Colon Cancer Neal J. Meropol 29(25): 3346

Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists

By Fiona L. Day, FRACP, et al

9. Trustworthiness Larry D. Cripe 29(25): 3483 10. A Time to Keep and a Time to Cast Away Categories of Tumor Response Michael L. Maitland, et al 29(23): 3109

Partners and Partnerships: Trends in Private Oncology Practice

By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

jop.ascopubs.org

1. Health Technology Assessment and Private Payers’ Coverage of Personalized Medicine Julia R. Trosman, et al 7(3S): 18s 2. Advancing Performance Measurement in Oncology: Quality Oncology Practice Initiative Participation and Quality Outcomes Francis X. Campion, et al 7(3S): 31s 3. Why Meaningful Use Matters Peter Paul Yu 7(4):206 4. Patient-Physician E-Mail Communication: The Kaiser Permanente Experience David Baer 7(4):230 5. Outcomes of Computerized Physician Order Entry in an Electronic Health Record After Implementation in an Outpatient Oncology Setting Cara A. Harshberger, et al 7(4):233

JCO Implements Rapid Review Program

I

n an effort to support the practicechanging or time-dependent results of select articles submitted to the Journal of Clinical Oncology, the publication has introduced a new Rapid Review program. This fastpaced track gives authors an opportunity to have their important findings accelerated through the peer-review and publishing process. Papers selected for Rapid Review will have a decision rendered within 72 hours from the time a paper is assigned to an Associate Editor. Once accepted, Rapid Review papers will be published online within 4 to 6 weeks of acceptance and will be freely available online, regardless of whether the reader is a JCO subscriber.

This program, designed by Editor-in-Chief Dr. Stephen Cannistra, will bring greater attention to papers with immediate, practice-changing implications. Dr. Cannistra believes that “information of such timely relevance that has the potential to affect

the lives of our patients should not be restricted solely to paid subscribers of JCO (or any other journal, for that matter).”1 By bringing these papers to the forefront of the publication timeline, authors benefit by having priority status during the review process, but more significantly, practicing oncologists and their patients will have prompt access to time-sensitive and clinically important information.

Authors who wish for their submissions to undergo Rapid Review may make this request in their submission letters. Ultimately, however, whether or not the paper will be rapidly reviewed is an editorial decision.

■

Reference 1. Cannistra S: New initiatives at Journal of Clinical Oncology. J Clin Oncol 29:2609-2610, 2011. © 2011. American Society of Clinical Oncology. All Rights Reserved.

ASCOPost.com | OCTOBER 15, 2011

PAGE 25

In the Clinic Metastatic Melanoma

Novel Drugs Ipilimumab and Vemurafenib for Advanced Melanoma

By Matthew Stenger

In this introductory installment of In the Clinic, The ASCO Post provides an overview of two new melanoma agents recently approved by FDA, with discussion on pivotal data leading to approval, dosage and administration, and managing drugrelated toxicities. Watch for more on clinical use of novel oncology agents in future issues of The ASCO Post.

Ipilimumab Indication—Ipilimumab (Yervoy) is indicated for the treatment of unresectable or metastatic melanoma. The pivotal trial of ipilimumab, performed in patients who had received at least one prior treatment with interleukin-2 (Proleukin), dacarbazine, temozolomide, fotemustine, or carboplatin, assessed ipilimumab with or without an experimental gp100 vaccine vs the gp100 vaccine alone. Patients receiving ipilimumab alone had a 34% reduction in risk for death (HR = 0.66, P = .0026), and those receiving ipilimumab plus gp100 vaccine had a 32% reduction in risk (HR 0.68, P = .0004) compared with patients receiving the gp100 vaccine alone. Median survival durations were 10 months in the two ipilimumab groups and 6 months in the gp100 group.

How it works— Cytotoxic T lymphocytes (CTLs) are SEE PAGE 48 immune cells that kill such target cells as those infected with virus or intracellular bacteria or protozoa and cancer cells. Ipilimumab is a fully human antibody that binds to the cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), a molecule on the surface of cytotoxic T cells that is an important negative regulator of T-cell response. By blocking CTLA-4, ipilimumab acts to sustain cytotoxic T lymphocyte activity by augmenting T-cell activation and proliferation. The immune-related adverse effects of ipilimumab are the result of this

Of Note It is important to assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose of ipilimumab.

sustained/augmented activity.

How it is given—The recommended dose of ipilimumab is 3 mg/kg given IV over 90 minutes every 3 weeks for a total of four doses.

Scheduled doses of ipilimumab should be withheld for any moderate immune-related reactions or symptomatic endocrinopathy. For patients with complete or partial resolution of adverse reactions (grade 0 or 1) who are receiving < 7.5 mg of prednisone (or equivalent) per day, ipilimumab can be resumed at this dosing schedule until the earlier of administration of all four planned doses or 16 weeks from the first dose.

Ipilimumab should be permanently discontinued for persistent moderate adverse reactions or inability to reduce prednisone dose to 7.5 mg/d; failure to complete the treatment course within 16 weeks from the first dose; and severe or life-threatening adverse reactions, including any of the following: (a) colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or more over baseline), stool incontinence, need for IV hydration for > 24 hours, or gastrointestinal hemorrhage or perforation; (b) AST or ALT > 5 times the upper limit of normal or total bilirubin > 3 times upper limit of normal; (c) Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; (d) severe motor or sensory neuropathy, GuillainBarré syndrome, or myasthenia gravis; (e) severe immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis, pancreatitis, noninfectious myocarditis); and (f) immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy.

Safety profile—Ipilimumab has a black box warning for immune-mediated adverse reactions. These reactions may affect any organ system and include enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. Although the majority of these reactions were observed to have onset during treatment, some occurred weeks to months after discontinuation of ipilimumab. Ipilimumab should be discontinued and systemic high-dose corticosteroid therapy initiated for any severe immune-mediated reaction.

In the pivotal clinical trial of ipilimumab, the most common adverse reactions were fatigue, diarrhea, pruritus,

Ipilimumab and Vemurafenib in Patients with Advanced Melanoma Ipilimumab

■■ A fully human monoclonal antibody indicated for the treatment of unresectable or metastatic melanoma.

■■ The recommended dose of ipilimumab is 3 mg/kg given IV over 90 minutes every 3 weeks for a total of four doses.

Vemurafenib

■■ A BRAF inhibitor indicated for the treatment of unresectable or

metastatic melanoma with the BRAF V600E mutation, detected by the Cobas 4800 BRAF V600 mutation test.

■■ The recommended dose of vemurafenib is 960 mg (four 240 mg tablets) orally twice daily.

rash, and colitis. Severe or fatal immunerelated reactions (grade 3-5) included enterocolitis in 7% of patients, dermatitis in 2.5%, hepatotoxicity in 2%, and endocrinopathies in 1.8% (all of these patients had hypopituitarism and some had such concomitant endocrinopathies as adrenal insufficiency, hypogonadism, and hypothyroidism). One case of fatal GuillainBarré syndrome and one case of severe peripheral motor neuropathy were reported in this study, and myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported in other experience in the ipilimumab clinical development program.

It is important to assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose of ipilimumab.

Suggested Readings 1. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-2526, 2011.

2. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010.

3. Wolchok JD, Thomas L, Bondarenko I, et al: Phase III randomized study of ipilimumab plus dacarbazine vs DTIC alone as first-line treatment in patients with unresectable stage II or IV melanoma. 2011 ASCO Annual Meeting. Abstract LBA5.

Presented June 5, 2011.

Vemurafenib Indication—Vemurafenib (Zelboraf) is indicated for the treatment of patients with unresectable or metastatic mela-

noma with the BRAF V600E mutation as detected by an FDA-approved test. It is not recommended for use in patients with wild-type BRAF. In the clinical trial supporting approval of vemurafenib, performed in treatment-naive patients with the V600E mutation, vemurafenib treatment reduced risk of mortality by 56% (HR = 0.44, P < .0001) and reduced risk of progression by 74% (HR = 0.26, P < .0001) compared with dacarbazine.

Median survival durations were not reached in the vemurafenib group vs 7.9 months in the dacarbazine group and median progression-free survival durations were 5.3 and 1.6 months, respectively.

Of Note Vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor, and a CYP3A4 inducer.

Thus, physicians should be aware of potential interactions with other drugs that are inhibitors or inducers of these enzymes.

Confirmation of the BRAF V600E mutation using an FDA-approved test is required for vemurafenib treatment.

All patients in the pivotal clinical trial had positive results on the cobas® 4800 BRAF V600 Mutation Test.

How it works—Vemurafenib is a low-molecular weight, orally available inhibitor of some mutated forms of the BRAF serine threonine kinase. This enzyme is involved in the transduction of mitogenic signals from the cell membrane to the nucleus. Some mutations in the BRAF gene, including V600E (valine replaced by glutamic acid), result in constitutively activated BRAF proteins, continued on page 28

ISTODAX® (romidepsin) for injection is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Important Safety Information WARNINGS AND PRECAUTIONS:

• Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Due to the risk of QT prolongation, ensure that potassium and magnesium are within the normal range before administration • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • Based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) • ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%),

thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%).

Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection.

The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).

DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

Introducing choice in treating PTCL ISTODAX® is now indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated

Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

ISTODAX® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation 06/11 IST11004T

For more information: Please visit www.istodax.com or call 1-888-423-5436

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Ipilimumab and Vemurafenib continued from page 25

which can cause cell proliferation in the absence of the growth factors normally required for proliferation. By inhibiting this enzyme, vemurafenib interrupts the BRAF/MEK step of the BRAF/MEK/ERK pathway and

causes programmed cell death in melanoma cells. Approximately one-half of melanomas have the BRAF V600E mutation.

How it is given—The recommended dose of vemurafenib is 960 mg (four 240 mg tablets) orally twice daily. Doses are taken approximately 12 hours

apart with or without a meal. The tablets are swallowed whole with water.

Dose reductions or interruption or discontinuation of treatment may be required for symptomatic adverse effects or QT interval prolongation.

For intolerable grade 2 or grade 3 adverse events, it is recommended that

Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information.

1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

• Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the therapy.

2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.

• Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)].

5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)].

In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.

Due to the risk of QT prolongation, potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

treatment be interrupted until resolution (grade 0 or 1) and resumed at 720 mg twice daily and 480 mg twice daily after the first and second occurrences, respectively, with treatment discontinued for a third occurrence. For grade 4 adverse events, treatment should be discontinued or

5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate.

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse outcomes.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)].

5.6 Use in Women of Childbearing Potential Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives. An in vitro binding assay determined that romidepsin competes with ß-estradiol for binding to estrogen receptors [See Nonclinical Toxicology (13.1)].

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

Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1.

Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1.

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) (continued)

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interrupted until resolution and then resumed at 480 mg twice daily for a first occurrence; in patients resuming treatment, treatment should be discontinued after a second occurrence.

Dose reductions to lower than 480 mg twice daily are not recommended.

Safety profile—In two clinical

studies providing safety data (one in treatment-naive patients and one in previously treated patients), the most common adverse reactions to vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common grade 3 adverse events were cu-

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8)

Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).

Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome.

Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsorconducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) (continued)

taneous squamous cell carcinoma and rash. Grade 4 adverse events occurred in < 4% of patients in both studies.

The following adverse reactions warrant warnings/precautions.

■■ Cutaneous squamous cell carcinoma occurred in 24% of patients and new primary malignant melanomas were

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience.

7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)].

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors.

Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital)

observed. These should be managed by excision and treatment continued without dose adjustment. Patients should undergo dermatologic evaluation prior to the start of treatment and every 2 months during treatment.

■■ Serious hypersensitivity reactions, incontinued on page 30

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Ipilimumab and Vemurafenib continued from page 29

cluding anaphylaxis, were seen during and at reinitiation of treatment and severe dermatologic reactions were reported, including StevensJohnson syndrome and toxic epidermal necrolysis. Treatment should be

discontinued in patients with serious hypersensitivity reactions and severe dermatologic reactions.

■■ QT prolongation was documented in a phase II QT substudy. ECG and electrolytes should be monitored before treatment and after any dose modification, and ECGs should be moni-

may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort.

7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse developmental outcomes. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential harm to the fetus.

In an animal reproductive study, pregnant rats received daily intravenous romidepsin during the period of organogenesis up to a dose of 0.06 mg/kg/day (0.36 mg/m2/day). This dose in rats is approximately equivalent to 18% the estimated human daily dose based on body surface area and resulted in 5% reduction in fetal weight. Embryofetal toxicities associated with the use of ISTODAX were not adequately assessed in this study.

8.3 Nursing Mothers It is not known whether romidepsin 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 ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)].

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of endstage renal disease on romidepsin pharmacokinetics has not been studied.

Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)].

10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal

tored on day 15, monthly during the first 3 months of treatment, and every 3 months thereafter. Vemurafenib treatment should be interrupted if the QTc exceeds 500 ms, with correction of electrolyte abnormalities other cardiac risk factors for QT prolongation.

■■ Since photosensitivity has been re-

vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose.

Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [See References (15)].

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling.

17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients.

Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)].

• Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)].

• Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flulike symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)].

• Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)].

• Use in Women of Childbearing Potential If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling.

ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogencontaining contraceptives [See Warnings and Precautions (5.6)].

• Patients should be instructed to read the patient insert carefully.

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBVPI.002/PPI.002 06/11

ported, patients should be advised to avoid sunlight during vemurafenib treatment.

■■ Liver enzymes and bilirubin should be measured before and monthly during treatment for liver function abnormalities.

Since serious ophthalmologic reactions, including uveitis, iritis, and retinal vein occlusion, were observed, patients should be regularly monitored for ophthalmologic changes.

Vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor, and a CYP3A4 inducer. Thus, physicians should be aware of potential interactions with other drugs that are inhibitors or inducers of these enzymes.

■

Suggested Readings 1. Chapman PB, Hauschild A, Robert C, et al: Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine in patients with V600E BRAF-mutated melanoma. 2011 ASCO Annual Meeting.

Abstract LBA4. Presented June 5, 2011.

2. Ribas A, Kim KB, Schucter LM, et al: BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positiove metastatic melanoma.

2011 ASCO Annual Meeting. Abstract 8509. Presented June 4, 2011.

Newly Elected ASTRO Officers Installed at Annual Meeting

R

ecently elected officers for the American Society for Radiation Oncology (ASTRO) began their terms at ASTRO’s 53rd Annual Meeting in Miami Beach, which was held October 2-6, 2011.

The new Board of Directors members are: ■■ President-elect: Colleen A. Lawton, MD, FASTRO, Medical College of Wisconsin, Milwaukee ■■ Health Policy Vice-chairman: Brian Kavanagh, MD, University of Colorado Denver, Aurora ■■ Research Council Vice-chairman: Mary K. Martel, PhD, FASTRO, The University of Texas MD Anderson Cancer Center, Houston Watch future issues of The ASCO Post for coverage of important news from the 53rd ASTRO Annual Meeting in Miami Beach, Florida.

■

ASCOPost.com | OCTOBER 15, 2011

PAGE 31

Best of ASCO® Hematology

Improvements Highlighted in Treatment of Leukemias and Preleukemias

By Susan London

C

ertain preleukemic conditions and leukemia in high-risk patients have remained challenging to treat despite advances in hematology, according to Wendy Stock, MD, of the University of Chicago. But studies reported at the Best of ASCO® Annual Meeting ‘11 in Seattle show progress even in these areas.

Fig. 1). This group also had reductions in symptoms, especially insomnia and fatigue, whereas those in the best available therapy group had increases. The drug had an acceptable safety profile, characterized mainly by increases in rates of thrombocytopenia and anemia.

The trial’s findings show that ruxolitinib has “marked and sustained clinical benefits,” according to Dr. Stock.

“Interestingly, these improvements were similar regardless of the presence or absence of the JAK2 V617F mutation,” she commented. “Is it a downstream effect? Is it an off-target effect?

We simply don’t yet know.”

Clofarabine in Acute Myeloid Leukemia Ruxolitinib in Myelofibrosis The randomized COMFORT-II trial concluded that the investigational compound ruxolitinib is more efficacious than best available therapy for reducing spleen size and symptoms in patients with myelofibrosis.1 About two-thirds of the patients had the JAK2 V617F mutation. In the best available therapy group, 67% of patients received at least one medication, usually hydroxyurea. Patients in the ruxolitinib group were more likely to achieve a reduction in spleen volume of at least 35% by 48 weeks (28.5% vs 0%; P < .0001;

Patients with > 35% spleen volume reduction

40% 35% 30%

Clofarabine (Clolar) achieves shortlived second remissions in older adults with relapsed or refractory acute myeloid leukemia, but at the price of increased toxicity, the CLASSIC 1 trial revealed.2 A total of 326 patients with a median age of 67 years were randomly assigned to cytarabine plus clofarabine (a novel purine nucleoside analog) or cytarabine plus placebo. The overall response rate was higher with clofarabine (47% vs 23%; P < .0001). The complete response rate was also higher (35% vs 18%; P = .0005).

Patients in the clofarabine group had better event-free survival (HR = 0.63; P = .0001), but the 4-month event-free survival rate was still only

40%

Ruxolitinib 95% CI = 21.3, 36.6 P < .0001

25% 20% 15%

28.5% n = 41

Best available therapy 95% CI = 0.0, 5.0

10% 5% 0%

0 Ruxolitinib

Best available therapy

Patients with > 35% spleen volume reduction

Wendy Stock, MD

35%

Key Leukemia Findings Presented at Best of ASCO® ■■ In myelofibrosis, the JAK1/2 inhibitor ruxolitinib is superior to best

available therapy at reducing spleen size and improving symptoms.

■■ Adding clofarabine to cytarabine achieves a 4-month event-free

survival of 38% in older adults with relapsed or refractory acute myeloid leukemia, although toxicity is increased.

■■ Children and young adults with high-risk acute lymphoblastic leukemia have better event-free survival with high-dose methotrexate compared with Capizzi methotrexate plus asparaginase as interim maintenance therapy (82% vs 75%).

38% in this group. Clofarabine was associated with higher rates of grade 3 or worse adverse events (98% vs 86%) and 60-day mortality (24% vs 17%).

“Clofarabine/cytarabine improves complete response rates in relapsed or refractory older adults with acute myeloid leukemia, but the responses are transient and the treatment is quite toxic,” Dr. Stock commented.

“This may provide a brief window to allow allogeneic transplant for fit older adults with acute myeloid leukemia in second remission,” she noted. “So if you’re thinking about that as a secondline treatment, you have to have your strategy lined up and have these patients already referred to a transplant center, looking for a donor, because that [event]-free survival is quite short.”

Alternatively, Dr. Stock said, oncologists may opt to use a hypomethylat-

Ruxolitinib 95% CI = 24.4, 40.2 P < .0001

30% 25% 20% 15%

31.9% n = 46

Best available therapy 95% CI = 00, 5.0

10% 5% 0%

0 Ruxolitinib

Week 48

Best available therapy

Week 24

• Median time to response, 12.29 weeks.

• Of the 69 patients who achieved ≥ 35% reduction in spleen volume at any time during the study, 44 (64%) did so at the first assessment (at 12 weeks).

Fig. 1: COMFORT-II efficacy results (intent-to-treat analysis). Courtesy of Wendy Stock, MD. Adapted from Harrison CN, et al.1

ing agent or some other less intensive approach to consolidate the second remission.

High-dose Methotrexate in Acute Lymphoblastic Leukemia Children and young adults with highrisk precursor B-cell acute lymphoblastic leukemia fare better if treated with highdose methotrexate as compared with Capizzi methotrexate for interim mainSEE PAGE 48 tenance therapy, a Children’s Oncology Group phase III randomized trial found.3 After induction and consolidation therapy, the 2,426 enrolled youth (up to 30 years old) received high-dose methotrexate plus leucovorin rescue, or Capizzi dose-escalating methotrexate plus asparaginase (Elspar)—the first head-to-head comparison of these methotrexate-intensifying approaches.

The 5-year rate of event-free survival was better with high-dose methotrexate (82.0% vs 75.4%, P = .006).

Benefit appeared greatest among patients who had a slow early response during induction therapy.

The drug was well tolerated. Rates of neurotoxicity were low, possibly because follow-up is still short, but perhaps also because central nervous system radiation was largely avoided, Dr. Stock noted.

She commended the trial for its good design, collaborative success, and resourcefulness, pointing out, “They refined an existing drug schedule and dosing, and led to significant improvements without the addition of any fancy new treatment.”

Yet, the trial leaves some questions unanswered. For example, only 2% of patients were older than 20 years, and continued on page 32

The ASCO Post | OCTOBER 15, 2011

PAGE 32

Best of ASCO® Leukemia continued from page 31

patients with T-cell acute lymphoblastic leukemia were excluded, so outcomes for these groups are unknown.

Nonetheless, “this is really a model for extending pediatric intensified approaches to young adults in the United States and elsewhere with [acute lymphoblastic leukemia],” Dr. Stock said.

To that end, a new trial is now accruing (Intergroup C-10403), with a very similar design but for patients 16 to 39 years old and having either precursor B-cell or T-cell acute lymphoblastic leukemia.

■

Disclosure: Dr. Stock receives research funding from Sigma Tau and served on the data safety monitoring board for Incyte for the COMFORT-I and COMFORT-II trials.

References 1. Harrison CN, Kiladjian J, Al-Ali HK, et al: Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or postessential thrombocythemia-myelofibrosis (PET-MF). 2011 ASCO Annual Meeting.

Novel Agents Are Still Needed to Address Cytopenias in Myelofibrosis

D

espite improving splenomegaly and symptoms in patients with myelofibrosis, ruxolitinib has not been helpful for managing cytopenias in this population, according to Wendy Stock, MD, of the University of Chicago.

“Additional trials are underway with novel [ JAK] inhibitors, with some hints about improvements in cytopenias,” she said. For example, in a phase I/II trial, CYT387 improved anemia in half of patients, including 58% of those who were transfusion dependent.1 “Novel agents are still desperately need for the patients with disease

progression and worsening cytopenias,” Dr. Stock contended. One showing promise in clinical trials is pomalidomide, which appears especially effective for anemia in patients with JAK2 mutations. And epigenetic modulators, such as decitabine (Dacogen), are showing impressive activity in small studies.

Dr. Stock concluded, “So we have hope for symptom management, some suggestion of actual change in natural history of the disease, but really a long way to go.” Nonetheless, this is “a very exciting time for the myeloproliferative disorders, which have been on the back burner for many years.”

Future Trials

Reference 1. Pardanani AD, Caramazza D, George G, et al: Safety and efficacy of CYT387, a JAK-1/2 inhibitor, for the treatment of myelofibrosis. 2011 ASCO Annual Meeting. Abstract 6514. Presented June 3, 2011.

Abstract LBA6501. Presented June 6, 2011.

2. Faderl S, Wetzler M, Rizzieri D, et al: Clofarabine plus cytarabine compared to cytarabine alone in older patients with relapsed or refractory (R/R) acute myelogenous leukemia (AML): Results from the phase III

CLASSIC 1 trial. 2011 ASCO Annual Meeting. Abstract 6503. Presented June 6, 2011.

3. Larsen EC, Salzer WL, Devidas M, et al: Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate plus asparaginase (C-MTX/ASNase) in

“Could you use these drugs in combination with the JAK inhibitors?” she asked. “I think those are the trials that we are going to see as the next generation of studies in these disorders.”

■

children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group Study AALL0232. 2011 ASCO Annual Meeting. Abstract 3. Presented June 5, 2011.

Yoga, Geriatric Assessment, and Nausea/Vomiting Addressed in Session on Supportive Care and Survivorship Issues

Supportive Care

By Caroline Helwick

M

arie E. Wood, MD, of the Familial Cancer Program at the University of Vermont, Burlington, addressed clinically relevant issues in supportive care and survivorship at the Best of ASCO® Annual Meeting ‘11 in Miami.

Marie E. Wood, MD

Delayed Nausea and Vomiting Two studies addressed the problem of chemotherapy-related delayed nausea and vomiting. In the large University of Rochester Community Clinical Oncology Program study (N = 1,021), 55% of patients experienced delayed nausea and 16% had delayed vomiting. In a comparison of four preventive approaches, palonosetron was no more effective than granisetron when both antiemetics were provided with dexamethasone on day 1

of chemotherapy and with prochlorperazine on days 2 and 3.1 Patients receiving dexamethasone on days 2 and 3 (in the comparison of dexamethasone vs no dexamethasone on these days) had significantly less delayed nausea but no reduction in delayed vomiting.

Patients receiving aprepitant (Emend)/ dexamethasone had significantly less delayed vomiting but no benefit over prochlorperazine in controlling nausea. The group receiving aprepitant plus palonosetron plus dexamethasone on day 1 and aprepitant/dexamethasone on days 2 and 3 had the lowest rate of delayed vomiting (8% vs 14%–24% in other groups).

“This was a large study that included many groups and comparisons, though it did not study aprepitant alone,” Dr. Wood noted, indicating that such data would help determine how best to use this agent. The study also raised doubts that palonosetron is more effective than other 5HT3 receptor antagonists when part of a combination regimen, she added.

A second randomized phase III study of 68 germ cell tumor patients receiving a 5-day cisplatin-based regimen found that aprepitant given with a 5HT3 receptor antagonist plus dexamethasone increased the complete

Key Supportive Care and Survivorship Findings Presented at Best of ASCO® ■■ Aprepitant plus dexamethasone reduced the occurrence of delayed nausea and vomiting.

■■ Palonosetron and granisetron were similar in preventing delayed nausea and vomiting.

■■ Yoga provided numerous psychological and biologic benefits in breast cancer survivors.

■■ A formal survivorship care plan did not improve patient-reported outcomes of breast cancer survivors, compared with usual care.

■■ A 5-minute geriatric oncology screening tool can be useful in predicting treatment-related toxicity.

response rate (no vomiting, no rescue medication).2 Aprepitant was started at 125 mg on day 3, with 80 mg given on days 4 to 7. Complete responses were observed in 42% of the aprepitant arm vs 13% of controls (5HT3 receptor antagonist/dexamethasone; P < .0001).

ASCO guidelines, which recommend aprepitant/dexamethasone for patients receiving high–emetic risk agents, are largely based on consensus. “But now we have more level 1 evidence that aprepitant/dexamethasone does improve delayed nausea and vomiting,” Dr. Wood said. “The results may challenge how we

think about and potentially treat delayed nausea and vomiting, in that we use aprepitant starting on day 3 of multiday cisplatin-based chemotherapy.… Unfortunately, no matter how you cut it, delayed nausea remains a significant problem.”

Thromboprophylaxis A study of 3,212 cancer patients demonstrated the benefit of thromboprophylaxis with a novel ultra-low-molecularweight heparin with high anti–factor Xa and residual anti–factor IIa activities.3 With subcutaneous semuloparin (20 mg/d), continued on page 34

ASCOPost.com | OCTOBER 15, 2011

PAGE 33

Best of ASCO® Who Should Manage Survivorship Care?

I

t has been suggested that after completing their treatment, cancer patients can be transitioned to primary care providers for continued “survivorship” care. But at the Best of ASCO meeting, speakers and audience members alike felt survivorship care is the domain of the treating oncologist.

Daniel F. Hayes, MD

Few hands went up in response to a question from meeting Chair Daniel F. Hayes, MD, “How many of you refer your patients to primary care physicians?” He was not surprised, he said. “The [methodology of the] Canadian study (abstract 9005) would be a major culture shift for us,” he said. The motive for retaining patients is not financial, Dr. Hayes and other oncologists at the meeting insisted. “Economic pressures encourage oncologists to see new patients, especially those who will receive subsequent therapy in their centers. Thus, filling a clinic with long-term follow-up patients may not be economically optimal,” he said.

Marie E. Wood, MD, of the University of Vermont, said she has started giving her breast cancer patients a choice of staying with her or transitioning to a

primary care physician. “The primary care providers I talk to are nervous,” she added. “They want recommendations and guidelines, and we do give

them a care plan,” but she wondered if this is adequate. “I was surprised at the outcome from the Canadian study,” she commented.

■

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A precious resource.

At McKesson Specialty Health, our vision of helping independent oncology practices thrive means providing more solutions to meet your unique challenges. Through the Onmark Select Program, you have access to proven clinical tools, integrated technology, revenue cycle and reimbursement solutions, all designed to help you strengthen your practice’s clinical services and business performance. With the Onmark Select Program, you have more choices than ever to support the success of your practice.

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Keeping up with Patient Needs “Still, many oncologists have concerns that the complicated problems inherent to our therapies for breast cancer (such as premature menopause and antiestrogenic therapy) may not be appreciated or treated appropriately by primary care physicians,” Dr. Hayes added.

The main concern was the ability of primary care providers to keep abreast of the various unique, and often changing, needs of cancer patients of all types. “Enormous training is required,” Dr. Hayes commented, adding that he has been disturbed to learn, for example, that some primary care providers prescribe estrogen-replacement therapy to treat vaginal dryness in breast cancer patients.

© 2011 McKesson Specialty Health. All rights reserved.

MSH193_PreciousResource_ASCO_7x10.indd 1

9/15/11 3:25 PM

The ASCO Post | OCTOBER 15, 2011

PAGE 34

Best of ASCO® Supportive Care

The G8 Screening Questionnaire

continued from page 32

the rate of venous thromboembolism was reduced by 64%, from 3.4% with placebo to 1.2% (P < .0001), with very low rates of major or clinically relevant bleeding.

“Prophylaxis reduces the thrombosis risk in cancer patients by 50% [64% in this study], but it does not change survival,” Dr. Wood noted, adding that cost (high copays) is an issue, as is quality of life, due to the need for daily injections.

Prophylaxis may be reasonable based on individual risk, she said. Most risk is related to site: stomach, pancreas, and brain carry the highest risk, while breast, colorectal, and head and neck cancer have the lowest. Other risk factors are prechemotherapy platelet count > 350 × 109/L, hemoglobin < 10 g/dL, white cell count > 11 × 109/L, and body mass index > 35.

A published predictive model based on risk factors can determine 6-month risk of venous thromboembolism.4 “It may be reasonable to think about thromboprophylaxis in patients with more than a 10% risk,” she said.

Yoga’s Benefits Documented In the first study of yoga to include a control group, regular practice of yoga was able to buffer the effects of radiotherapy on both patient-reported and biologic endpoints.5 The benefits were more than “stretching and social support,” the authors concluded.

The study randomized 178 breast cancer patients undergoing radiotherapy to yoga or stretching three times a week for 6 weeks during treatment, or to a waitlist control group. Fatigue was diminished in the yoga and stretch groups, whereas it increased among waitlist controls (P < .05). Yoga also significantly improved physical functioning (as assessed by the SF‑36 health survey) compared SEE PAGE 48 with controls, and was associated with significantly higher general health scores, steeper cortisol slope, and greater heart rate variability vs the control or stretch groups.

“There is mounting support for the importance of yoga and other integrated therapy in the care of cancer patients,” Dr. Wood commented.

Survivorship Plans Survivorship care plans are advocated by the Institute of Medicine, but do they really improve health outcomes?

Canadian researchers concluded that

• 8 questions

Items

Possible answers (score) 0: severe decrease in food intake

• Takes 5‐10 min to perform

Has food intake declined over the past 3 months due to loss of appetite, digestive problems, or chewing or swallowing difficulties?

• Nurse administered

A

– Appetite, weight loss, BMI – Mobility

– Mood and cognition

1: moderate decrease in food intake 2: no decrease in food intake 0: weight loss > 3 kg

B

Weight loss during the last 3 months

– Age categories

• Abnormal if score ≤ 14 – Preliminary analysis – Sensitivity: 89.6%, Specificity: 60.4%

2: weight loss between 1 and 3 kg 3: no weight loss

– Number of medications – Patient‐related health

1: does not know

0: bed or chair bound

C

Mobility

E

Neuropsychological problems

F

Body mass index (BMI weight in kg)/ (height in m2)

1: BMI = 18.5 to BMI < 21

H

Takes more than 3 prescription drugs per day

0: yes

P

In comparison with other people of the same age, how do they consider their health status?

1: able to get out of bed/chair but does not go out 2: goes out 0: severe dementia or depression 1: mild dementia or depression 2: no psychological problems 0: BMI < 18.5 2: BMI = 21 to BMI < 23 3: BMI = 23 and > 23 1: no 0: not as good 0.5: does not know 1: as good 2: better 0: > 85 yr

Age

1: 80-85 yr

Total Score

0-17

2: < 85 yr

Fig. 1: The G8 Screening Questionnaire. BMI = body mass index. Courtesy of Marie E. Wood, MD. Adapted from Soubeyran P, et al.7

the survivorship care plan adopted by their centers had no impact on patientreported outcomes or adherence to follow-up guidelines.6 All 408 early breast cancer patients were transitioning from oncology care to their primary care physician. One group received a formal survivorship care plan, which consisted of a treatment summary, patient version of follow-up guidelines, and local supportive care resources, reviewed with the patient by a nurse. Their primary care physician received copies of these documents, guidelines, and a reminder table of recommended follow-up visits and tests. The control group had a discharge visit and their physicians received a discharge letter, according to usual practice.

At 12 months, the intervention group demonstrated no additional improvement in psychosocial adjustment (the primary endpoint) or any of the secondary outcomes (continuity of care, healthrelated quality of life [SF-36], patient satisfaction, and guideline adherence).

“This was a different result than the investigators had hypothesized,” she noted. However, the study did prove that patients can be successfully transferred to a primary care physician; less than 10% in each arm returned to their oncologist for care.

Brief Screening Tool The comprehensive geriatric assessment (CGA) is an appropriate but time-consuming method of predicting tolerance to cancer treatment in older patients.7 French investigators reported that the brief G8 assessment (Fig. 1) was more sensitive than the Vulnerable Elders Survey (VES)-13, a 13-item function-based self-report questionnaire, in predicting an abnormal CGA. The ONCODAGE project validated the G8 among 1,425 patients with a variety of cancer types. Overall, abnormal test rates on the CGA, G8, and VES13 were, respectively, 80.1%, 68.4%, and 60.1%. The G8 screening tool was more sensitive than the VES-13 though equivalent in other parameters. Both brief screening tests were administered in less than 5 minutes, whereas the mean time for the CGA was 67 minutes.

“An abbreviated tool is good at picking up patients who may benefit from a more thorough evaluation (CGA) or collaborative care,” she said, reminding physicians that “geriatric assessment that screens for vulnerability actually predicts survival in cancer patients.”

■

Disclosure: Dr. Wood reported no potential conflicts of interest. Dr. Hayes holds stock in Oncimmune, LLC, has served as a consultant for Chugai Pharmaceuticals and Biomarker Strategies, and has received research funding from Pfizer, Novartis, and Veridex (Johnson & Johnson).

References 1. Morrow GR, Roscoe JA, Heckler C, et al: A phase III study for prevention of delayed nausea. 2011 ASCO Annual Meeting.

Abstract 9012. Presented June 6, 2011.

2. Brames MJ, Picus J, Yu M, et al: Phase III, double-blind, placebo-controlled, crossover study evaluating a 5HT3 antagonist plus dexamethasone with or without aprepitant in patients with germ cell tumor receiving 5-day cisplatin combination chemotherapy. 2011 ASCO Annual Meeting.

Abstract 9013. Presented June 6, 2011.

3. Agnelli G, George DJ, Fisher W, et al: The ultra-low molecular weight heparin semuloparin for prevention of venous thromboembolism in patients with cancer receiving chemotherapy. 2011 ASCO Annual Meeting.

Abstract LBA9014. Presented June 6, 2011.

4. Khorana AA, Kuderer NM, Culakova E, et al: Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 111:4902-4907, 2008.

5. Cohen L, Chandwani K, Raghuram NV, et al: Effect of yoga on quality of life, cortisol rhythm, and heart rate variability for women with breast cancer undergoing radiotherapy. 2011 ASCO Annual Meeting. Abstract 9009. Presented June 6, 2011.

6. Grunfeld E, Levine MN, Julian JA, et al: Results of a multicenter randomized trial to evaluate a survivorship care plan for breast cancer survivors. 2011 ASCO Annual Meeting. Abstract 9005. Presented June 4, 2011.

7. Soubeyran P, Bellera C, Goyard J, et al: Validation of the G8 screening tool in geriatric oncology. 2011 ASCO Annual Meeting. Abstract 9001. Presented June 5, 2011.

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T HE 5 - Y E AR S UR V IVAL R ATE I S 17 % F O R PATIENTS W ITH M E TAS TATIC S OF T TIS S UE SA RC OMA , YE T S I G N I F ICANT THER APEUTIC A D VAN CE MENTS AR E LAG GING. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Merck Oncology

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1003549-0001

The ASCO Post | OCTOBER 15, 2011

PAGE 36

Health-care Policy

ASCO Issues Policy Statement to Reduce Cancer Care Disparities Proposals call for broad-based reforms.

By Jo Cavallo

L

ast August, ASCO issued the policy statement, “Opportunities in the Patient Protection and Affordable Care Act to Reduce Cancer Care Disparities” in the Journal of Clinical Oncology.1 The statement builds on ASCO’s policy on disparities in cancer care released in 2009. It calls on both the oncology community and public policymakers to find ways to improve elements in the Patient Protection and Affordable Care Act signed into law last year, as well as amendments to the Act under the Health Care and Education Reconciliation Act of 2010, with an eye toward expanding access to cancer SEE PAGE 48 care to vulnerable population groups that suffer disproportionately from cancer.

Opportunities and Limitations “One of our main recommendations in ASCO’s policy statement on cancer disparities published in 2009 was the need to provide universal health care, and that was essentially established with the passage of Patient Protection and Affordable Care Act,” said Blase N. Polite, MD, Assistant Professor of Medicine, Center for Gastrointestinal Oncology, Center for Interdisciplinary Health Disparities Research at the University of Chicago Medical Center. He is also ChairElect of ASCO’s Health Disparities Advisory Group and coauthor of the policy statement. “We felt that now it was important to look at the opportunities and limitations contained in the new law to end disparate outcomes in cancer.”

ASCO’s policy statement calls for several measures to address elements of the health-care reform legislation that may hinder greater access to cancer care for older adults and lower-income and minority groups, including: ■■ Ending Medicare reimbursement cuts for oncology care.

Any additional cuts to Medicare reimbursement for oncology care will cause undue burden for oncology practices, thereby limiting access to care for people with cancer, according to results from a poll ASCO conducted in 2010.

In the poll, nearly one-third of re-

spondents said that they would be forced to accept fewer Medicare patients as a result of the proposed sustainable growth rate cuts. Inadequate reimbursement for Medicaid patients may also lead to reduced access to health care for low-income groups. One recommended strategy ASCO makes in its statement is to raise Medicaid reimbursement rates to Medicare levels, similar to the increased reimbursement rates temporarily allowed for primary care physicians under the Affordable Care Act. “Some of our recommendations for Medicare and Medicaid include considering immediate eligibility for Medicare once a patient is diagnosed with cancer, similarly to what has been done for patients with kidney disease undergoing dialysis treatment,” said Dr. Polite.

■■ Establishing oncology health teams and medical homes. The

that we realize our patients tend to require a variety of professional services in addition to those provided by their oncology medical team, such as nutritionists, social workers, psychologists, and palliative care physicians. Currently, we’re all paid separately and some of the services are not reimbursed at all,” he said.

“One option we need to consider is how we could bring all of these services under one umbrella, coordinated by the oncologist in consultation with the primary care physician, and combined with the financial flexibility to fund these various services. That is the essence of the medical home. The law as written considers these factors soley from the perspective of the primary care physician, but it does speak to the care of the cancer patient undergoing complex multidisciplinary treatment,” Dr. Polite added.

■■ Expanding health-care coverage to include follow-up diagnostic

ASCO is supporting the Comprehensive Cancer Care Improvement Act, which calls for development of a Medicare-funded cancer care plan, including a treatment summary outlining follow-up care.

Patient Protection and Affordable Care Act calls for grants from the U.S. Department of Health and Human Services to develop community-based interdisciplinary health teams that would be coordinated by primary care physicians. While this provision in the law doesn’t specifically address the clinical needs of cancer patients, it provides an opportunity for ASCO members to identify better ways of coordinating their care through so-called oncology medical homes, according to Dr. Polite.

“The way the health-care law is written, it’s very clear that it will be incumbent upon providers to figure out ways to better coordinate patient care, and we think there are a lot of opportunities for oncology practices to think broadly in terms of that care,” commented Dr. Polite. “So the idea of a community oncology home starts with the fact

tests without patient deductibles or copayments. Although the Affordable Care Act requires health insurers to pay for preventive screenings without charging a deductible or copay, the law does not mandate the same provision for follow-up examinations and biopsies.

■■ Protecting access to clinical trial participation by low-income and minority groups. Although Affordable Care Act regulations require health insurers to cover routine costs associated with clinical trial participation, ASCO is asking for additional steps to ensure greater access to minority and low-income patients, such as funding for the infrastructure needed to collect data on race and ethnicity to address cancer disparities and the development of cancer-specific payment models to reduce disparities in cancer outcomes under the

Center for Medicare and Medicaid Innovation.

■■ Improving long-term cancer survivorship plans. With more than 12 million cancer survivors, according to the latest figures from NCI, there is an increasing need to establish long-term coordinated care.

To achieve this goal, ASCO is sup-

Blase N. Polite, MD

porting the Comprehensive Cancer Care Improvement Act, which calls for development of a Medicarefunded cancer care plan, including a treatment summary outlining follow-up care, for each patient.

The Next Step Members of ASCO’s Health Disparity Advisory Group will be bringing their recommendations for improvements to the Affordable Care Act to key members of Congress, to determine how these measures could be incorporated into legislation being written to implement the health-care law.

“ASCO has a very good sense of what a top-flight cancer care system in this country would look like. Substantive discussions about how we get to that top-flight system should be part of any broad-based entitlement reform discussion. To step forward and say cancer is different and that this is the way that cancer care should be delivered in this country is the right thing to do,” said Dr. Polite.

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

Reference 1. Moy B, Polite BN, Halpern MT, et al: American Society of Clinical Oncology Policy Statement: Opportunities in the Patient Protection and Affordable Care Act to Reduce Cancer Care Disparities. J Clin Oncol. August 1, 2011 (early release online).

ASCOPost.com | OCTOBER 15, 2011

PAGE 37

FDA Update

FDA Announces Changes in Drug Center’s Oncology Office

T

he FDA recently announced organizational changes within the office responsible for reviewing all drug and biologic applications for cancer therapies. The Center for Drug Evaluation and Research’s (CDER) Office of Oncology Drug Products has been reorganized and renamed the Office of Hematology and Oncology Products (OHOP).

Two unique features of the reorganization include the creation of DOP1 and DOP2, the agency’s primary review divisions for cancer solid tumor therapies, and the creation of DHOT, which will review nonclinical

information.

DOP1 and DOP2 will have disease-specific therapeutic areas of reB:8.625 in sponsibility regardless of whether the T:7.625 in product is a drug or biologic. DHOT S:6.75 in is a newly created division that will

be dedicated to reviewing nonclinical pharmacology and toxicology aspects of cancer therapies. DHP will continue reviewing hematology therapies, including those for benign disorders and malignancies.

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Greater Efficiencies Anticipated

C M

20402a

Cosmos Communications 718.482.1800 1 Q1 LS 09.20.11 133 M8

“Under the new office structure, the agency anticipates greater clarity JOB#: 10157D and more transparent with PROOF#: interactions 1 Exelixis companies aboutCLIENT: the requirements to DESC: Journal Ad bring cancer treatments to market,” Color: 4C AD: TB said CDER Director Janet Woodcock, TRAFFIC: EA OPERATOR: VV MD. “We GALLEY#: 1 expect DATE: 9/19/11 - 8:35don’t PM CREATED: 9/15/11 - 9:08 PM these changFONTS: Neo Sans Pro Medium, Neo Sans Pro Bold,es Neo Sans toPro slow Regular, Helvetica Neue LT Std 77 Bold Condensed,down Helvetica pendNeue LT Std 47 Light Condensed, ing applicaHelvetica Neue LT Std 47 Light Condensed Obliquetions. In fact, IMAGES: Exelixis_KO.eps, we expect to 10157_JA_twk.tif COLORS: C=24 M=0 seeY=98 K=8,greater Janet Woodcock, C=0 M=7MD Y=80 K=0 efficiencies NOTES: DOC PATH: Macintosh that will better support our work to get HD:Users:lakek:Desktop:EXL_ XLX_Q10157D_JA_M01.indd cancer treatments to patients.”

DOC SIZE: 10” X 13” Richard Pazdur, MD, PRINT SCALE: 100% will continue to serve as the office Director. Dr. Pazdur will also continue to head the agency-wide oncology program that coordinates oncology activities within the FDA as well as with external stakeholders. This program will remain in OHOP. “As the practice of oncology and the treatments being d eve l o p ed for these diseases have become Richard Pazdur, MD more complex, we’ve recognized the need and importance of taking a more disease-specific review approach to these therapies,” said Dr. Pazdur. “Reorganizing the office in this manner also aligns FDA with the organizational structure of leading cancer treatment centers, academic programs and the NCI.”

Despite advances in targeted cancer therapy,

an important escape pathway remains: MET

Y K

Although advanced antitumor therapies have become available, many tumor types continue to evade treatment.1 Research has identified the MET pathway as one of the most critical escape pathways utilized by tumors. In most normal tissues, MET and its only known ligand, hepatocyte growth factor (HGF), are found in low levels. But in a range of malignancies—including thyroid, prostate, ovarian, lung, and breast cancers—MET is upregulated and drives more invasive and aggressive behavior of tumor cells, resulting in metastasis.2-7 Recent evidence also shows that inhibition of angiogenesis creates hypoxic conditions in the tumor that may further upregulate MET and ultimately promote disease progression.5,7 Exelixis is fully devoted to shutting down MET-driven escape in cancer. Therefore, we are investigating the dual targeting of the MET and VEGF pathways to simultaneously inhibit metastasis and angiogenesis in several cancers.

Visit www.METinhibition.com/asco to learn more about the role of MET in tumor escape.

Reorganization Features Q2

The new structure contains four divisions: Division of Hematology Products (DHP), Division of Oncology Products 1 (DOP1), Division of Oncology Products 2 (DOP2), and Division of Hematology Oncology Toxicology (DHOT).

References: 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, based on November 2010 SEER data submission, posted to the SEER Web site, 2011. http://seer.cancer.gov/csr/1975_2008/. Accessed May 10, 2011. 2. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth [draft manuscript]. 2011. Data on file, Exelixis, Inc. 3. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1-26. 4. Danilkovitch-Miagkova A, Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest. 2002;109:863-867. 5. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3:347-361. 6. Capdevila J, Argiles G, Rodriguez-Frexinos V, Nuñez I, Tabernero J. New approaches in the management of radioiodine-refractory thyroid cancer: the molecular targeted therapy era. Discov Med. 2010;9:153-162. 7. Eder JP, Vande Woude GF, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 2009;15:2207-2214.

© 2011 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 09/11

The ASCO Post | OCTOBER 15, 2011

PAGE 38

Health-care Policy

Oncology Community Faces Complex Challenges in Evolving Policy Arena

By Ronald Piana

A

s the political environment heats up in advance of the upcoming presidential campaign season, many issues crucial to the oncology community are being placed on the political chopping block as policymakers seek ways to reduce the mounting debt and soaring health-care spending. To help clarify some of the current policy concerns crucial to the delivery of cancer care, The ASCO Post spoke with Ms. Shelagh Foster, Director of Government Relations for ASCO.

The SGR Problem Resurfaces As reported previously in The ASCO Post, a “patch” for the sustainable growth rate (SGR)—the instrument used to calculate physicians’ fee schedule—was passed at the end of last year, averting a 23% cut in Medicare reimbursement for physician services. However, if Congress does not act by January 1, 2012, a 29.5% cut in physician reimbursement could take effect. Congress faces a dilemma: A true SGR fix— eliminating the problematic instrument—would cost taxpayers well in excess of $300 billion.

“Current talks on the Hill include a permanent fix to the SGR formula or a freeze of some period to allow ample time for policymakers to develop a permanent fix. However, these proposals do not outline what the fix will be, and any solution will likely be tied to quality reporting,” said Ms. Foster. “ASCO continues to work hard with members of Congress to include the SGR fix into any of the comprehensive budgetary packages that are put forth,” she added.

Cuts to Medicare Reimbursement The cancer community is expressing deep concern over a proposed $3 billion cut in Medicare

reimbursement for oncology drugs.

ASCO and other leading cancer groups signed onto a letter, sent to the White House and congressional leadership on July 14, urging both parties to oppose a proposed $3 billion funding cut to Medicare reimbursement for oncology drugs.

While these cuts were originally proposed in the debt ceiling negotiations, they will likely be on the table for any Medicare reform or proposed SGR fix.

Ms. Foster explained that cuts would shave another 2 points off the average sales price, which is linked to the reimbursement rate, bringing it from 106% of average sales price, down to 104%. “The message we impress on policymakers is that many community practices are already struggling to make up the shortfall from Medicare drugs currently ‘underwater’ [ie, insufficiently covered by current Medicare payments], and cuts of this proportion would have a devastating effect on access,” said Ms. Foster.

She stressed that in the grand scheme, the cuts to oncology being proposed have little effect on the overall budget or Medicare, but will hamper an already fiscally challenged cancer care delivery system.

Reporting System Signals Change In 2007, Medicare began operating the Physician Quality Reporting System (formerly known as the Physician Quality Reporting Initiative)

n the 2006 Physician Fee Schedule, the Centers for Medicare & Medicaid Services (CMS) interpreted the Medicare Modernization Act definition of average sales price to include “prompt pay” in its calculation. CMS maintains that since the statute includes the words “prompt pay discount,” it must include the method when calculating average sales price, which artificially lowers Part B reimbursement for physicians and could adversely affect access to care for patients with cancer.

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E

xcerpt from a letter signed by ASCO and other leading cancer organizations to President Barack Obama ( July 13, 2011) urging him to resist proposed cuts to Medicare reimbursement for oncology drugs: “Due to financial and administrative burdens that currently exist, community oncology practices already are reducing services and closing their doors across the United States at alarming rates. Additional Medicare cuts will result in a delay of services if providers are forced to eliminate or cut back on services. According to one study, over the past 3 years 199 cancer clinics have closed and 369 practices, with multiple clinic locations, are struggling financially. Specifically, practices already face significant Medicare cuts imposed on chemotherapy drugs and services.”

■

on a voluntary basis. The Centers for Medicare & Medicaid Services (CMS) program provides incentive payments to eligible professionals who report data on quality measures.

Providers also receive confidential feedback reports.

However, the Affordable Care Act established penalties for providers who do not successfully participate in this reporting system. That change in the program—from bo-

In the grand scheme, the cuts to oncology being proposed have little effect on the overall budget…but will hamper an already fiscally challenged cancer care delivery system.

Customary Prompt Pay

I

Letter to President Obama

nuses for voluntary participation to reductions in payment for nonparticipation—has increased the pressure on physicians to participate.

It is important for the oncology community to keep abreast of how this program unfolds in the coming months, in order to prepare for any changes that might affect the delivery of care.

Prompt Pay Hurts Community Practices Another issue that has been on ASCO’s front burner for numerous legislative calendars is the customary prompt pay discounts that are based on negotiated terms between the manufacturer and the distributor for payment within a certain time frame and represent the time value of money. These discounts are typically not passed on to the physician purchasing the drugs.

“Removing prompt pay from

the average sales price formula for physicians creates a more accurate reimbursement for drugs, closer to the average sales price plus 106%, which we should be getting based on the 2003 Medicare Modernization Act, said Ms. Foster. She pointed out two bills currently in Congress: H.R. 905 and S. 733. These bills are bipartisan and were introduced by Representatives Al Green (D-TX) and Ed Whitfield (R-KY) in the House and Senators Debbie Stabenow (D-MI) and Pat Roberts (R-KS) in the Senate.

Cognitive Services Still Underreimbursed Under certain Affordable Care Act provisions, Medicare will transition physicians to a value-based purchasing reimbursement system using quality and cost measures as calipers to gauge proper payment.

Reimbursement will be tied to CMS reporting on physicians’ relative patterns of use—but it is unclear how this will be implemented as a way to pay for difficult-to-quantify oncology services.

To that end, Ms. Foster addressed a long-standing problem for oncology providers—getting proper compensation for cognitive services and other complex, difficult-to-bill practices.

“We need to look at the reimbursement system differently. We should be paying oncologists for cognitive services, such as treatment plans,” said Ms. Foster.

Put simply, oncologists are reimbursed for evaluation and management, for administering chemotherapy drugs in the office setting (plus related services), and for the cancer continued on page 40

The case for Vectibix® QQ2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

660-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

PPremedication not standardized1

– The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown

NNo loading dose1

– No loading dose is required

11% severe infusion reactions reported1

– Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4) – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

INDICATION:

Vectibix® is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal cancer with these mutations.

Important Safety Information, including Boxed WARNINGS: WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. [See Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].

In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported. Withhold or discontinue Vectibix® for severe or life-threatening dermatologic toxicity and monitor for inflammatory or infectious sequelae.

Terminate the infusion for severe infusion reactions.

occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Cases of fatal and non-fatal interstitial lung disease (ILD) have been observed in patients treated with Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, Vectibix® therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, Vectibix® should be permanently discontinued and the patient should be treated appropriately. In patients with a history or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® must be carefully considered. In clinical studies, patients with a history of, or evidence of, interstitial pneumonitis or pulmonary fibrosis were excluded.

In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed.

Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose.

Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis.

Interrupt or discontinue Vectibix® for acute or worsening keratitis.

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

Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized clinical trial, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in patients treated with Vectibix® included rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); Please see brief summary of stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC Reference: 1. Vectibix® (panitumumab) grade 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® prescribing information, Amgen.

(7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea

©2011 Amgen Inc. All rights reserved.

61007-R1-V1

Prescribing Information on next page.

08-11 G61228-R1-V1

The ASCO Post | OCTOBER 15, 2011

PAGE 40

Health-care Policy

Evolving Policy Arena continued from page 40

drugs they purchase and deliver.

However, all the other cognitive services, such as treatment planning, follow-up care, and survivorship support, are not adequately reimbursed.

ASCO continues its efforts to edu-

cate lawmakers about the uncompensated services that are delivered every day in community practices.

Cuts to Oncology Impact Care Ms. Foster acknowledged that gaining headway on tough-to-sell Trim: 7.875” political issues such as adequate Live: 6.75”

Vectibix® (panitumumab) Injection for intravenous Infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Dermatitis Acneiform 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0.

Body System Body as a Whole

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibixtreated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported.

Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration].

Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%). For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies. No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

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

Postmarketing Experience: The following adverse reactions has been identified during post-approval. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Angioedema [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Skin and subcutaneous tissue disorders: Skin necrosis • Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.7)] DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix.

USE IN SPECIFIC POPULATIONS Pregnancy – Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients.

Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations].

Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations].

This brief summary is based on the Vectibix® prescribing information v12, 06/2011 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, and 7,807,798 as well as other patents or patents pending. ©2006-2011 Amgen Inc. All rights reserved.

MC46026-F

In general, many of the issues and challenges in today’s tough environment have overlapping problems and solutions. ASCO and other major cancer organizations are working with bipartisan groups of policymakers to focus on developing ways to fairly compensate oncologists for delivering evidence-based, cost-effective quality care.

“We’re cautioning members from both sides of the aisle on the Hill that proposing wholesale reductions in funding and reimbursement for oncologists as a way to generate revenue will have the unintended consequence of hampering access to care for the nation’s patients with cancer,” concluded Ms. Foster.

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Disclosure: Ms. Foster reported no potential conflicts of interest.

CONTACT

The ASCO Post EDITOR IAL COR R ESPONDENCE James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Trim: 10.75” Live: 9.75”

INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) in Full Prescribing Information].

The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progressionfree survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. [see Clinical Studies (14) in Full Prescribing Information].

DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions.

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

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

Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix.

• If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose.

– If toxicities recur, permanently discontinue Vectibix.

– If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached.

Do not administer Vectibix as an intravenous push or bolus.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported.

Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration].

Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCICTC grade 3–4).

Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [see Dosage and Administration].

Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCICTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated with Vectibix in combination with chemotherapy.

Pulmonary Fibrosis: Cases of fatal and non-fatal interstitial lung disease (ILD) have been observed in patients treated with Vectibix. In the event of acute onset or worsening of pulmonary symptoms, Vectibix therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, Vectibix should be permanently discontinued and the patient should be treated appropriately. In patients with a history or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix must be carefully considered. In clinical studies, patients with a history of, or evidence of, interstitial pneumonitis or pulmonary fibrosis were excluded.

Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed.

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

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

EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis.

Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions].

The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial.

The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

reimbursement for physicians is an uphill battle for the oncology community. “It’s not that we find policymakers unsympathetic to our concerns; it basically boils down to taking a back seat to the economic challenges of the day,” Ms. Foster explained.

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ASCOPost.com | OCTOBER 15, 2011

PAGE 41

In the News Controversy

‘Hot Chemotherapy’ Generates Heated Debate about Its Use with Cytoreductive Surgery to Manage Peritoneal Metastases

By Charlotte Bath

Divergent Views

In the News focuses on media reports that your patients may have questions about at their next visit.

This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

“H

ot chemotherapy” has become the common term for hyperthermic intraperitoneal chemotherapy (HIPEC), which together with cytoreductive surgery is being used by some surgeons to treat patients with carcinomatosis from colorectal cancer. While HIPEC is not considered the most important component of the combined therapy, the term “hot chemotherapy” is creating the most buzz. A New York Times article1 reported that some hospitals have capitalized on this buzz by “publicizing the treatment as a hot ‘chemo bath.’”

But does it work? Is there evidence to show that hyperthermic intraperitoneal chemotherapy used with cytoreductive surgery improved outcomes for patients with carcinomatosis (or peritoneal metastases) from colorectal cancer?

Yes, Paul H. Sugarbaker, MD, a leading proponent and practitioner of the procedure, told The ASCO Post.

“We have all sorts of data, a randomized trial performed in the Netherlands,2 five multi-institutional studies, and numerous phase II studies from single institutions that say peritoneal metastases can be adequately treated with this new combined treatment,” he said. “Gathering data together from probably 25 different institutions that have been involved in this for a decade or more, we are now able to come up with the prognostic indicators, which give us about a 40% cure.” Dr. Sugarbaker is Director of Peritoneal Surface Oncology at Washington Hospital Center in Washington, DC. “It is a clinical practice that has very

Expect Questions from Patients and Colleagues

A

mong the merits of good clinical studies, according to David P. Ryan, MD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, is being able to cite them when a physician sits down with a patient to explain the possible benefits and drawbacks of treatment. Dr. Ryan stressed, however, that such studies are lacking for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). “In the absence of good data,” he said, physicians should explain to patients that “this is a highly debated area.

Nobody knows for sure what the overall impact of this procedure is.”

He said he tells a patient, “While I’m not a supporter of the procedure, I am supportive of you, and if you want to talk to one of the surgeons who does this all the time, by all means do so. But I can tell you that we really don’t know what impact, if any, this will have on the natural history of your cancer.”

Informed Decisions “I think physicians ought to inform patients that these treatments are available, and it then becomes the patient’s decision,” commented Paul H. Sugarbaker, MD, of Washington Hospital Center in Washington, DC. “A lot of people come to me and say, ‘I’m just here for information. I want to know what your statistics are, and here’s my particular situation. What do you think?’ Some of them come back and some of them do not.”

Dr. Sugarbaker’s advice to colleagues is to refer patients early and “minimize surgery if they think the patient might be a candidate for cytoreductive surgery and HIPEC. If the patient has a primary colon cancer, that must be dealt with.

But leave the peritoneal metastases for the peritoneal surface oncology team.”

At the Washington Hospital Center, the procedure is a multidisciplinary effort, he noted. “The patients come from the colorectal surgeons. We discuss the patients. They get their FOLFOX chemotherapy. Five months later, they are back in the operating room and having their definitive peritonectomies and intraperitoneal chemotherapy.”

■

little to no basis in science,” countered David P. Ryan, MD, a gastrointestinal oncologist. “The argument against cytoreductive surgery and HIPEC in peritoneal carcinomatosis from colon cancer can be summed up in four lines,” Dr. Ryan said. “One, it is bioPaul H. Sugarbaker, MD David P. Ryan, MD logically flawed. Two, there is tremendous selection bias inherent in all the surgical series. Three, “In every cancer, there is always a it is toxic. And four, the only way to ansubset of patients who will live for a swer the question is with a randomized long time,” Dr. Ryan noted. “What we controlled trial.” He called the Netherdon’t know is whether the surgeons are lands study “highly flawed” and said that just selecting out that group of people, randomized controlled studies of the with the cytoreductive surgery and the therapy are needed to prove its worth.

HIPEC really having no impact on the Dr. Ryan is Clinical Director of the Masnatural history.” Dr. Ryan said that the sachusetts Gen5-year survival eral Hospital for patients Is there evidence to Cancer Center with colon canin Boston and cer and peritoshow that hyperthermic Associate Proneal carcinointraperitoneal fessor of Medimatosis who cine at Harvard are receiving chemotherapy used Medical School. chemotherapy with cytoreductive Dr. Ryan and without any Dr. Sugarbaker surgery may surgery improved presented their approach 20%. outcomes for patients divergent views That 5-year in a debate at survival estiwith carcinomatosis (or the ASCO Anmate, Dr. Ryan peritoneal metastases) nual Meeting explained, 3 in June, and in represents an from colorectal cancer? separate followextrapolation up interviews from data acwith The ASCO Post. cumulated over the past 15 years since the introduction of oxaliplatin (Eloxa‘Mother of All Surgeries’ tin), irinotecan, bevacizumab (AvasDr. Sugarbaker’s practice is exclutin), and cetuximab (Erbitux) and the sively devoted to cytoreductive surgery widespread use of liver resection. Fiveand HIPEC procedures, and he estiyear survival increased from 1% among mated that he does two to three such patients receiving fluorouracil (5-FU), procedures each week. “When we first Dr. Ryan stated, to 9.8% among pastarted this 20 years ago, patients all had tients receiving FOLFOX (5-FU, leuvery advanced pseudomyxoma peritocovorin, oxaliplatin) in Intergroup trial nei and peritoneal mesothelioma, and N9741.4 “If patients get all three cytothere were some patients with colorectoxic drugs (5-FU, oxaliplatin, irinotetal cancer. It was a horrendous surgical can), the 5-year survival is 15%.5 This procedure, the ‘mother of all surgeries.’ was before bevacizumab,” he pointed This was true for all those neglected out, adding that information in the patients, but it is not the situation anyBRiTE registry showed “5-year surmore,” he said. Patients now are more vival for bevacizumab-treated patients carefully selected, so those who endure approached 20%.”6 With the addition this rigorous therapy are those most of cetuximab to FOLFIRI (irinotecan, likely to benefit. “You do big surgical 5-FU, leucovorin) for patients with procedures and initiate chemotherapy KRAS and BRAF wild-type metastatic in the operating room when you have colorectal cancer, 5-year survival also curative intent,” Dr. Sugarbaker said. continued on page 43

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ASCOPost.com | OCTOBER 15, 2011

PAGE 43

In the News

Hyperthermic Intraperitoneal Chemotherapy Debate continued from page 41

approaches 20%,7 he continued. “But the best data,” Dr. Ryan said, “comes from Kopetz, 2009.8 He tried to tease out the independent effects of liver resection and the additional chemotherapy and concluded that the 5-year Kaplan-Meier survival for those patients treated between 2004 and 2006 was between 20% and 25%.”

“What if I had the ability to only look at the best 50%? All of a sudden my 5-year survival goes from 20% to 40%,” he speculated. The 5-year survival rate in surgical series reported

by Dr. Sugarbaker “goes from 20% to 40% because he never operated on the half that died very quickly,” Dr. Ryan maintained.

“For me as a surgeon, this debate over whether patients should be selected is kind of a nonargument,” Dr. Sugarbaker said. “We have learned through the analysis of thousands of patients that there are selection

For patients referred very early, I would say we are successful nearly 100% of the time.

– Paul H. Sugarbaker, MD

factors. They are based on extent of disease—the so-called peritoneal cancer index. We can quantitate the amount of disease that is present.

Whether lymph nodes are positive or not gives us another indication as to how likely the disease is to become metastatic to other sites at some time in the future.”

How It’s Done According to Dr. Sugarbaker, patients with colorectal cancer recommended for cytoreductive surgery and perioperative chemotherapy are those with positive peritoneal cytology, ovarian involvement, peritoneal seeding on the serosal surface of the primary tumor, rupture of a necrotic tumor, adjacent organ involvement, intraoperative tumor spill, perforation of the primary tumor, or limited peritoneal seeding with a peritoneal cancer index < 20, so that complete cytoreduction can be achieved.

“When patients are diagnosed with

peritoneal metastases, we make sure that they have had their best systemic treatment, usually a short course of FOLFOX chemotherapy, with a little bit of a wait to let them recuperate from that. Then they go for the cytoreduction surgery and the HIPEC,” Dr. Sugarbaker explained.

“We are committed to trying to optimize the use of 5-FU with HIPEC,” he continued. “In order to do that, we give the 5-FU with the HIPEC intravenously and then for 4 days afterward intraperitoneally. Not all the groups use intraperitoneal 5-FU after cytoreductive surgery plus HIPEC. We talk all the time about the optimal HIPEC procedure. That is going to evolve, hopefully with trials, over the next decade. Following the cytoreduction with HIPEC, patients usually complete their FOLFOX chemotherapy.

That is the ideal setup from my perspective, and I think that is how people do the best,” he said.

“Early referral by the colorectal surgeon or the medical oncologist is absolutely essential in getting a good result for the patient,” Dr. Sugarbaker asserted. “For patients referred very early, I would say we are successful nearly 100% of the time. We can get a complete cytoreduction with the primary cancer resection, removing the peritoneal metastases, and using HIPEC. We can almost promise those patients that they will not have further peritoneal metastases.”

A Package Deal?

“The crucial aspect of this combined treatment,” Dr. Sugarbaker said, “is the surgery. What we have done is assume—and it is an assumption— that both the HIPEC and the early postoperative intraperitoneal chemotherapy are absolutely essential, and we have tried to improve on the strategy. We don’t use single drugs anymore; we use multiple drugs. We administer a combination of intraperitoneal and systemic chemotherapy in the operating room, using heat-synergized or heat-augmented drugs intravenously.

We still need a lot of help from the pharmacists and the medical oncologists to optimize HIPEC, because I don’t think it is optimized at all.”

Dr. Ryan said that thinking of the therapy as “a package deal” might be a mistake. “Maybe the cytoreductive surgery is really beneficial, but the HIPEC has no benefit and may actually be damaging,” he said. “For peritoneal carcinomatosis, we still don’t

ASCO’s Role Recognized

O

ne point that Paul H. Sugarbaker, MD, and David P. Ryan, MD, agreed on was that ASCO has done a service to the oncology community by presenting their debate about cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. That debate, conducted at the 2011 ASCO Annual Meeting, sparked interest from colleagues and patients and coverage by the national media.

Dr. Ryan said that continuing coverage of the issue would be beneficial. “We have to do something about this to fully educate people because the approach is incredibly controversial, and we don’t know whether it is beneficial or harmful,” he said.

“From my perspective, the educational value of this ASCO debate is almost incredible,” Dr. Sugarbaker said, “because I think medical oncologists are beginning to think that peritoneal metastases are potentially curable. This thinking needs to be part of the multidisciplinary team’s considerations. Patients deserve attention to this option when intraperitoneal metastases are first diagnosed.”

■

know whether either of the two interventions do anything to the natural history of the disease,” he said.

a gentle—sometimes not so gentle— percussion to try to keep the chemo moving around,” he explained.

Why Heat the Drugs?

Unintended Consequences

The chemotherapy is hyperthermic because “pharmacologically it makes a lot of sense,” Dr. Sugarbaker said.

“Heated drugs can be augmented in their activity from 20% to 30% up to 1,000%. We try to use the more heataugmented drugs, like mitomycin, cisplatin, and doxorubicin. We use those in the peritoneal cavity, and then for the early postoperative intraperitoneal work we use drugs that aren’t as affected by heat, like paclitaxel and 5-FU,” he noted.

“With all due respect to the folks who did the original studies of heating chemotherapy that came out in the 1960s and early 1970s, those studies would not stand up to intense scrutiny today,” Dr. Ryan stated. “There is precious little data that heating chemotherapy does anything.”

Evenly distributing the chemotherapy in the peritoneal cavity “increases the effectiveness and it decreases the possible complications from the HIPEC,” Dr. Sugarbaker said. “When you infuse the chemotherapy into the abdomen from the heater circulator, it comes in at about 44°C maybe even 45°C, and then you move it around so that you don’t have any hot spots. Even more important than avoiding hot spots is you don’t have areas that are untreated.”

In most cases, Dr. Sugarbaker uses the open technique, inserting his hands into the peritoneal cavity to swish the drugs around. But for some drugs, such as melphalan, Dr. Sugarbaker prefers to use the closed technique. “You can close the abdomen and then use

Dr. Ryan said that he could understand why patients would be interested in aggressive therapy such as this. “It is countercultural for patients to not do anything,” he said. “It is very American to think that you can control your destiny when it comes to cancer. The truth is, it’s all about biology. Either the cancer is sensitive to the treatments we offer, or it is not. Either it is fast-growing, or it is not. And being aggressive about therapy has nothing to do with it. We learned that lesson in bone marrow transplant,” he said, referring to breast cancer trials with high-dose chemo-

The truth is, it’s all about biology. And being aggressive about therapy has nothing to do with it.

– David P. Ryan, MD

therapy and bone marrow transplant.

“In every part of medicine we always learn about the unintended consequences from the randomized, controlled trials,” Dr. Ryan continued.

“The unintended consequence of highdose chemotherapy in breast cancer was that we gave women leukemia and myelodysplastic syndrome. We didn’t realize we were doing that. Not only were we immediately killing 3% to 5% of people who underwent the procedure, but 10 years later a bunch of continued on page 44

The ASCO Post | OCTOBER 15, 2011

PAGE 44

In the News

Hyperthermic Intraperitoneal Chemotherapy Debate continued from page 43

those folks were getting leukemia and myelodysplastic syndrome from the high doses of chemotherapy,” he said.

“One of the unintended consequences of cytroreductive surgery plus

HIPEC could be that maybe cytoreductive surgery is beneficial, but the HIPEC is hurting you. Maybe it causes multiple small bowel obstructions. Or maybe you don’t respond to chemotherapy as you would have, and therefore you have shortened your survival.

We don’t know the unintended con-

sequences because we haven’t done the randomized, controlled study,” Dr. Ryan said. “Increasingly, procedures and devices are being used just like medicines to alter the natural history of a particular cancer,” he added.

“What we really need to do is hold them to the same level of scrutiny.”

Ongoing Clinical Trial An ongoing clinical trial is comparing standard systemic chemotherapy with or without cytoreductive surgery and HIPEC, but patient recruitment has been very difficult. “We are committed to seeing that study through, if possible,” Dr. Ryan said. “We really want to offer every single patient candidate that particular study.” At Massachusetts General, Dr. Ryan’s institution, Dr. James Cusack, a surgical oncologist, will be performing cytoreductive surgery and HIPEC. A second study is also needed to evaluate the role of cytoreductive surgery alone, Dr. Ryan said. “We need these studies,” he said. “Our patients need them.

And we need to end the argument.”

■

Disclosure: Dr. Sugarbaker reported no potential conflicts of interest. Dr. Ryan reported giving expert testimony in a related medical malpractice case.

What role may MUC1 play in NSCLC

MUC1 (mucin 1) is a transmembrane glycoprotein that is normally found on the apical surface of most simple secretory epithelial cells and is associated with a number of diverse cellular functions.1 The functions of the extracellular domain of MUC1 are largely dictated by the extent of its glycosylation.1,2 The cytoplasmic tail of MUC1 can serve as a scaffold for interactions with intracellular proteins that affect cell survival and proliferation and can have direct effects on transcription within the nucleus.1,2

110718-140032

Select functions of MUC1 in normal cells • Lubricates epithelial surfaces3 • Acts as a physical barrier against microbes3 • Protects against proteolytic degradation3 • Involved in adaptive immunity against pathogens4 • Mediates normal T-lymphocyte responses and regulates T-lymphocyte proliferation5 • Involved in signal transduction, which regulates cell survival and proliferation2 • Can directly affect transcription within the nucleus1 Overexpression, altered distribution, and aberrant glycosylation of MUC1 have been observed in a variety of cancers, including non-small cell lung cancer (NSCLC).1,2,6 Aberrant overexpression of MUC1 by tumor cells is associated with several mechanisms of tumor cell survival.6-8 Overexpression of MUC1 may play a role in

abnormal cell signaling through interactions with regulatory proteins, such as with EGFR.2,7 In addition, the cytoplasmic tail of MUC1 can be targeted to the nucleus, where it interacts with transcription factors for genes related to invasion, angiogenesis, and metastasis.7,8 Furthermore, cells overexpressing tumor-associated MUC1 may escape the host immune response by suppression of the T-cell proliferation response and by failure to process and present MUC1 on class II major histocompatibility complexes.9,10 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC. Visit www.emdserono.com to learn more about EMD Serono Oncology.

1. Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol. 2008;70:431-457. 2. Bafna S, Kaur S, Batra SK. Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene. 2010;29(20):2893-2904.

3. Carson DD. The cytoplasmic tail of MUC1: a very busy place. Sci Signaling. 2008;1(27):pe35.

4. McAuley JL, Linden SK, Png CW, et al. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J Clin Invest. 2007;117(8):2313–2324. 5. Agrawal B, Longenecker BM. MUC1 mucin-mediated regulation of human T cells. Int Immunol. 2005;17(4):391-399.

6. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816. 7. Ahmad R, Raina D, Joshi MD, et al.

MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor.

Cancer Res. 2009;69(17):7013-7021. 8. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42):5667-5677. 9. Agrawal B, Krantz MJ, Reddish MA, Longenecker BM. Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2.

Nat Med. 1998;4(1):43-49. 10. Hiltbold EM, Vlad AM, Ciborowski P, Watkins SC, Finn OJ. The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells. J Immunol. 2000;165:3730-3741.

EMD Serono Oncology | Combination is key™

EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

003296_emddsa_de_muc1_lv_fa1.indd 1

8/2/11 12:42 PM

References 1. Pollack A: Hot chemotherapy bath: Patients see hope, critics hold doubts. New York Times, August 11, 2001.

2. Intraperitoneal chemotherapy and cytoreductive surgery in colon cancer: A debate. 2001 ASCO Annual Meeting.

Presented June 2011. Available at http:// www.asco.org/ASCOv2/MultiMedia/ Virtual+Meeting?vmview=vm_session_ presentations_view&conf ID=102&trackI D=13&sessionID=3991.

3. Verwaal VJ, van Ruth S, De Bree E, et al: Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy vs systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 21:3737-3743, 2003.

4. Sanoff HK, Sargent DJ, Campbell ME, et al: Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol 26:5721-5727, 2008.

5. Masi G, Vasile E, Loupakis F, et al: Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: An updated analysis. J Natl Cancer Inst 103:21-30, 2011.

6. Polite BN, Sing A, Sargent DJ, et al: Exploring racial differences in outcome and treatment for metastatic colorectal cancer: Results form a large prospective observational cohort study (BRiTE). Cancer. July 28, 2011 (early release online).

7. Van Cutsem E, Kohne CH, Lang I, et al: Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to KRAS and BRAF mutation status. J Clin Oncol 29:2011-2019, 2011.

8. Kopetz S, Chang GJ, Overman MJ, et al: Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 27:3677-3783, 2009.

ASCOPost.com | OCTOBER 15, 2011

PAGE 45

In the Literature

Emerging Clinical Data on Cancer Management OVARIAN CANCER Elderly Patients with Ovarian Cancer Least Likely to Receive Chemotherapy An analysis of data for 4,617 women aged 65 years or older diagnosed with epithelial ovarian cancer found that those in the oldest age group, 80 and up, were least likely to receive any chemotherapy.

While 53% of patients 80 and older received no chemotherapy, the rate was less than half (22%) for those 75 to 79, dropped down to 15.3% for those aged 70 to 74, and to 9.7% for those aged 65 to 69.

“We found that advanced age, disease stage, and comorbidities were the predominant factors in determining whether a woman initiated and completed chemotherapy,” the researchers reported in the Journal of Clinical Oncology.

While having two or more comorbidities was associated with failure to complete chemotherapy, no specific comorbidities were more common in women who did not complete chemotherapy. “Women with stage IV disease were least likely to complete SEE PAGE 48 their chemotherapy and most likely to be hospitalized following diagnosis,” the authors wrote.

“Among the women who received any chemotherapy, 75% had cancerdirected surgery, but only 40% who received no chemotherapy had cancer-directed surgery,” the authors noted. The women were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.

Goals and Recommendations The stated goal of the study “was to test the hypothesis that the oldest women who received chemotherapy would use more health-care resources when compared with younger women,” but the results showed otherwise. “Among women who received either a partial or complete course of chemotherapy, we did not find an increase in use of health services (hospitalizations, emergency department visits, or physician visits) for the oldest women (age 80 years or older)

compared with younger women,” the authors wrote.

The investigators suggested “increased efforts to involve elderly women in clinical trials of ovarian cancer treatment and report on their ability to complete therapy, treatment toxicity, use of health services, and quality of life.” They also called for increased efforts to improve access to chemotherapy for ovarian cancer and “to reduce disparities in treatment initiation and completion.”

Fairfield KM, et al: J Clin Oncol. Sept. 12, 2011 (early release online).

BREAST CANCER Doxorubicin/ Cyclophosphamide with Docetaxel Equally Effective in Combination or Sequentially Five-year disease-free survival and overall survival rates were “indistinguishable” in patients with operable, node-positive, HER2nonamplified breast cancer treated with the sequential or combination regimens of doxorubicin/cyclophosphamide (AC) and docetaxel (T). The Breast Cancer International Research Group (BCIRG) 005 Trial compared four cycles of doxorubicin with cyclophosphamide, followed by docetaxel (AC > T) with six cycles of the triple combination TAC. Following completion of chemotherapy, radiation was administered as indicated and patients with hormone receptor–positive disease received adjuvant hormonal therapy with tamoxifen and/or aromatase inhibitors.

Major Findings BCIRG 005 involved 335 centers in 37 countries and enrolled 3,298 patients, equally divided between the two study arms and with wellbalanced characteristics. The median age of the patients was 50. Nearly 60% had a primary tumor greater than 2 cm and nearly 40% had four or more lymph nodes involved. As reported in the Journal of Clinical Oncology, the 5-year disease-free survival rates were 78.6% in the AC > T group and 78.9% in the TAC group.

The 5-year overall survival rates were 88.9% in the AC > T group and 88.1% in the TAC group.

“When put into the context of re-

ported adjuvant chemotherapy studies, it becomes evident that both TAC for six cycles and AC for four cycles followed by docetaxel for four cycles are among the most active regimens currently available for the adjuvant treatment of early, HER2-nonamplified breast cancer,” the investigators stated.

“The toxicity of both regimens was manageable,” the authors reported.

While the incidence of neutropenic infection was similar in both groups, other aspects of the toxicity profiles were different. “TAC was associated with more febrile neutropenia and thrombocytopenia, and AC > T was associated with more sensory neuropathy, nail changes, and myalgia,” the investigators noted. Because the two regimens “have equivalent efficacy, the choice of regimen requires balancing the differences in toxicity and treatment duration,” they concluded.

Eiermann W, et al: J Clin Oncol. Sept. 12, 2011 (early release online).

Comparing Therapies for Managing Hot Flashes in Women with Breast Cancer In a double-blind, placebo-controlled trial, two often-prescribed treatments recommended in clinical guidelines for the management of hot flashes were found to be effective in managing hot flashes in patients with breast cancer. Patient-reported hot flash scores showed that venlafaxine, a selective serotonin reuptake inhibitor, induced a more immediate reduction of hot flashes, compared to clonidine, a centrally acting alpha-adrenergic agonist. At the end of the 12-week study, however, hot flash scores were lower in the women taking clonidine. The results were published in the Journal of Clinical Oncology.

A total of 102 women were enrolled from three hospitals in the Netherlands and randomly assigned to daily venlafaxine, clonidine, or placebo. Patients were instructed to keep a diary, recording the frequency and severity of hot flashes every day for the 2 weeks before administration of the study medications and the 12 weeks of the study treatment period. Patients were also asked to record weekly the frequency and severity of adverse events, including reduced appetite, nausea, sleepiness, dizziness, fatigue, dry mouth, abnormal sweating, and constipation.

Week 12 data were available for analysis from 80 patients (78%)—35 in the venlafaxine group, 28 in the clonidine group, and 17 in the placebo group.

“During the 12th week of treatment, there was a reduction in hot flash scores by roughly 45% (two treatments combined) in comparison with placebo (P = .03), with no detectable difference between the two treatments (P = .58). Comparing clonidine with placebo, hot flash scores were significantly lower in the clonidine group at week 12 (P = .03); for venlafaxine vs placebo, the difference in hot flash scores was borderline not significant (P = .07),” the researchers reported.

Placebo Effect “In contrast to the week 12 assessment, the reduction compared with placebo in hot flash scores over the entire 12-week period in the venlafaxine group was 41% (P = .001) and only 26% (P = .045) in the clonidine group,” the investigators stated. “In particular, hot flash scores decreased sooner after commencement of venlafaxine treatment than with clonidine treatment.”

The authors also noted a substantial placebo effect, “with hot flash scores being reduced by 29% during the 12 weeks of treatment compared with baseline (P =. 001).”

Patients taking venlafaxine were more likely to experience nausea and constipation than those in the placebo group, and there was also a trend toward a higher incidence of appetite loss. At week 12, the anxiety score was higher in the clonidine group and the depression score was higher in the venlafaxine group.

The authors pointed out study limitations include the relatively small number of participants at week 12 and the reliance on self-reported data.

“Thus it is hard to guarantee either the quality of the data or the objectivity.”

The researchers concluded that venlafaxine “resulted in a more immediate reduction of hot flash scores and was more effective in the management of hot flashes over 12 weeks of treatment. It is advisable to treat patients to manage hot flashes with venlafaxine 37.5 mg daily in the first week and increase the venlafaxine dose to 75 mg if greater efficacy is desired.”

Boekhout AH, et al: J Clin Oncol. Sept.

12, 2011 (early release online).

continued on page 47

ASCOPost.com | OCTOBER 15, 2011

PAGE 47

In the Literature

Emerging Clinical Data continued from page 45

BREAST CANCER Replacing Epirubicin with Docetaxel for Three Cycles Improved Outcomes for Node-positive Breast Cancer Substituting docetaxel for epirubicin in the final three cycles of chemotherapy resulted in improvement in disease-free and overall survival in a trial among postmenopausal women with node-positive early breast cancer. Following complete excision, women enrolled in the Docetaxel Epirubicin Adjuvant (DEVA) trial were randomly assigned to receive epirubicin for six cycles (n = 397) or for three cycles, followed by three cycles of docetaxel (n = 406). At a median follow-up of 64.7 months, the 5-year disease-free survival rates were 72.7% for women taking epirubicin alone and 79.5% for women taking epirubicin followed by docetaxel. The investigators found a statistically significant improvement in overall survival in favor of epirubicin/docetaxel.

The 5-year survival rates were 81.8% for the epirubicin arm and 88.9% for epirubicin/docetaxel—an absolute difference in overall survival at 5 years of 7.1%, they noted.

“The improvement in overall survival, however, comes at a cost in terms of adverse effects, because patients who switch to docetaxel suffer significantly in terms of febrile neutropenia, skin disorders, and stomatitis, and they have a higher incidence of other chemotherapy-related toxicities,” the authors stated. There was, however, no impact on quality of life during the follow-up period.

“One potential benefit of reducing the anthracycline dose would be to reduce the incidence of cardiac events,” the authors added. “Indeed, cardiac failure (n = 4) was restricted to those receiving epirubicin alone.”

Other Trials Considered “These results suggest, within a relatively small trial, that substitution of docetaxel for epirubicin for the last three cycles of chemotherapy results in improved outcome in postmenopausal women with node-positive, early breast cancer compared with six cycles of epirubicin monotherapy,” the authors concluded.

Since the initiation of the DEVA trial, other groups have reported re-

sults of adjuvant studies of taxanes.

Meta-analyses of these trials “have shown modest benefits in terms of disease-free survival for taxane-treated patients,” the authors noted. “Our results represent a slightly larger benefit than that seen overall,” they added “and it is noteworthy that DEVA is the only trial with a single-agent control regimen.”

Coombes RC, et al: J Clin Oncol. July 18, 2011 (early release online).

LIVER METASTASES Hepatic Resection Remains Preferred Strategy for Colorectal Liver Metastases Hepatic resection was shown to be superior to radiofrequency ablation (RFA) for the treatment of colorectal liver metastases, according to a model used to stimulate a randomized controlled trial. Researchers from the Hepatobiliary and Pancreatic Surgery Program at the Providence Portland Medical Center in Oregon used Markov modeling to analyze data from 30 articles culled from a systematic literature search, with additional data for the RFA arm obtained from a prospective database of more than 900 patients considered for liver surgery there.

“The model produced a 5-year overall survival of 38.2% after hepatic resection vs 27.2% for RFA, and the 5-year disease-free survival was 29.8% after resection vs 15.5% after RFA,” the authors reported in the Archives of Surgery.

“Based on the existing published data, our decision analysis demonstrates that hepatic resection remains the preferred strategy for the treatment of [colorectal liver metastases]. However, at present RFA is primarily used for the treatment of patients with unresectable [liver metastases] or advanced disease, introducing significant bias into the comparison of outcomes of RFA vs hepatic resection. Markov modeling demonstrates that RFA can provide outcomes equivalent to those of hepatic resection if the median disease-free survival following RFA can be improved.”

input was limited to laparoscopic RFA of resectable colorectal liver metastases performed at our institution, the quality-adjusted life expectancy after ablation was found to be superior to that after hepatic resection” and “the overall survival was better at all time points.”

The authors acknowledge that these results “will need to be reproduced at other institutions, and randomized controlled trials will be required before more widespread use of RFA becomes acceptable.”

Khajanchee YS, et al: Arch Surg. Aug. 15, 2011 (early release online).

CANCER RESOURCES Cancer Information on Wikipedia as Accurate as on PDQ but Harder to Understand A comparison of cancer information on Wikipedia and the patient version of information on the NCI’s Physician Data Query (PDQ) “found that although Wikipedia had similar accuracy and depth to the PDQ, the written style was more complex and thus might be less understandable to patients.” According to the comparative study, which was published in the Journal of Oncology Practice, neither website scored well in

tackling controversial issues, but Wikipedia did better in integrating new data.

While Wikipedia articles appeared to be more up-to-date, the study authors acknowledged that this may reflect PDQ’s policy of not discussing published studies until pharmaceutical agents have been approved by the FDA. Using appraisal forms and readability scores, medically trained personnel evaluated Wikipedia and PDQ articles on five of the most common cancers—lung, breast, prostate, colon, and melanoma— and five of the least common—anal, vulvar, small intestine, testicular, and osteosarcoma. Inaccuracies were rare, less than 2%, on both websites.

The authors acknowledge that the implications of the differences in readability are unknown. “Several studies have concluded that those patients who look for information online have above-average educations. However, many patients with cancer have impaired cognitive function,” the authors wrote. They concluded that further research to determine how Internet information is understood and absorbed will help to design new Web-based information systems.

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Rajagopalan MS, et al: J Oncol Pract.

Aug. 4, 2011 (early release online).

Don’t mIss tHe nIH state-of-tHe-scIence conference Role of aCtIve suRveIllanCe In tHe management of men wItH loCalIzed pRostate CanCeR

Sensitivity Analysis Using sensitivity analysis, the researchers found that RFA “becomes a better strategy if the median diseasefree survival after treatment is at least 1.42 years, which is lower than the median disease-free survival for hepatic resection (1.56 years) from the pooled data.” In addition, they noted, “when

DECEMBER 5–7, 2011 NatChER CoNfERENCE CENtER NatioNal iNstitutEs of hEalth, BEthEsDa, MaRylaND

InformatIon/ regIstratIon: Consensus.nIH.gov Consensus@maIl.nIH.gov 888-644-2667

The ASCO Post | OCTOBER 15, 2011

PAGE 48

Letters to the Editor

Treating Cancer or Fear?

I

read the article by Deb Stewart, “Acting on Fear” (The ASCO Post, August 15, 2011, page 1) with interest, disappointment, and empathy.

“Acting on fear” in cancer treatment generally, and particularly in breast cancer, is not uncommon. Hence, I was most interested in the article’s major thrust, as expressed in the first two paragraphs. Ms. Stewart describes how she rushed through with the decision to undergo mastectomy for her breast cancer. As she states, “I just acted on fear.” Or as some might cynically say, “the patient’s fear was exploited by the caregivers,” leading to major disfiguring surgery, which was most likely unneccessary.

Reading through the rest of the article, I was disappointed to find that the author—a nurse and breast health educator at Johns Hopkins Avon Foundation Breast Center—makes another unfortunate decision. After a second breast cancer diagnosis, she chooses mastectomy for her contralateral breast. Despite her claim that she “took control” this time, I believe she was again acting on fear, or at best, basing her decision on erroneous science.

Ms. Stewart claims, “I felt that having had cancer before and having it now, I would likely have it again.” Her second cancer in the opposite breast 20 years later is a new cancer. There is no reason to believe that she is at higher risk to “have it again.” If the patient does have breast cancer again, it

will most likely be recurrent disease, elsewhere. Risk for distant recurrence is identical whether the patient has had breast conservation therapy or modified radical mastectomy.

In fact, an article in the same issue of The ASCO Post (“Patients with Early Breast Cancer Benefit from Regional Nodal Irradiation,” page 3) reports that breast preservation and regional node irradiation (if indicated) reduces distant recurrence, based on results of the Canadian MA.20 trial. Radiation is not generally administered with modified radical mastectomy but is always done with breast conservation (per the National Comprehensive Cancer Network guidelines).

All surgeons (and others) should be encouraged to read the last section of Ms. Stewart’s article, headed “Loss and Change.” Her insights here might help caregivers guide mastectomy-leaning patients “in their transition through the stages of treatment and beyond” the initial phase of fear and anger.

—Gilbert A. Lawrence, MD, DMRT, FRCR Radiation Oncology, Faxton Hospital Utica, New York

■

To view the articles discussed in these Letters to the Editor, scan this QR code with your smartphone.

‘Unrealistic Optimism’ or Losing Sight of the Forest for the Trees?

T

he article: “Unrealistic Optimism Poses Ethical Challenges, May Affect Informed Consent Process” (The ASCO Post, September 1, 2011, page 35) seems to be delving into a subject with an intent that is unclear.

I agree fully with Dr. Jimmie Holland that discrimination between “optimism” and “unrealistic optimism” is not only unhealthy, but also purports to illustrate that these researchers, from their “superior stance,” are attempting to judge the “hope” and “optimism” qualities of our patients.

As a hematologist-oncologist, hope is crucial, and I believe it is of significant benefit to the overall well-being and health of my patients. Good dialog, ongoing discussions, and a connection to one’s oncologist allow a patient’s expectations, and hope and optimism, to change

■

Using QR Codes The QR (Quick Response) codes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading. These barcodes can be read by any mobile device with a camera, QR code–reading software, and internet access. Some devices come with the software preinstalled; if not, visit your device’s application store (such as the iTunes Store or the Android Market) and download the software of your choice.

Scanning the Codes 1 2

3 4

© Peter C. Vey/The New Yorker Collection/www.cartoonbank.com

and adjust with time and circumstances.

The participants in trials always hope for some benefit, whether to the larger base of knowledge and patients in general, or also for themselves if possible. This is human nature, which is remarkably resilient and courageous. It appears these researchers from their “ethics platform” are confusing this subject and have lost sight of the forest for the trees, so to speak.

The real focus in hematologyoncology ought to be directed more accurately toward addressing the travesty in our country of having patients who are uninsured, let alone the staggeringly high cost of chemotherapy treatments. Now, that would be practicing “ethics” at a very high level.

—Stephen G. Chandler, MD Portland, Oregon

When you see a code that you would like to scan, start your code-reading application.

Position your device in front of the code so that it fills about half your screen.

The code will scan automatically.

If the scan is successful, you will be rerouted to the targeted link.

ASCOPost.com | OCTOBER 15, 2011

PAGE 49

Awards

Susan G. Komen for the Cure® Announces 2011 Brinker Award Winners for Scientific Distinction

A

rmando Giuliano, MD, and Carlos Arteaga, MD, are being honored as this year’s winners of the Susan G. Komen for the Cure® Brinker Awards for Scientific Distinction in basic science and clinical research.

The awards will be presented on December 7 at the 34th Annual San Antonio Breast Cancer Symposium where both Dr. Giuliano and Dr. Arteaga will deliver keynote lectures.

Dr. Giuliano is Executive Vice Chair of Surgery for Surgical Oncology at Cedars-Sinai Medical Center and Dr. Arteaga is Professor of Medicine and Cancer Biology at Vanderbilt University in Nashville, Tennessee. Their institutions will receive a $25,000 award to further their activities in breast cancer research.

Dr. Giuliano is receiving the Brinker Award for Armando E. Giuliano, MD S c i e n t i f i c Distinction in Clinical Research for work that has led to less invasive surgical treatments for breast cancer, specifically the removal of fewer lymph nodes in certain women with early-stage breast cancer.

Dr. Arteaga is receiving the Brinker Award for Scientific Distinction in Basic Science for his work ex plaining the role of several key proteins and growth factor receptors in Carlos Arteaga, MD the pathogenesis of breast cancer. His translational research helped provide the rationale for many of new targeted therapies.

“The pioneering work of these two scientists has had, and will continue to have, a significant impact on the quality of treatment and quality of life for breast cancer survivors,” said Eric P. Winer, MD, Komen’s Chief Scientific Advisor and Chair of Komen’s Scientific Advisory Board. “We’re moving ever closer to an era of more personalized and less

invasive treatments for this disease, thanks in large part to the foundation that these two scientists have built in translational science and clinical practice.”

Komen is the largest private funder of breast cancer research, this year investing $66 million to new research and programs to advance understanding, prevention and treat-

ment of breast cancer. The Brinker Awards for Scientific Distinction were established in 1992 to recognize the efforts of pioneers in clinical research and basic science.

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The ASCO Post | OCTOBER 15, 2011

PAGE 50

Perspective

Giving Women a Fighting Chance When They Have Breast Cancer

By Congresswoman Debbie Wasserman Schultz

I

knew there was a chance I could get breast cancer, I just never thought it would really happen to me.

I am one of 2.5 million breast cancer survivors living in our country today. Just weeks after getting a clean mammogram and my 41st birthday, I felt a lump in my breast. As a young and otherwise healthy mother of three, I heard the words that all women hope they never hear: “You have cancer.” It was like an anvil crashing down on me.

With an early diagnosis and confirmation of a hereditary form of the disease, I underwent seven major surgeries—but not radiation or chemotherapy—to ensure that my cancer would not return. But that fear is never truly abated; once you have had cancer, you know it could always come back.

Improving Cancer Statistics As a breast cancer survivor, I understand intimately how important it is that women have every possible cancer-fighting tool at their disposal.

Our nation has been a leader in discovering innovative methods of detection and treatment. A cancer diagnosis is no longer the death sentence it used to be, and the statistics are only getting better. But our health-care system is still rife with disparities—especially in knowledge and access—that prevent these advances from reaching everyone.

As a woman living in the United States, you have a 1 in 8 chance of developing invasive breast cancer during your lifetime, and a 1 in 35 chance that the disease will take your life. This year, approximately 261,100 women in America will be diagnosed with breast cancer. Nearly 40,000 of those women will not see another birthday.

Despite that harrowing number, there is good news on the horizon: Breast cancer death rates have been decreasing. There is more hope for survival as we discover and access new

treatments, guarantee more women comprehensive health-care coverage, and focus on education and early detection.

Affordable Care Act That is why the Patient Protection and Affordable Care Act that Congress passed last year is so important. The bill seeks to eliminate these disparities by driving down the cost of health care and extending coverage to 31 million uninsured or underinsured Americans. This comprehensive law puts an emphasis on prevention and wellness, so that medical professionals can turn our nation’s sick care system into a true health-care system.

In the years since my diagnosis,

eliminating cost-sharing for routine tests like mammograms and colonoscopies; it abolishes annual and lifetime caps on what an insurance policy will pay; and it finally ends the egregious practice of denying coverage to patients with preexisting conditions. This provision is gamechanging for cancer survivors.

EARLY Act After I was diagnosed with breast cancer and experienced the importance of early detection firsthand, I knew that I had to introduce legislation to help other young women facing this terrible disease. There have been so many advances in the screening and treatment of cancer, but all of that is moot if women are not

A cancer diagnosis is no longer the death sentence it used to be, and the statistics are only getting better. But our health-care system is still rife with disparities that prevent these advances from reaching everyone. countless women have approached me to talk about their own personal health-care struggles. There are women who have foregone their annual mammograms because they could not afford the copay of the exam. I have heard from women who have had to choose one therapy—surgery, radiation, or chemotherapy—despite a physician’s recommendation for multiple treatments, because the cost was simply too great to bear. And there are those women who avoid getting a diagnosis altogether, despite discovering what they feel could be cancer, because of the very real fear that an insurance company might rescind their coverage.

Thankfully, the Affordable Care Act will make these fears a thing of the past. The law limits health disparities and stresses prevention by

Congresswoman Debbie Wasserman Schultz

learning about their bodies, taking steps to reduce risk factors, and getting regular and appropriate screenings. And that is why, as soon as I was cancer-free, I introduced the Breast Health Education and Awareness Requires Learning Young Act, or the EARLY Act. The EARLY Act, which became law as part of the Affordable Care Act, focuses on a central tenet: that we must empower young women to understand their bodies and speak up for their health. The law works to educate certain groups, such as African-American women and Jewish women of Eastern European descent, who are disproportionately at risk for breast cancer at a young age.

The EARLY Act also contains an education program for medical profes-

October is

Breast Cancer Awareness Month

sionals, who all too often turn young women away.

Personal Perspective My twins, Rebecca and Jake, were 8 and my daughter Shelby was 4 when I learned I had breast cancer. Naturally, I was worried about the impact my illness would have on their lives.

Would I be there to attend their Girl Scout meetings and baseball games, and tuck them in at night? Would I be around to see them grow up, go to college, fall in love, and get married?

Rebecca, now 12, has started to ask if she too will get breast cancer someday. I know I can’t promise her that she will not face the same cancer that I faced—especially because I carry the BRCA2 genetic mutation that dramatically increased my chances of getting breast or ovarian cancer. But what I can promise my daughters is that they will grow up in a world that is determined to give them the best health-care opportunities possible.

All women need to know the early warning signs of cancer and to be aware of their own personal risk factors. Going through this experience, it became undeniably clear to me: Women facing cancer need and deserve all of the knowledge and tools available that can help save their lives. We must continue to help make it possible for all Americans to access quality, affordable health care.

■

Congresswoman Debbie Wasserman Schultz (D) represents Florida’s 20th Congressional district.

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis.

[See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

AVASTIN® (bevacizumab) Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy.

[See Dosage and Administration (2.4).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

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

The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy.

Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin as compared to 4% (1/25) of patients who received bolus-IFL alone.

In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone.

The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus-IFL plus Avastin as compared to patients receiving bolus-IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients).

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.

Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).]

Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3-4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo.

Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1.

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in MBC is based on an improvement in progression free survival.

There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

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

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever.

Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery.

In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%.

[See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm.

Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied.

Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Table 1 Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with NCI-CTC Grade 3−4 Adverse Events in Study 1 appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control) monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated Arm 1 Arm 2 hypertension after discontinuation of Avastin.

IFL + Placebo IFL + Avastin Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive (n = 396) (n = 392) encephalopathy. [See Dosage and Administration (2.4).]

NCI-CTC Grade 3-4 Events 74% 87% 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms Body as a Whole Asthenia 7% 10% occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder Abdominal Pain 5% 8% which can present with headache, seizure, lethargy, confusion, blindness and other visual and Pain 5% 8% neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Cardiovascular Hypertension 2% 12% Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of Deep Vein Thrombosis 5% 9% reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Intra-Abdominal Thrombosis 1% 3% Dosage and Administration (2.4).]

Syncope 1% 3% 5.8 Proteinuria Digestive The incidence and severity of proteinuria is increased in patients receiving Avastin as Diarrhea 25% 34% compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in Constipation 2% 4% clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a Hemic/Lymphatic published case series, kidney biopsy of six patients with proteinuria showed findings Leukopenia 31% 37% consistent with thrombotic microangiopathy.

14% 21% Neutropeniaa Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine aCentral laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. dipstick reading should undergo further assessment with a 24-hour urine collection.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving Table 4 bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2.

NCI-CTC Grades 1−5 Adverse Events in Study 9 Grade 1–4 adverse events were collected for the first approximately 100 patients in each of (Occuring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo) the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued.

System Organ Class/ IFN-α + Placebo IFN-α + Avastin (n = 304) (n = 337) Preferred terma Table 2 Gastrointestinal disorders NCI-CTC Grade 1-4 Adverse Events in Study 1 Diarrhea 16% 21% (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) General disorders and administration Arm 1 Arm 2 Arm 3 site conditions IFL + Placebo IFL + Avastin 5-FU/LV + Avastin Fatigue 27% 33% (n = 98) (n = 102) (n = 109) Investigations Weight decreased 15% 20% Body as a Whole Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders Weight Loss 10% 15% 16% Hypertension 9% 28% Dry Mouth 2% 7% 4% a Adverse events were encoded using MedDRA, Version 10.1.

Colitis 1% 6% 1% Hemic/Lymphatic The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Thrombocytopenia 0% 5% 5% Avastin arm compared to IFN-α alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) Respiratory and pulmonary embolism (5 vs. 1).

Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.

Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second-line mCRC The following adverse reactions have been identified during post-approval use of Avastin.

Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 always possible to reliably estimate their frequency or establish a causal relationship to non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence drug exposure. (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving Body as a Whole: Polyserositis FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Eye disorders (reported from unapproved use for treatment of various ocular disorders): hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection to under-estimate the true adverse event rates due to the reporting mechanisms used including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual in Study 2. disturbances; Ocular hyperemia; Ocular pain and/or discomfort Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected Hemic and lymphatic: Pancytopenia in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension Respiratory: Nasal septum perforation, dysphonia (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), 7 DRUG INTERACTIONS febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 A drug interaction study was performed in which irinotecan was administered as part of the or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

(3% vs. 0%).

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in be a difference in the mean exposure of either carboplatin or paclitaxel when each was Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving administered alone or in combination with Avastin. However, 3 of the 8 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% In Study 9, there was no difference in the mean exposure of interferon alfa administered in vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation combination with Avastin when compared to interferon alfa alone.

(3% vs. 0.3%) and proteinuria (3% vs. 0%).

8 USE IN SPECIFIC POPULATIONS Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in 8.1 Pregnancy the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.

Pregnancy Category C Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in abdominal, and pain/weakness/hypotension (2). teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations.

Avastin is not approved for use in combination with capecitabine or for use in second or third Adverse fetal outcomes were observed at all doses tested. Other observed effects included line treatment of MBC. The data below are presented to provide information on the overall decreases in maternal and fetal body weights and an increased number of fetal resorptions. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, [See Nonclinical Toxicology (13.3).] controlled study in which all adverse events were collected for all patients. All patients in Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for from the mother to the developing fetus, and has the potential to cause fetal harm when metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients administered to pregnant women. Because of the observed teratogenic effects of known inhibitors receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential in Table 3. benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers Table 3 It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk.

NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone) substantial amounts. Because many drugs are secreted in human milk and because of the potential for Capecitabine serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab Capecitabine + Avastin (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical (n = 215) (n = 229) Pharmacology (12.3).]

Body as a Whole 8.4 Pediatric Use Asthenia 47% 57% The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Headache 13% 33% been established.

Pain 25% 31% Antitumor activity was not observed among eight children with relapsed glioblastoma treated Cardiovascular with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Hypertension 2% 24% Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Digestive to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and Stomatitis 19% 25% exposure). The incidence and severity of physeal dysplasia were dose-related and were partially Metabolic/Nutrition reversible upon cessation of treatment.

Weight loss 4% 9% 8.5 Geriatric Use Musculoskeletal In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 Myalgia 8% 14% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Respiratory hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, Dyspnea 18% 27% leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Epistaxis 1% 16% survival was similar in elderly patients as compared to younger patients.

Skin/Appendages In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk Exfoliative dermatitis 75% 84% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

Urogenital In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Albuminuria 7% 22% Precautions (5.8).]

In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received the overall adverse events profile was different in the elderly as compared with younger patients.

Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of cough, and voice alteration. any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two incidence of arterial thromboembolic events was increased in all patients receiving Avastin with deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions Avastin-related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (5.5).]

(26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), 10 OVERDOSAGE arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 16 patients and with severe headache in three of 16 patients.

163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Avastin Avastin® (bevacizumab) compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), 02/11 AVA0000306600 asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including Manufactured by: 10127309 hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Initial U.S.Approval: February 2004 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Genentech, Inc. haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract A Member of the Roche Group Code Revision Date: February 2011 hemorrhage, and traumatic hematoma).

1 DNA Way Avastin® is a registered trademark of Genentech, Inc. Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN-α plus South San Francisco, CA 94080-4990 ©2011 Genentech, Inc. Avastin compared to the IFN-α plus placebo arm are presented in Table 4.

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

Think Avastin

Because survival matters most Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991 1-year survival:

Percentage Surviving

100

51% vs 44%2

80

2-year survival:

23% vs 15%2

60 40

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

20 0

10

20

30

40

50

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

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

Indication Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control

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Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2 included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%).

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions Based on animal data, Avastin may cause fetal harm and may impair fertility. Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin. For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother Grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/ embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

References: 1. Avastin Prescribing Information. Genentech, Inc. February 2011.

2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

(06/11)

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