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JANUARY 15, 2012

ASCOPost.com

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

53rd ASH Annual Meeting

Improved Survival with Chemotherapy Alone in Limited-stage Hodgkin Lymphoma

Sentinel Lymph Node Biopsy for Thin Melanomas?

But current radiation techniques less toxic

By Alice Goodman

By Michael S. Sabel, MD

A

n important study suggests that radiotherapy may not be a necessary addition to chemotherapy in previously untreated patients with limited-stage Hodgkin lymphoma, sparing patients the risks of late radiation-induced cardiac Ralph M. Meyer, MD effects and second cancers.

These data were based on 12 years of follow-up of the Hodgkin’s Disease 6 trial (HD.6), which was presented at the 53rd Annual Meeting of the American Society of Hematology in San Diego1 and published online simultaneously in The New England Journal of Medicine.2 (See added perspective on page 7.)

The study showed that ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy

alone achieved improved overall survival compared with radiation alone or radiation combined with ABVD. The 12-year overall survival rate was 94% for ABVD vs 87% SEE PAGE 83 for those who received radiation (P = .04). The rate of freedom from disease progression was lower in the ABVD arm vs radiation therapy at 12 years—87% vs 92% (P = .05)—demonstrating that in this trial, at least, progression-free survival was not predictive of overall survival.

Controversial Strategy “The strategy of treating limited-stage Hodgkin lymphoma with chemotherapy alone is controversial. Our results alter this debate. The 12-year rates of 87% for freedom from disease progression and 94% for overall survival in the ABVD arm suggest

Bevacizumab Breast Cancer Indication Rescinded: What Are the Downstream Implications?

By Ronald Piana

L

hen sentinel lymph node biopsy for the regional staging of melanoma was first introduced, it was recommended for any patient with a melanoma 1.0 mm in Breslow thickness or greater. Patients with thin melanomas were not thought to have a sufficiently high risk to warrant the additional cost and morbidity of the procedure.

As experience grew, several retrospective series identified risk factors beyond Breslow thickness that were associated with an increased risk of regional metastases, and should therefore prompt consideration of sentinel lymph node biopsy for patients with melanomas shy of 1.0 mm (in a range generally considered to be 0.76 to 0.99 mm). These risk factors were continued on page 2

continued on page 6

Expert’s Corner

eading up to FDA’s resolution to revoke the breast cancer indication for bevacizumab (Avastin), the debate over the drug’s clinical value was imbued with contentious ideologic overtones, which culminated in a 2-day public hearing that exposed deep divisions not only in the scientific community, but also among breast cancer advocacy groups and

W

individual patients and survivors. In the face of the recent FDA decision, the Centers for Medicare & Medicaid Services will continue coverage for bevacizumab in metastatic breast cancer, further complicating the issue for providers and payers. To clarify this ongoing debate, The ASCO Post spoke with nationally regarded health-care expert Lee N. Newcomer, MD, Senior Vice President of Oncology for UnitedHealthcare.

Drug manufacturers need to develop drugs that make a significant difference for the patient.

— Lee N. Newcomer, MD

Coverage Decisions FDA Commissioner Margaret A. Hamburg, MD, said she revoked bevacizumab’s approval in breast cancer after concluding that the drug was not effective or safe. As an oncologist and payer, how do you determine whether a cancer therapy warrants coverage?

Dr. Sabel is Associate Professor of Surgery at the University of Michigan Health System and Director of the University of Michigan Comprehensive Cancer Center Breast Cancer Clinical Outcomes Project, Ann Arbor.

MORE IN THIS ISSUE Oncology Meetings Coverage San Antonio Breast Cancer Symposium ���� 3 53rd ASH Annual Meeting ���������������� 6, 7 97th Annual American College of Surgeons Clinical Congress ������ 15, 16 NIH State-of-the-Science Conference ������������������������������������� 22, 25 Eighth Annual Society for Integrative Oncology Conference ������������������� 32, 33 2011 Health IT/EHR Symposium �������� 60 Direct from ASCO ��������������������������������������� 38

continued on page 14

A Harborside Press® Publication

The ASCO Post | JANUARY 15, 2012

PAGE 2

Opinion

Thin Melanomas continued from page 1

Editorial Board James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

ASSOCIATE EDITORS

William T. McGivney, PhD Philadelphia, Pennsylvania

Joseph S. Bailes, MD Texas Oncology

James L. Mulshine, MD Rush University Medical Center

Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

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 Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Robert W. Carlson, MD Stanford University Medical Center

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

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

Lynn D. Wilson, MD Yale University School of Medicine

Jay S. Cooper, MD Maimonides Medical Center

Stanley H. Winokur, MD Singer Island, Florida

John Cox, DO Texas Oncology

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

E. David Crawford, MD University of Colorado 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 John A. Fracchia, MD New York Urological Associates 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

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

Staging Revision When the most recent version of the American Joint Committee on Cancer (AJCC) staging system for melanoma was released,1 one of the most significant changes was the classification of stage T1b as any melanoma ≤ 1.00 mm with ulceration or a mitotic rate ≥ 1/mm2. Despite the authors’ stressing that this decision was made based on survival data and that “the AJCC Melanoma Staging Database did not contain sufficient data to assess risk of occult nodal micrometastases in this population,” many surgeons have advocated extending the indications for sentinel lymph node biopsy to include any T1b melanoma. This would include any melanoma < 0.76 mm with a mitotic rate of at least 1/mm2.

Performing sentinel lymph node biopsy even for intermediate-thickness melanoma remains slightly controversial, as the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) has yet to demonstrate an overall sur-

Statistical Extrapolation Advocates for sentinel lymph node biopsy for thin melanoma state that T1b melanomas have a sufficient risk, but this is based on statistical models extrapolated to thin melanomas. A careful analysis of papers advocating sentinel lymph node biopsy for thin melanomas show most if not all potential benefit is limited to patients with melanomas between 0.75 and 0.99 mm, the group for whom we currently recommend consideration. Retrospective series consistently show a sentinel lymph node positivity rate of only 2% to 3% for melanoma < 0.75 mm.3 As these patients were specifically selected for sentinel lymph node biopsy based on adverse features, this may even overestimate the risk among the entire T1b population.

Even if we assume a 2% to 3% risk and extrapolate the same 10% to 15% benefit among the node-positive subcontinued on page 73

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.

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Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

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.

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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quite varied and included Clark level IV, ulceration, mitotic rate, angiolymphatic invasion, and the age of the patient (with younger patients having a higher rate of sentinel lymph node metastases than their older counterparts). Findings implicating the last three of these risk factors were the most consistent.

vival benefit for the addition of sentinel lymph node biopsy to wide excision of intermediate-thickness (1.2–3.5 mm) melanoma.2 This is primarily because any potential benefit is limited to the node-positive population (16% in the MSLT-I trial) and subset analysis suggests the benefit is only around 10% to 15%. As the likelihood of finding regional metastases decreases, the benefit of the procedure also decreases, and the risk-benefit ratio tilts more toward risk.

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ASCOPost.com | JANUARY 15, 2012

PAGE 3

34th Annual San Antonio Breast Cancer Symposium Gene Classifier Spots Different Recurrence Patterns in Patients with ER-positive Breast Cancer

By Susan London

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new gene classifier differentiates between women with estrogen receptor (ER)-positive breast cancer who go on to develop metastases early vs late, possibly paving the way for tailored adjuvant therapy.

Minetta C. Liu, MD

Using pretreatment tumor biopsies, a team led by Minetta C. Liu, MD, of the Georgetown University Lombardi Comprehensive Cancer Center in Washington, DC, analyzed the genetic makeup of cancers from 366 women with ER-positive breast cancer who received adjuvant endocrine therapy with tamoxifen alone.

Analyses identified a set of 91 genes whose altered expression clearly separated patients having a distant recurrence early (within 3 years of diagnosis) from those having such a recurrence late (more than 10 years after diagnosis), acSEE PAGE 83 cording to results reported at the 34th Annual San Antonio Breast Cancer Symposium.1

Reliable Prediction Certain genes, such as those for the calmodulins and MAP kinase 1, were overexpressed in the former tumors, whereas others, such as those for the estrogen receptors and the androgen receptor, were overexpressed in the latter.

“Robust molecular differences clearly exist between ER-positive breast cancers that recur early vs much later despite adjuvant tamoxifen,” Dr. Liu commented.

“The reliable prediction of early treatment failure may identify those patients who require agents beyond

endocrine therapy to prevent the early onset of distant metastases,” she added.

“Exploiting the molecular differences between very early vs late recurrences may guide novel drug combinations in early-stage ER-positive breast cancer,” such as the addition of biologics to endocrine therapy.

The findings are being validated further, according to Dr. Liu. Additionally, the investigators are studying the patients whose breast cancers never recurred, again hoping to identify a classifier that can be applied clinically.

“The goal is to convert an early recurrence to a late or never recurrence, and a late recurrence to a never recurrence, and hopefully avoid recurrences completely,” she explained.

Also of interest are women treated with adjuvant aromatase inhibitors. Al-

Predicting Recurrence in Breast Cancer ■■ Analyzing a set of 91 genes, investigators were able to distinguish

patients with ER-positive breast cancer who would experience disease recurrence early (within 3 years of diagnosis) vs late (more than 10 years after diagnosis) after adjuvant tamoxifen.

■■ This finding may help tailor treatment based on tumor genetics rather than on anatomic features of disease.

study as a step toward personalized medicine.

“This type of work is very important as we look to individualize the treatment that we give to patients based on their actual tumors rather than on an algorithm based primarily on the anatomic features of their disease,” she said. “This tool may one day allow us to identify patients at risk of early relapse, who may derive benefit

The question will be, can you convert an early recurrence to a late or never recurrence, and a late recurrence to a never recurrence, and hopefully avoid recurrences completely.

— Minetta C. Liu, MD

though assessing gene classifiers in this group will be limited by their relatively shorter length of follow-up, doing so “is certainly provocative in this day and age.”

Personalized Medicine In a related press conference, Jennifer A. Ligibel, MD, Assistant Professor of Medicine and a breast oncologist at the Dana-Farber Cancer Institute in Boston commended the

Jennifer A. Ligibel, MD

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and

from chemotherapy, and patients at risk of late relapse, who may benefit from extended endocrine thereapy.”

Study Rationale and Design Dr. Liu noted that the molecular basis for different recurrence patterns in ER-positive breast cancer “is largely unknown.”

“Our group hypothesized that early recurrences during tamoxifen treatment exhibit different biological characteristics than those that recurred years later,” she said. “Furthermore, these differences can be identified by looking at variations in the transcriptomes, or the gene patterns from these tumors.”

The investigators analyzed gene expression data generated from tumor biopsies from two cohorts of patients with early ER-positive breast cancer who received adjuvant tamoxifen for

approximately 5 years.

One cohort, used as the training set, included 111 patients with stage I through III disease and a median 13year follow-up, during which time 23% and 20% had an early and late distant recurrence, respectively. The other cohort, used as the validation set, had 255 patients with stage I or II disease and a median 9-year follow-up, during which 10% and 3% had an early and late distant recurrence, respectively.

Key Data A classifier based on 91 genes—the majority of which related to proliferation and apoptosis—“essentially separated those patients that were going to recur early vs those that recurred late,” Dr. Liu reported. In receiver-operating characteristic curve analysis, the area under the curve for the classifier was 0.87 in the training set and 0.81 in the validation set.

Statistical network modeling predicted a high level of signaling between many of the affected genes, hinting at some potential mechanistic explanations for the observed clinical behavior.

“We also looked at 5 years vs 10 years [as recurrence intervals] and different time frames,” Dr. Liu noted. “And although the weighted significance of certain genes may vary, the classifier still holds.”

■

Disclosure: Drs. Ligibel and Liu reported no potential conflicts of interest.

Reference 1. Liu MC, Dixon JM, Xuan JJ, et al: Molecular signaling distinguishes early ER positive reast cancer recurrences despite adjuvant tamoxifen. 2011 San Antonio Breast Cancer Symposium. Abstract S1-8.

Presented December 7, 2011.

the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

The ASCO Post | JANUARY 15, 2012

PAGE 6

2011 American Society of Hematology Annual Meeting Hodgkin Lymphoma continued from page 1

that chemotherapy alone can now more confidently be a therapeutic option for this population,” stated lead author Ralph M. Meyer, MD, Director of the NCIC Clinical Trials Group, and Professor at Queens Uni-

versity in Kingston, Ontario, Canada.

Regarding the lower rate of freedom from disease progression in the ABVD arm, he said, “The standard paradigm that keeping disease away leads to living longer doesn’t hold in this trial. These results show that improved long-term survival is less de-

pendent than previously assumed on further reducing deaths due to progressive Hodgkin lymphoma and instead emphasize a need for treatments that will not lead to deaths from late treatment effects,” Dr. Meyer said.

Patients with limited-stage Hodgkin lymphoma are typically treated

with combination chemotherapy plus radiation. This treatment has been highly effective, but late effects of radiation are concerning.

Data Breakdown The NCIC Clinical Trials Group HD.6 trial enrolled 405 previously untreated patients with stage IA or IIA nonbulky Hodgkin lymphoma and compared 12-year overall survival in patients treated using ABVD alone or radiation with or without ABVD. Patients were stratified into low- or high-risk categories prior to randomization.

Findings related to overall survival and freedom from disease progression in the overall study population were generally similar among the high-risk patients. The rate of overall survival for high-risk patients was 92% in the ABVD arm vs 81% in the radiation arm. Overall, late treatment effects were lower in the ABVD arm. Second cancers were reported in 10 patients in the ABVD arm vs 23 in those treated with radiation. Cardiac events were reported in 16 patients treated with ABVD vs 26 patients who received radiation. Deaths due to second cancers occurred in 10 patients in the radiation arm vs 4 in the ABVD arm, and deaths from causes other than Hodgkin lymphoma or second cancers were also higher in the radiation arm: 10 vs 2, respectively. continued on page 7

Chemotherapy with vs without Radiation in Hodgkin Lymphoma ■■ Analysis of 12 years’ follow-

up from the NCIC HD.6 trial supports use of chemotherapy alone without radiation for limited-stage Hodgkin lymphoma.

■■ Long-term overall survival was 7% higher in the ABVD-alone arm of the trial than in the radiation arms.

■■ Late effects, including second cancers and cardiovascular events, were higher with radiation therapy.

■■ Freedom from disease

progression did not translate to improved overall survival.

■■ Current radiation techniques

are less toxic than the subtotal radiation therapy used in this trial.

ASCOPost.com | JANUARY 15, 2012

PAGE 7

2011 American Society of Hematology Annual Meeting Opinion

Favorable Early-stage Hodgkin Lymphoma and HD.6: The Take-Home and Don’t–Take-Home Messages

By Joachim Yahalom, MD

T

he Canadian HD.6 randomized study in patients with nonbulky early-stage Hodgkin lymphoma is mostly of historic interest.1,2 It has little relevance to current treatment standards or questions, and the risk for its inappropriate interpretation is of great concern.

Radical Radiation Approach Long Abandoned The study evaluated three treatment programs (see article beginning on page 1); two of these programs have been abandoned at most centers for almost 2 decades. Indeed, the National Cancer Institute of Canada closed HD.6 earlier than planned (in 2002), recognizing that it was testing treatment strategies that were no longer considered appropriate.

The radiation field in these programs was sub–total nodal irradiation (STNI) to 35 Gy. STNI included all lymph nodes sites in the upper body (bilateral neck, full mediastinum with hilar areas, and both axillae), whether they were involved with Hodgkin lymphoma or not.

It continued with radiation to the clinically uninvolved spleen and abdominal lymph nodes. Many organs were unnec-

essarily irradiated. This field was shown in multiple randomized and nonrandomized studies to be unwarranted and potentially toxic.

The total/subtotal nodal radical radiation approach was designed more than 50 years ago, when in the absence of effective and relatively safe chemotherapy for Hodgkin lymphoma, radiation was primarily used alone. For almost 20 years, it has become highly exceptional to use STNI, either alone or, particularly, in combination with chemotherapy.

It should be underscored that STNI bears no resemblance to the currently practiced limited radiation field called involved-field radiotherapy. During the past decade, even smaller and more precise involved-node radiotherapy fields have been defined and are used in many combined-modality programs. These limited fields irradiate roughly only around 10% of the STNI volume, and they include merely the tissue volume containing the originally involved lymph nodes with tight margins. Furthermore, involved-field or involved-node radiotherapy nowadays is administered more precisely, owing to the progress in advanced imaging

Hodgkin Lymphoma

■

Disclosure: Dr. Meyer has received honoraria from Celgene regarding his role on the Independent Response Committee of a clinical trial and from Lilly regarding his role as Chair of an Independent Data Safety Monitoring Committee. He is Director of the NCIC CTG Clinical Trials Group which has received research funding from Amgen Canada, Ariad Pharmaceuticals, Astex Therapeutics, AstraZeneca, Bristol-Myers Squibb, Celgene, Lilly, GlaxoSmithKline, Janssen-Ortho, Merck Frosst Canada, Novartis, Oncothyreon, Orthobiotech, Pfizer, Roche, S*Bio Ptd Ltd, sanofi-aventis, Schering Canada, Zymogenetics.

Joachim Yahalom, MD

disease control, with an overall survival rate of 98%.

In contrast, most early or late mortality events—a total of 23—occurred in the less favorable group (older patients, more disease sites, mixed-cellularity histology) that received ABVD combined with excessive radiation (STNI). Thus, in spite of significantly superior disease control provided by adding STNI in comparison to ABVD alone, even after doubling or tripling the = .006), morABVD dose (HR = 3.2; P ������������� tality events were more common than in the group that received only ABVD (11 events), resulting in a better overall survival (P = .04) for the ABVD-alone group—the main message of this study.

Lessons from Mortality and Second Cancers in HD.6 The authors and interpreters of HD.6 grouped together the cohort that received STNI alone (their more favorable group) with the less favorable cohort that received two courses of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed

by STNI. They often call all these patients together the “radiation therapy group.” Interestingly, these two groups had different mortality risk profiles, although both achieved excellent disease control. STNI-alone patients had excellent survival, with only one death from any cause, and obtained excellent

continued on page 8

EXPERT POINT OF VIEW

continued from page 6

“Overall survival is superior in patients treated with ABVD alone because there are fewer deaths from causes other than Hodgkin lymphoma. We recognize that radiation as used in this trial is outdated and excessive, and likely contributed to the excess deaths. However, our 12year results with ABVD rival those described using current combinedmodality strategies and reported with shorter follow-up,” Dr. Meyer said.

and modern radiotherapy techniques, and in lower doses (20 or 30 Gy).

Radiation-related long-term risks are a function of field size, organs included, and dose. Not surprisingly, several studies with long follow-up have already demonstrated that the toxicity and long-term risk profile of involvedfield radiotherapy is markedly reduced in comparison to the known risks of the obsolete extensive radiation field used in HD.6.

A

criticism of the HD.6 trial is that current radiation techniques are probably less toxic than subtotal nodal radiation therapy, which was used in this investigation. Responding to this in an accompanying editorial in The New England Journal of Medicine,1 David J. Straus, MD, of the lymphoma service at Memorial Sloan-Kettering Cancer Center, New York, wrote that studies show a high rate of second cancers and increased deaths due to second cancers and cardiovascular events with radiation therapy of Hodgkin lymphoma.

“It is possible that these complications may still increase long-term mortality despite reductions in the doses and fields of radiation therapy,” he wrote. He also noted that PETadapted therapy, which is coming into vogue, may actually result in increased volumes of radiation.

Dr. Straus emphasized that radiation is still a useful tool for a subgroup

of patients—yet to be defined—where the benefits would outweigh the risks.

“Limiting the use of radiation therapy to the fraction of patients who require it should make an important contribution to the ultimate goal of maximizing the long-term cure rate while minimizing late morbidity and mortality,” Dr. Strauss wrote.

Growing Trend Speaking at a press conference at the ASH Annual Meeting, Jane N. Winter, MD, Professor of Medicine at the Feinberg School of Medicine, Northwestern University, Chicago, said, “Despite differences in radiation ports and doses between the radiation prescribed in the trial and current strategies, it is likely that the findings will encourage the growing trend in the United States to use chemotherapy alone in early-stage patients. Ongoing trials that do not include radiotherapy

Jane N. Winter, MD

are incorporating early PET-scanning [risk-adapted therapy] for early-stage patients and need the support of the [oncology] community to provide additional evidence for this strategy.”

■

Disclosure: Dr. Straus reported no potential conflicts of interest. Dr. Winter was ECOG Chair involved in design of this trial.

Reference 1. Straus DJ: Chemotherapy alone for early-stage Hodgkin’s lymphoma. N Engl J Med. December 11, 2011 (early release online).

The ASCO Post | JANUARY 15, 2012

PAGE 8

2011 American Society of Hematology Annual Meeting HD.6 Take-home Messages continued from page 7

Unexplained Anomaly An unexplained anomaly from this study is the finding that one STNI group was so safe and the other was not.

Unfortunately, some important information regarding mortality and second cancers was not provided. A key analysis that needs to be performed is to determine the number of second cancers that were within the radiation field and, furthermore, how many cancers were in the involved sites. The latter is particularly important as it allows a fairer comparison with the current standardof-care therapy that limits radiation to the involved field. Information on what types of second cancers were included in the mortality events is also missing.

Yet, from the limited information in the New England Journal of Medicine paper,2 some intriguing observations can be made—namely, that all mortality events (n = 5) titled “others” have peculiarly occurred only in the ABVD/ STNI cohort. These events included Alzheimer’s disease, accidental drowning, and suicide. In addition, three deaths “related to infection” were again noted only in the ABVD/STNI arm. Perhaps these deaths were related to unnecessary irradiation of the spleen in STNI, but in practice, it is extremely rare to see lethal infections related to radiation of Hodgkin lymphoma. The number of deaths from cardiac events was identical in both arms; deaths from Hodgkin lymphoma were also similar (five in the ABVD arm, four in the ABVD/STNI arm).

The remaining difference in mortality in this study is from second tumors (four in the ABVD arm, nine in the ABVD/STNI arm). The list of second malignancies is revealing, and many of those listed in the “radiation therapy” column (n = 23) are most unlikely to be related to radiation of sites in the upper part of the body. These include six tumors in the pelvis, and it is difficult to understand how they could even be related to STNI (bladder, rectum, cervix, prostate, etc). Leukemia cases (n = 2) were only seen in the STNI group. These events are rare even with

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total nodal radiation and clearly are not seen with ABVD and involvedfield radiotherapy. Seven other tumors have unclear relationships to the radiation field. In fact, among the reputably radiation-related cancers, tumors of the lung and breast were reported in a single patient each, and the ABVD-only group had the same number of each.

In a study that had significantly fewer events than it was statistically designed for, and that insinuates that the “radiation” reversed its obvious and highly significant benefit in disease control by causing excessive mortality, attention to the specific events and their possible relationship to any radiation or to mere coincidence is even more important. Information is missing on which second cancers caused death, but from the data presented, it seems likely that omitting deaths that could not be attributed to radiation— and in particular not to modern su-

like the German Hodgkin Study Group (GHSG) HD10 trial achieved an overall survival of 97% with only two cycles of ABVD and involved-field radiotherapy of 20 Gy. Why should we settle for an inferior outcome with more systemic therapy? And why use data from a radiation approach that is more extensive by several magnitudes and obviously more toxic? Unnecessarily increasing the total exposure to ABVD has significant acute and late toxicity associated with it. The dose-related cardiac and pulmonary toxicity of ABVD is well documented and is troublesome.

The ability to salvage with bone marrow transplantation many chemotherapy-alone failures that could have been avoided with limited radiotherapy brings only relative comfort to approximately 15% of patients with nonbulky, early-stage disease who will still require salvage after chemotherapy alone. They still have to deal with

Although we are moving toward an era when some selected patients can be safely treated with chemotherapy alone on the basis of risk-adjusted therapy using interim FDG-PET scans, we are not there yet.

—Joachim Yahalom, MD

pradiaphragmatic radiotherapy—the number of deaths among patients with an unfavorable risk profile would be the same in both arms of the study.

Toward Individualized Treatment HD.6 confirms once again that the long-ago decision of lymphoma experts to restrict the radiation field in a combined-modality setting was correct. Yet, it would be wrong to conclude from this study that “radiation” of any kind should be omitted and six cycles of ABVD alone (or four in some) as used in HD.6 is the best way to go.

The authors are content that this approach yielded an overall survival of 87%, but other treatment programs

tough treatment, sterility, enhanced short- and long-term toxicity risk, and disruption of their young lives. It would be of interest to know where the failures with ABVD alone were. As in all other similar studies, most relapses were probably at the sites of original disease and thus could have been avoided with limited radiotherapy.

Although we are moving toward an era when some selected patients can be safely treated with chemotherapy alone on the basis of risk-adjusted therapy using interim FDG-PET scans, we are not there yet. Now we rely on clinical judgment to estimate the benefit/ risk ratio of a certain approach. For example, we will avoid irradiating an axilla (and with it part of the breast) in

a young woman who has had a complete remission by PET. Yet, most other patients will extract the SEE PAGE 83 best benefit, even if rendered PET-negative, from less-intensive ABVD therapy supplemented with reduced radiation field and dose.

Unfortunately, negative PET after chemotherapy alone has not yet provided us with the security that we hoped for. The EORTC/GELA/IIL HD10 randomized study that looked into this question of safe omission of radiotherapy had to close the chemotherapy-only arms because of too many relapses. Perhaps better interpretation of PET-negative scans or emergence of other predictive imaging and molecular tests will help in the future.

In the meantime, we should offer early-stage, highly curable patients therapy that combines mini-ABVD with miniradiotherapy, like the German HD10 and HD11 trials, and avoid outdated therapies like STNI or long courses of ABVD alone. We have already been doing better than that.

■

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

References 1. Meyer RM, Gospodarowicz M, Connors JM, et al: Final analysis of a randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin lymphoma: NCIC CTG/ECOG HD.6. 53rd Annual Meeting of the American Society of Hematology. Abstract 590.

Presented December 12, 2011.

2. Meyer RM, Gospodarowicz M, Connors JM, et al: ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med. December 11, 2011 (early release online).

Dr. Yahalom is Chairman, International Lymphoma Radiation Oncology Group; Coleader of the Lymphoma Disease Management Team, Attending Radiation Oncologist, and Member, Memorial Sloan-Kettering Cancer Center; and Professor of Radiation Oncology, Weill Cornell Medical College, New York.

website at ASCOPost.com

The Latest Addition to an Established Line of Indications for SCCHN

AP N PR OW OV ED

erbitux: now approved new indication

for the First-Line Treatment of Recurrent Locoregional or Metastatic SCCHN in Combination With Platinum-Based Therapy With 5-FU ERBITUX Indications

new

■ ERBITUX® (cetuximab) is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck ■ ERBITUX, 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 patients with squamous cell carcinoma of the head and neck treated in a clinical trial with ERBITUX and radiation therapy and in 3% of patients with squamous cell carcinoma of the head and neck treated in a clinical trial with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU). Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration SCCHN=squamous cell carcinoma of the head and neck.

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

Scan QR code for more information. By scanning the QR code, you are confirming you are a US Healthcare Professional.

Important Safety Information Including Boxed WARNINGS 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. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone — Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX 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 for confirmed ILD 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 Electrolyte Depletion ■ Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX and was severe (NCI CTC grades 3 & 4) in 6-17%. In the squamous cell carcinoma of the head and neck study in combination with platinumbased therapy with 5-FU, there was an increased incidence of hypomagnesemia in subjects who received

Important Safety Information Including Boxed WARNINGS Important (continued)Safety Information Including Boxed WARNINGS (continued)

concomitant EU-approved cetuximab and cisplatin therapy with 5-FU compared to cisplatin with 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX (cetuximab) 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 halflife 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 therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) ■ The most frequent adverse events for EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) vs CT alone (n=215) (incidence ≥40%) were acneiform rash (70%/2%), nausea (54%/47%), and infection (44%/27%). The most common grade 3/4 adverse events for cetuximab in combination with CT (≥10%) vs CT alone included: infection (11%/8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

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.

693US11AB07106

11/11

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

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

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration.

[See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing Information.]

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

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

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

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 Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information.]

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 Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information.]

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 Pharmacology (12.1), Clinical Studies (14.2) in Full Prescribing Information].

CONTRAINDICATIONS None.

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

[See Clinical Studies (14.1, 14.2) in Full Prescribing Information.]

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

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

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

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1.

Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.]

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

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

[See Dosage and Administration (2.4) in Full Prescribing Information.]

Use of Erbitux in Combination With Radiation and Cisplatin: 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 365 patients receiving Erbitux in Study 4 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%.

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

Erbitux1111PBSwip3.indd 1

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

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

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

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

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

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

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

The most common adverse reactions with Erbitux (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 Studies 1,3,4, and 5, 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 4) or Phase 2 (Studies 3 and 5) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

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

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

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

Squamous Cell Carcinoma of the Head and Neck: Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse 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 29 1 13 1 Fevera Headache 19 <1 8 <1 b 15 3 2 0 Infusion Reaction Infection 13 1 9 1 a 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 c 43 2 21 1 Alanine Transaminase, high 38 1 24 1 Aspartate Transaminase, highc c 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

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

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

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

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

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Table 2:

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

Colorectal Cancer: Erbitux Monotherapy — Table 3 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 4. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 3:

Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinomaa Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Grades Any Grades Body System Any b 3 and 4 Grades 3 and 4 Preferred Term Grades % 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 20 5 Infusion Reactionsc 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 a Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. b Adverse events were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusion-related. BSC = best supportive care Erbitux in Combination with Irinotecan — 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%).

Erbitux1111PBSwip3.indd 2

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 (cetuximab) 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.

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

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

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

Pediatric Use: The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

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.

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.

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PAGE 14

Expert’s Corner

Lee N. Newcomer, MD continued from page 1

When our physicians read the literature and made subsequent clinical decisions, we were consistently accused of making those decisions based on cost-savings, no matter how carefully we were working to adhere to best practices. So about 4 years ago, UnitedHealthcare made a commitment to use the National Comprehensive Cancer Network (NCCN) compendium as our way of determining what we did and did not cover for cancer chemotherapy. We decided that using an authoritative instrument, respected by both the physician and patient communities, was the best way to have a transparent, easyto-understand, process.

We know that the NCCN compendium is not perfect, but it is widely respected by oncologists as a reasonable standard. One always knows what our coverage policy is by simply going to the NCCN website. If that requested drug has a level 1, 2A, or 2B recommendation, we’ll cover it.

But in some respects our coverage decisions are legal as well as medical.

We say legally in our documents that the NCCN is the way we make coverage decisions—that is what I must do, no matter what the evidence shows or what my personal opinions might be.

However, now I’ll change hats. As a medical oncologist, I do not see that bevacizumab offers a lot of value to a patient with breast cancer. I think the toxicity outweighs the gains, and if I were in the clinic, it would not be one of the drugs I would use to treat that disease. But as a payer I will cover bevacizumab because the NCCN recommends it.

What the Data Tell Us Bevacizumab was granted accelerated approval in 2008. From the ensuing 3 years, are there “real-world” data to give us a read about bevacizumab’s efficacy?

There really are not. At United, we’ve actually been looking at our data in the claims area, trying to understand whether patients who receive bevacizumab have better survival rates. Claims data alone are not good enough to reveal the answers.

For instance, we have a number of patients who for a variety of reasons change carriers, so when we see an end to claims, we never know whether

that particular patient has died or just changed insurance carriers. So for us to aggregate accurate outcomes information is very difficult.

Moreover, I don’t know of any organized or systemic effort that does postmarketing analyses of these drugs. And that is a central point that the bevacizumab issue is raising. For drugs with marginal benefit to begin with—as illustrated by the Oncologic Drugs Advisory Committee’s decision to revoke bevacizumab’s indication in metastatic breast cancer—should there have been an organized, systematic review of whether these patients with breast cancer had good responses? I think there should have been, but there is no process in place that harvests these important data.

What do your internal data tell you about bevacizumab usage?

What information we do have shows that the drug is being delivered to patients in a very inconsistent manner. Thus, the data might not be analyzable in a meaningful way. We looked to see how often bevacizumab was used according to the very detailed NCCN recommendations. We probed three usage areas: what line of therapy bevacizumab was given for, whether the drug was given for more than one line, and whether it was given with the correct medications. We found that 55% of the bevacizumab that we covered for all cancers at UnitedHealthcare in 2009 failed those criteria. That indicates that even when you collect postmarketing data, there is so much variation in clinical application that it makes it difficult to analyze and come up with workable conclusions.

Bevacizumab in Breast Cancer: Additional Perspective

A

recent poll by MDoutlook1 concluded that payer coverage would have a significant role in bevacizumab’s use in metastatic breast cancer. Usage of the drug could be cut by two-thirds in the United States and by one-third outside the United States. The NCCN has kept its recommendation of bevacizumab with paclitaxel in their guidelines, which are an important metric for private payer coverage decisions.

Chair of the NCCN Guidelines Panel for Breast Robert Carlson, MD Cancer, Robert Carlson, MD, told The ASCO Post that after deliberating on the issue, the panel found no compelling evidence to alter it recommendations. “The data from the E2100 study really had not changed, so if the data were compelling 2 years ago, they are compelling enough today,” said Dr. Carlson.

Dr. Carlson offered that FDA’s decision is defensible given the modest activity seen with bevacizumab. However, he explained, the agency has historically approved drugs showing prolonged progression-free survival but no overall survival advantage in breast cancer.

“If NCCN decided progression-free survival was not a worthwhile metric for a new drug, we would go back and apply the same metric for all other drugs. And if you do that in metastatic breast cancer, you end up with only a couple of drugs, because most have not shown a clear qualityof-life advantage or meaningful difference in overall survival,” Dr. Carlson said, adding, “It is important to take a patient-centric approach when asking these questions.”

■

Disclosure: Dr. Carlson’s institution has received funds from Genentech for participation in a multi-institutional trial of which he is the Stanford principal investigator.

Reference 1. Oncology Business Review: Immediate market feedback and global clinical impact of the FDA’s revocation of Avastin in metastatic breast cancer. Available at http://bit.ly/uhkp7G. Accessed December 21, 2011.

cancer care community is questioning bevacizumab’s usefulness in colon cancer. It is a terrific and very interesting agent. However, all this back and forth within the regulatory agencies sends a message to drug manufacturers: They need to develop drugs that

The bevacizumab issue has benefited the cancer community because it gave more credence to the larger discussion of value.

—Lee N. Newcomer, MD

Drug Development Has this ongoing turmoil with bevacizumab hurt our ability to move drugs through the pipeline and into the clinic?

I don’t believe it’s hurt the process.

In fact, I think it has helped clarify the basic fact that we need drugs that have unquestionably good clinical responses. Those are the drugs we want coming out of the pipeline. No one in the

make a significant difference for the patient. Bevacizumab never showed a survival benefit in breast cancer.

Closing Thoughts Any last thoughts on this issue?

For UnitedHealthcare, having the NCCN approach to our coverage decisions has proved to be a good program.

Again, our answers are consistent no

matter what drug or what study we’re dealing with. It also gives oncologists in the community a stable resource for accessing information about coverage.

The bevacizumab issue has benefited the cancer community because it gave more credence to the larger discussion of value. Moving forward, how are we going to reach consensus about the right methods to decide whether a cancer drug has value for patients? Bevacizumab did shrink tumors, but it did not prolong survival and it has some fairly toxic side effects, including cost. The question becomes, how are we going to balance these factors in a decision-making process? The FDA finally concluded that there just wasn’t enough benefit to justify its indication in metastatic breast cancer. There are those who disagree, but it is this kind of review and action that helps create a needed dialogue about value.

■

Disclosure: Dr. Newcomer is Senior Vice President of Oncology for UnitedHealthcare.

ASCOPost.com | JANUARY 15, 2012

PAGE 15

97th Annual American College of Surgeons Clinical Congress Oncology Research a Strong Presence at the American College of Surgeons Meeting: New Data in Pancreatic, Rectal, Thyroid, and Breast Cancers

By Caroline Helwick

R

esearch in cancer staging, surgical procedures, outcomes, and medical treatment was included among the 2,000 abstracts presented at the 97th Annual American College of Surgeons Clinical Congress in San Francisco. The ASCO Post was there to capture the latest findings.

Neoadjuvant Chemotherapy in Pancreatic Cancer Neoadjuvant therapy is increasingly being used in patients who present with locally advanced pancreatic cancer, but chemoradiotherapy did not result in tumor regression in a study reported by University of Minnesota, Minneapolis, investigators.1 The study included 16 patients with locally advanced (n = 6) or borderline resectable (n = 10) pancreatic cancer staged by CT and endoscopic ultrasound who received radiotherapy plus concurrent fluorouracil and cisplatin. After restaging, they received surgery if deemed resectable by radiologic response, or additional chemotherapy if deemed unresectable; those who eventually became resectable underwent surgery.

After neoadjuvant treatment, 10 patients remained stable and 6 had disease progression. No tumors regressed, and only 5 patients (31%) underwent surgery, all in the borderline resectable group, reported Vikas Dudeja, MD. “Radiologic regression of locally advanced unresectable pancreatic cancer, in response to neoadjuvant therapy, is an unlikely event,” said Dr. Dudeja. He suggested that PET imaging be considered for monitoring tumor response to neoadjuvant therapy.

Novel Method for Staging Pancreatic Cancer Researchers from the University of California in San Diego developed a laparoscopic technique that uses fluorophore-conjugated antibodies and a light-emitting diode (LED) light source to stage pancreatic cancer.2 In a mouse model, the novel technique enabled real-time visualization of fluorescence-labeled tumors and detected more and smaller (submillimeter) lesions, compared to standard xenon bright field laparoscopy.

“You can see both the normal

background of the anatomy plus the fluorescent tumor signal at the same time,” said Michael Bouvet, MD. The mean identification time was 63 seconds with the standard approach but < 10 seconds with fluorescence laparoscopy (P = .003). Fluorescence laparoscopy identified metastasis with a sensitivity of 96% vs 40% for bright light laparoscopy (P < .001); the positive predictive value was 91% and 65%, respectively (P < .001).

Co-investigator Hop Tran Cao, MD, estimated that fluorescence laparoscopy could prevent unnecessary resections. “About 15% of staging laparoscopies are currently inadequate

compared to patients over 40 (4.63% vs 0.78%; P = .001), for a fivefold increased risk, reported Patrick Tawadros, MD, PhD, of the University of Minnesota, Minneapolis.

Thyroid Cancer Recurrence in Older Patients Thyroid cancer recurs in almost 40% of elderly patients, but the mortality risk from recurrence is limited to the papillary subset, researchers from Penn State Milton S. Hershey Medical Center in Hershey, Pennsylvania, reported.4 “Elderly patients with follicular disease and recurrence did not have

Research Highlights from the 2011 American College of Surgeons Meeting ■■ Minneapolis researchers found little benefit for neoadjuvant

chemotherapy in locally advanced unresectable pancreatic cancer.

■■ San Diego investigators presented promising findings with an LEDbased laparoscopic technique for staging pancreatic cancer.

■■ A SEER database analysis revealed that aggressive rectal cancer is on the rise in patients under 40 years old.

■■ A review of SEER-Medicare–linked data showed a link between thyroid cancer recurrence and death for elderly patients with papillary cancer but not for those with follicular cancer.

■■ A National Cancer Data Base analysis demonstrated that rates of breast reconstruction after mastectomy have doubled since 1998, but the technique remains underutilized in some populations.

■■ In a preclinical study, investigators from Memorial Sloan-Kettering

Cancer Center discovered that the herpesvirus NV1066 represses triplenegative breast cancer cells.

for identifying small tumor deposits.

This means that these metastatic lesions are only discovered at the time of surgery, and these patients would not be candidates for resection,” he said.

Aggressive Rectal Cancer in Young Patients An analysis of the Surveillance, Epidemiology, and End Results (SEER) database showed that rectal cancer is escalating in young adults, and their risk of an aggressive histology is five times greater than for patients over age 40.3 Over the past 20 years, the incidence of rectal cancer has doubled in persons ≤ 40 years old, and this age group had a significantly higher prevalence of signet cell histology,

a significantly different risk of death compared to patients without recurrences,” said Melissa M. Boltz, DO. From the SEER-Medicare–linked database, researchers identified 2,883 patients, of whom 1,126 (39%) recurred, mostly within 2 years. Risk factors for recurrence included older age, advanced stage, lack of surgical treatment and regional disease. At 10 years, 662 (23%) died of cancer, 273 (41%) from thyroid cancer. Mortality risk was related to recurrence in papillary cancer (HR = 1.96) but not follicular cancer. For follicular thyroid cancer, cancer-specific mortality was related only to the presence of distant disease (HR = 17.78). For both histologies, increased age and advanced stage at diagnosis were also linked to mortality.

Breast Reconstruction Rates The use of breast reconstruction after mastectomy has doubled since 1998 but is still underutilized, a review of the National Cancer Data Base of the American College of Surgeons and the American Cancer Society revealed.5 The analysis included 396,434 patients undergoing mastectomy for primary breast cancer, of whom 134,479 had immediate or early reconstruction between 1998 and 2000 (n = 134,479) and 105,114 had the procedure between 2005 and 2007.

The use of breast reconstruction increased from 12% in 1998 to 23% in 2007, reported Mark Sisco, MD, of the NorthShore University HealthSystem, Evanston, Illinois.

The underutilization was most acute among certain subpopulations.

Patients were less likely to have immediate reconstruction if they were over age 50, African-American, not privately insured, not cared for at an academic medical center, not living in a large metropolitan area, or had a census-derived household income lower than $46,000.

“A rate of 23% still means that 77% of women were not, as of 2007, having immediate postmastectomy breast reconstruction. And a disproportionate share of the increase we observed is among the more affluent patients and those in major medical centers. In that ‘low hanging fruit’ we are getting somewhere, but clearly we haven’t done a very good job of narrowing the gap in all patients,” he said.

Oncolytic Virus for Breast Cancer Exposure to the mutant herpesvirus NV1066 killed 70% to 90% of triple-negative breast cancer cells among five cell lines studied, Memorial Sloan-Kettering Cancer Center investigators reported.6 Triple-negative breast cancer cells have high levels of phosphorylated MAPK, a protein that promotes tumor growth and contributes to chemotherapy resistance. The herpesvirus specifically targets cells that overexpress MAPK, explained Sepideh Gholami, MD. Flank tumors injected with NV1066 experienced a near-complete regression, with mean volumes continued on page 16

The ASCO Post | JANUARY 15, 2012

PAGE 16

97th Annual American College of Surgeons Clinical Congress Surgical Oncology

Resection of Metastatic Lesions Extends Survival in Multiple Tumor Types

By Caroline Helwick

S

urgical oncologists urged other cancer providers to appreciate the potentially curative role that surgery can play in the management of many stage IV solid tumors, in a session during the American College of Surgeons 97th Annual Clinical Congress in San Francisco.

Stephen G. Swisher, MD

Pulmonary Metastases

with long-term survival.2 “We have been pushing the boundaries recently, and we see that longterm cure is possible after metastasectomy,” he said.

Dr. Swisher considers surgery in fit patients with no other curative options when the primary tumor is controlled and when complete resection of thoracic and extrathoracic metastases is possible. Complete resection, response to chemotherapy, disease-free interval > 24 months, number of nodules < 3, and germ cell histology are good prognostic factors.

For 1,225 patients with pulmonary metastasectomy in the MD Anderson Thoracic Surgery database, 3-year survival was 60%, 5-year survival was 46%, and 10-year survival was 28%.

Stephen G. Swisher, MD, of The University of Texas MD Anderson Cancer Center, Houston, acknowledged there is no level 1 evidence for resecting pulmonary metastases. But since morbidity and mortality rates are very low, “the risk-benefit ratio is good, and even without level 1 evidence, you can argue for pulmonary metastasectomy,” he said.

When patients with colorectal cancer have pulmonary metastases in addition to liver metastases, this is not a poor prognostic factor or a contraindication to resection of liver metastases, he said. A recent review of the MD Anderson experience of 1,260 patients with colorectal cancer and liver-only or liver-plus-lung metastases found 5-year survival for the latter (50%) to exceed that of patients with liver-only metastases (40%; P = .01).1 The same investigators also reported that in patients with sarcoma, resection of both pulmonary and extrapulmonary lesions is associated

Colorectal Liver Metastases

Oncology Research

et al: Neoadjuvant chemoradiotherapy for locally advanced pancreas cancer does not lead to tumor regression. 97th Annual American College of Surgeons Clinical Congress. Abstract S133. Presented October 24, 2011.

2. Metildi CA, Kaushal S, Hardamon C, et al: Staging of metastatic pancreatic cancer in orthotopic mouse models by fluorescence laparoscopy is improved by an LED light source. 97th Annual American College of Surgeons Clinical Congress. Abstract S131. Presented October 24, 2011.

continued from page 15

reduced 42-fold, compared with controls, she reported. The team is also studying the oncolytic virus in combination with a MEK inhibitor and an mTOR inhibitor “with very promising results,” she added.

■

Disclosure: Drs. Boltz, Bouvet, Cao, Dudeja, Gholani, Tawadros, and Sisco reported no potential conflicts of interest.

References 1. Dudeja V, Walker SP, Greeno EW,

Yuman Fong, MD, of Memorial Sloan-Kettering Cancer Center, New York, advocated resection of colorectal metastases to the liver if an R0 resection can be safely performed.

He noted that the primary colorectal tumor and liver metastases can be safely resected during the same operation. Ablation is a potentially curable, liver parenchyma–sparing alternative to resection that can also be combined with resection.

“We can cure 20% of patients with metastatic colorectal cancer in the liver with surgery alone,” he said. “And more patients can be resected now because of our ability to downstage with neoadjuvant chemotherapy.”

The overall survival rate postresection is 60% at 5 years, and the 10-year disease-free survival rate is 20%.

While resectability used to be defined by number and size of lesions and presence of extrahepatic disease, it is now based on whether negative mar-

gins can be achieved and whether a liver remnant (> 20%) can be preserved.

“Neoadjuvant chemotherapy allows 15% of patients with initially unresectable disease to be converted to resectable status, but neoadjuvant chemotherapy is controversial, and most patients do not need it,” Dr. Fong added.

The absolute and relative indications for neoadjuvant chemotherapy can be a guide. Absolute indications are a dominant rectal tumor (bulky, very near the sphincter, or with nodal metastases, where there is a high risk of recurrence in the pelvis) and the need for medical optimization of the patient. Relative indications are a high clinical risk score based on a node-positive primary, disease-free interval < 12 months, presence of more than one tumor, size > 5 cm, and carcinoembryonic antigen level > 200 ng/mL.

Melanoma Metastatic to Distant Sites “Surgery should be part of the multidisciplinary approach to metastatic melanoma. With medical treatment, the possibility of long-term survival after metastasis is rare. Resection of all metastatic sites can induce a complete clinical remission that may be durable for 5 to 10 years, and compared to the new targeted agents, surgery is also far less expensive,” said Donald L. Morton, MD, of John Wayne Cancer Institute, Santa Monica, California.

The low morbidity and mortality from surgery, improved staging, and the fact that 80% of patients have no more than three initial synchronous metastatic sites forms the rationale for cytoreductive surgery for metastatic melanoma, he said.

3. Tawadros PS, Paquette IM, Hanly AM, et al: Adenocarcinoma of the rectum in patients under age 40 is increasing: Impact of signet ring cell histology. 97th Annual American College of Surgeons Clinical Congress. Abstract S24. Presented October 26, 2011.

4. Boltz MM, Hollenbeak CS, Schaefer E, et al: Prevalence and outcomes for recurrent thyroid cancer. 97th Annual American College of Surgeons Clinical Congress. Abstract S95. Presented October 27, 2011.

5. Sisco M, Du H, Howard MA, et al:

Donald L. Morton, MD

Prolonged survival (approximately 40% at 5 years and 20% to 30% at 10 years) was observed in resected stage IV disease in two large trials: a phase II trial evaluating the Canvaxin vaccine,3 and the phase III MMAITIV trial.4 The outcomes in these trials were far superior to those observed with trials of medical therapies, he noted.5 Survival is equally good for patients with two to three metastases vs one.

Reoperation for recurrent disease postresection yields a median survival exceeding 17 months and a 5-year survival of almost 20%, compared with < 6 months and a 2% survival at 5 years for patients who do not undergo surgery, Dr. Morton noted. A trial of surgery vs nonsurgical treatment of stage IV melanoma is being proposed.

Metastatic Breast Cancer Approximately 50% of patients with metastatic breast cancer receive some form of local therapy, said Seema Khan, MD, of Northwestern University Feinberg School of Medicine, Chicago.

This is surprising but may be occuring for several potential reasons: Women who have favorable features such as young age, small tumor size, hormone receptor–positive disease, or low volume of metastatic disease may selectively be offered surgery Have we expanded the equitable delivery of postmastectomy breast reconstruction in the new millennium? Evidence from the National Cancer Data Base. 97th Annual American College of Surgeons Clinical Congress. Abstract SE101. Presented October 25, 2011.

6. Gholami S, Chen C-H, Gao SP, et al: Oncolytic herpes simplex virus: Effective treatment against triple-negative breast cancer with activated MEK/MAPK pathway. 97th Annual American College of Surgeons Clinical Congress. Abstract S140. Presented October 24, 2011.

ASCOPost.com | JANUARY 15, 2012

PAGE 17

97th Annual American College of Surgeons Clinical Congress more frequently. It is also possible that an intact primary tumor can be the source of new metastatic lesions, may not respond to systemic therapy in parallel with metastatic sites, (which can lead to uncontrolled chest wall disease), and may serve as a continued source of tumor stem cells that seed new chemotherapy-resistant lesions, Dr. Khan noted.

The possible benefit of primary tumor resection can be seen in a growing body of data. In numerous studies, resection of the primary is associated with a mortality reduction of 30% to 40%, and 3-year survival rates improve by an absolute 16% to 20%, she said.

Response to systemic therapy prior to surgery is a good prognostic factor, she added.

“It is possible that primary site therapy, which should be thought of

with local therapy used only if needed for palliation of symptoms) or full local therapy for the primary site as is practiced in the non-metastatic setting.

■

Seema Khan, MD

as a combination of surgery and radiotherapy, will prolong survival in stage IV breast cancer, but this is still a hypothesis and needs to be demonstrated in prospective trials,” said Dr. Khan, who is heading up E2108, which will enroll women with intact primary tumors and metastatic disease. In the trial, a period of induction systemic therapy will be followed by randomization to the standard of care (continuation of systemic therapy

Disclosure: Dr. Morton was an independent contractor, consultant, board member, and stock owner for CancerVax Corporation, the company that produced Canvaxin, the investigational agent in the MMAIT trials. Dr. Khan reported no potential conflicts of interest.

References 1. Brouquet A, Vauthey JN, Contreras CM, et al: Improved survival after resection of liver and lung colorectal metastases compared with liver-only metastases: A study of 112 patients with limited lung metastatic disease. J Am Coll Surg 213:6269, 2011.

2. Blackmon SH, Shah N, Roth JA, et al: Resection of pulmonary and extrapulmonary sarcomatous metastases is associ-

ated with long-term survival. Ann Thorac Surg 88:877-884, 2009.

3. Hsueh EC, Morton DL: Antigenbased immunotherapy of melanoma: Canvaxin therapeutic polyvalent cancer vaccine. Semin Cancer Biol 13:401-407, 2003.

4. Morton DL, Mozzillo N, Thompson JF, et al: An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites. MMAIT Clinical Trials Group. J Clin Oncol 25(18 suppl):Abstract 8508, 2007.

5. Korn EL, Liu P-Y, Lee SF, et al: Meta-Analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 26:527-534, 2008.

JCO Spotlight

Further Individualizing Staging Offers Benefits in Patients with Colon Cancer

By Charlotte Bath

S

upplementing the American Joint increasing number of variables,” the Committee on Cancer (AJCC) authors explained.

TNM classification system with addiMultivariable Models tional information available from tumor “The first, most basic model was registries can assist in personalizing the AJCC staging algorithm version, treatment and follow-up care for patients which included the T- and N-stage with colon cancer, according to a collabelements of the AJCC collaborative orative study by investigators at Memoalgorithm.

The rial Sloan-Kettering second model inCancer Center As therapeutic cluded number in New York, the of lymph nodes Cleveland Clinic, options have examined, as well and Dana-Farber expanded, more as number of exCancer Institute in refined and accurate amined lymph Boston. The study nodes containing was prompted by predictions of tumor, instead of AJCC’s request for survival are needed the N-stage eleproposals to dement. The third velop alternative to direct treatment model included staging algorithms decision-making. elements in the based on “readily second model, as available informawell as tumor diftion beyond clasferentiation, patient age, and sex. sical Tumor Node Metastases (TNM) These variables were chosen a priori staging.” The results were published in 1 on the basis of their well-established the Journal of Clinical Oncology.

The investigators used records independent associations with overfrom 128,853 patients with primary all survival and their availability in colon cancer reported to the Surveilthe SEER registry.” lance, Epidemiology, and End Results Prognostic Value Superior to (SEER) Program from 1994 to 2005 TNM System to construct and validate three survival The TNM staging system and models for patients with primary curamodels were compared by calculating tive-intent surgery. “Each of the three a concordance index, performing calimultivariable models incorporated an

bration, and identifying the area under receiver operating characteristic curves. “Inclusion of additional registry covariates improved prognostic estimates,” the investigators reported.

The concordance index increased from 0.60 for the AJCC model, with T- and N-stage variables, to 0.68 for the model including tumor grade, number of collected metastatic lymph nodes, age, and sex.

“As therapeutic options have expanded, more refined and accurate predictions of survival are needed to direct treatment decision-making. Individualized prognostication empowers patients, enhancing their ability to make informed and meaningful choic-

es,” the authors stated. “We extended the AJCC TNM schema to include data elements routinely available from tumor registry data. With the addition of just a few variables, we were able to generate a prognostic model with performance superior to that of the TNM system. Because it is based on SEER data, the model can be regularly updated.”

■

Disclosures: Drs. Weiser, Gonen, Chou, Kattan, and Schrag reported no potential conflicts of interest.

Reference 1. Weiser MR, Gonen M, Chou JF, et al: Predicting survival after curative colectomy for cancer: Individualizing colon cancer staging. J Clin Oncol 29:4796-4802, 2011.

Personalized Staging in Patients with Primary Colon Cancer ■■ More refined and accurate predictions of survival are needed to direct

treatment decision-making in patients with curative-intent surgery for primary colon cancer.

■■ Records from 128,853 patients with primary colon cancer reported

to SEER from 1994 to 2005 were used to construct and validate three survival models, each incorporating an increasing number of variables associated with overall survival and availability in the SEER registry.

■■ Prognostic estimates were improved by including additional registry

covariates, such as tumor grade, number of collected metastatic lymph nodes, age, and sex, with the AJCC TNM staging algorithm.

■■ Investigators generated a prognostic model with performance superior to that of the TNM system.

For chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab

EXPAND YOUR OPTIONS A study population in need of additional treatment options1,2

5

median prior therapies

59%

of patients received prior rituximab

93%

of patients received prior alkylating agents

100%

of patients received prior fludarabine and alemtuzumab

The following serious adverse events (AEs) are discussed in greater detail below: Infusion reactions, cytopenias, progressive multifocal leukoencephalopathy, hepatitis B infection and reactivation, and intestinal obstruction.

To learn more, please visit www.ARZERRA.com.

Indication ARZERRA (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab.

The effectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Important Safety Information Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions. Premedicate with acetaminophen, an antihistamine, and a corticosteroid.

Interrupt infusion for infusion reactions of any severity.

Institute medical management for severe infusion reactions including angina, or other signs and symptoms of myocardial ischemia. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. Infusion reactions occurred in 44% of patients on the day of the first infusion

(300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions.

Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration.

Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture.

Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers

When treated with ARZERRA monotherapy, 42% of patients with CLL refractory to fludarabine and alemtuzumab achieved a partial response1 Patients had received a median of 5 prior therapies

Overall response rate with ARZERRA 60 50 40

42%

The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) There were no complete responses The effectiveness of ARZERRA is based on the demonstration of durable objective responses

30 20 10

FLUDARABINE AND ALEMTUZUMAB REFRACTORY (n=59)

of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insufficient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis.

Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected.

Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied.

Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

Most Common Adverse Reactions In the pivotal study (total population, n=154) the most common adverse reactions (≥10%, all grades) were neutropenia, followed by pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%).

No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA 6.5 months—median duration of response (95% CI: 5.8, 8.3)

Most Common Serious Adverse Reactions In the pivotal study (total population, n=154), where ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses, the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia.

A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%.

Please see Brief Summary of Prescribing Information on adjacent pages.

How Supplied: Available as 2 different single-use glass vials for dilution and intravenous administration. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution.

References: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Tam CS, O’Brien S, Lerner S, et al. Leuk Lymph. 2007;48(10):1931-1939.

The ASCO Post | JANUARY 15, 2012

PAGE 20

FDA Update

ODAC Backs Axitinib for Kidney Cancer

T

he FDA’s Oncologic Drugs Advisory Committee voted 13-0 that Pfizer’s drug axitinib (Inlyta) had a favorable benefit-risk profile for patients with advanced renal cell carcinoma

after initial treatment has failed. The FDA is due to make a final decision in the first half of 2012.

Panelists said the oral drug was at least as safe and effective as previ-

ously approved treatments, such as sorafenib (Nexavar). It also had different side effects than other drugs for the disease, which could be important for patients who cannot tolerate older

BRIEF SUMMARY ARZERRA® (ofatumumab) Injection, for intravenous infusion The following is a brief summary only; see full prescribing information for complete product information.

1 INDICATIONS AND USAGE ARZERRA® (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The effectiveness of ARZERRA is based on the demonstration of durable objective responses [see Clinical Studies (14) of full prescribing information]. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. 4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions [see Adverse Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing information]. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3) of full prescribing information]. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insufficient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. 5.6 Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Infusion Reactions [see Warnings and Precautions (5.1)] • Cytopenias [see Warnings and Precautions (5.2)] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)] • Hepatitis B Reactivation [see Warnings and Precautions (5.4)] • Intestinal Obstruction [see Warnings and Precautions (5.5)] The most common adverse reactions (≥10%) in Study 1 were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. The most common serious adverse reactions in Study 1 were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The data described in Table 1 and other sections below are derived from 154 patients in Study 1. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were White.

treatments, said Wyndham Wilson, MD, Chair of the panel and Chief of the Lymphoma Therapeutics Section at NCI. “It’s my take that the toxicity pro-

Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset of Study 1 (MedDRA 9.0) Total Population (n = 154)

Fludarabine- and AlemtuzumabRefractory (n = 59) Grade All ≥3 Grades % %

Grade All ≥3 Grades Body System/ % % Adverse Event Infections and infestations Pneumoniaa 23 14 25 15 Upper respiratory tract 11 0 3 0 infection Bronchitis 11 <1 19 2 Sepsisb 8 8 10 10 Nasopharyngitis 8 0 8 0 Herpes zoster 6 1 7 2 Sinusitis 5 2 3 2 Blood and lymphatic system disorders Anemia 16 5 17 8 Psychiatric disorders Insomnia 7 0 10 0 Nervous system disorders Headache 6 0 7 0 Cardiovascular disorders Hypertension 5 0 8 0 Hypotension 5 0 3 0 Tachycardia 5 <1 7 2 Respiratory, thoracic, and mediastinal disorders Cough 19 0 19 0 Dyspnea 14 2 19 5 Gastrointestinal disorders Diarrhea 18 0 19 0 Nausea 11 0 12 0 Skin and subcutaneous tissue disorders Rashc 14 <1 17 2 Urticaria 8 0 5 0 Hyperhidrosis 5 0 5 0 Musculoskeletal and connective tissue disorders Back pain 8 1 12 2 Muscle spasms 5 0 3 0 General disorders and administration site conditions Pyrexia 20 3 25 5 Fatigue 15 0 15 0 Edema peripheral 9 <1 8 2 Chills 8 0 10 0 a Pneumonia includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. c Rash includes rash, rash macular, and rash vesicular.

Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections.

A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration.

6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from patients with CLL in Study 1 were tested by enzyme-linked immunosorbent assay (ELISA) for anti-ofatumumab antibodies during and after the 24-week treatment period.

Results were negative in 46 patients after the 8th infusion and in 33 patients after the 12th infusion. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading.

ASCOPost.com | JANUARY 15, 2012

PAGE 21

FDA Update

file is different, there’s benefit there, and it’s not inferior to currently approved [tyrosine kinase inhibitors],” Dr. Wilson said. “If you have two

drugs that are equivalently effective, ... different toxicity profiles can be very useful for the individual.”

Overall, in Pfizer’s clinical trial, axitinib slowed down the progression of cancer by 2 months compared to sorafenib for patients who had already been treated for ad-

7 DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with ARZERRA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the recommended human dose of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use Clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information].

8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted.

10 OVERDOSAGE No data are available regarding overdosage with ARZERRA.

■

Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared to the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared to control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared to the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals.

17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.2)] • Signs of infections including fever and cough [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)] • New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.3)] • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.4)] • New or worsening abdominal pain or nausea [see Warnings and Precautions (5.5)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring for blood counts [see Warnings and Precautions (5.2)] • Avoiding vaccination with live viral vaccines [see Warnings and Precautions (5.6)] Manufactured by: GLAXO GROUP LIMITED Greenford, Middlesex, UB6 0NN, United Kingdom U.S. Lic. 1809 Distributed by:

GlaxoSmithKline Research Triangle Park, NC 27709

New System for Cervical Cancer Screening Approved

H

ologic announced that the FDA has approved its Cervista HTA (high throughput automation) system for use with its previously approved Cervista human papillomavirus (HPV) HR test. The Company’s Cervista HTA system automates the DNA extraction and detection steps of the Hologic Cervista HPV HR test, allowing users to walk away after loading the instrument and return the next morning to review the test results.

■

Investigational New Drug Application Filed for ONT-10

O

ncothyreon Inc announced the filing of an Investigational New Drug (IND) application with the FDA for ONT-10, a therapeutic vaccine directed at cancers expressing MUC1.

Upon completion of the FDA’s review of the IND, Oncothyreon expects to initiate a phase I trial.

ONT-10 is a therapeutic vaccine targeting MUC1, a tumor-associated antigen present on many types of human malignant tumors, including lung, breast, colorectal, prostate, and ovarian cancer. ONT-10 was designed to stimulate both the humoral and cellular arms of the immune response.

B:15.125” T:14” S:12”

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the human dose of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies. 13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared to control values).

vanced kidney cancer. But the findings differed depending on which drug patients took beforehand.

For those who initially took sunitinib (Sutent), axitinib slowed the disease by only 1.4 months, vs 5.6 months in patients previously treated with cytokines.

■

©2011, GlaxoSmithKline. All rights reserved.

September 2011 ARZ:6BRS ©2011 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. AZA295R0 September 2011

Package Inserts Revised for IV Methotrexate Products

T

he FDA has approved changes to the package inserts for methotrexate products for intravenous administration. Additional information regarding concomitant proton pump inhibitor (PPI) therapy has been added to the Warning section of the label.

Specifically, the new text includes the following statement: “Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.”

■

The ASCO Post | JANUARY 15, 2012

PAGE 22

NIH State-of-the-Science Conference NIH Panel Endorses Active Surveillance in Low-risk Prostate Cancer

By Caroline McNeil

A

ctive surveillance of localized prostate cancer is a viable management option that should be offered to lowrisk patients in place of immediate treatment, said a panel of experts convened by the National Institutes of Health.

A fairly new concept, active surveillance takes a more proactive approach to early prostate cancer than the better-known observational strategy of watchful waiting. Both strategies involve monitoring rather than immediate intervention. But watchful waiting forgoes curative treatment and uses intervention only to relieve symptoms.

Active surveillance delays curative treatment until indicated by the results of regular exams, prostate-specific antigen (PSA) tests, and/or repeat biopsies. Repeat biopsies are not necessarily part of active surveillance, and are often done only if PSA rises.

The state-of-the-science meeting, which took place December 5–7 in Bethesda, Maryland, concluded that many unanswered questions still surround this emerging strategy—too many to issue formal guidelines regarding active surveillance protocols, for instance. But the 3 days of presentations, discussion, and panel deliberations highlighted oncologists’ growing recognition of active surveillance as a management option for low-risk disease.

Patricia Ganz, MD

“Physicians … will now have an NIH-vetted document that describes

it as a reasonable approach,” said Patricia Ganz, MD, Director of the Division of Cancer Prevention and Control Research at the Jonsson Comprehensive Cancer Center at UCLA, who chaired the panel. Some centers in the United States and Canada are already using active surveillance, and the meeting’s final statement, she said, will “give them much more support in their practice and research.”

Many of the remaining questions involve the best way to implement the strategy; For instance, who should be a candidate for active surveillance, what follow-up protocols should be used,

ress very slowly and may never need treatment, the less aggressive strategy gives men a chance to safely avoid, or at least postpone, the side effects.

Nonetheless, 90% of those who are eligible for active surveillance opt instead for immediate treatment.

Moreover, men who begin active surveillance often change their minds for reasons other than disease progression.

The reasons for this low acceptance rate were one major focus of the meeting.

Physicians’ recommendations are probably a key factor in patient acceptance, the panel concluded. Ganz said that even when a patient is given

If there is no difference in mortality [between active surveillance and immediate treatment], then quality of life is the defining issue.

— Mark Litwin, MD, MPH

and what are the indicators for starting active treatment?

Patient Acceptance In current practice, the panel said there was an “emerging consensus” that men with a PSA less than 10 ng/ dL and a Gleason score less than or equal to 6 are considered low-risk and eligible for active surveillance.

About 130,000 newly diagnosed patients in the United States fall into that category, but few currently opt for active surveillance. Instead they have immediate treatment—radical prostatectomy or radiation therapy—which can cause urinary, bowel, and sexual problems in a substantial portion of men.

Because many prostate cancers prog-

Active Surveillance in Prostate Cancer ■■ Active surveillance instead of immediate treatment is a viable management option for localized, low-risk prostate cancer.

■■ Active surveillance takes a more proactive approach to early prostate cancer than watchful waiting.

■■ More research is needed on protocols for monitoring disease progress and determining when to move from active surveillance to treatment.

■■ Because of the very favorable prognosis of low-risk prostate cancer, strong consideration should be given to removing the anxietyprovoking term “cancer” for this condition.

a choice of an observational strategy, “the way in which it is presented [by the physician], the order in which it is presented to the patient … may indicate that the observational strategy is not preferred, that it is not desirable.”

Studies suggest that doctor’s recommendations are very powerful. For instance, there is evidence that “if a patient goes to a urologist, he is more likely to be offered surgery, if he first sees a radiation oncologist, he is more likely to be offered radiation,” said panel member Nananda F. Col, MD, MPH, FACP, from the University of New England College of Osteopathic Medicine.

New Terminology Yet some of the reluctance to consider active surveillance is patient-driven. “The word ‘cancer’ sets off an emotional response in many patients that encourages them to choose what they perceive as a more active treatment regimen,” said panel member, Barry Kogan, MD, FAAP, FACS, Chief of Urology at Albany Medical College.

The panel’s final statement included a recommendation that “strong consideration should be given to removing the anxiety-provoking term for this condition.” Questioned about alterna-

tive wording, panel members had no immediate suggestions but noted that terms such as dysplasia and others “on the early edge of the cancer continuum” were possibilities. Pathologists and communication specialists need to make this decision, Dr. Ganz said.

Dr. Donald Gleason, the early researcher who devised the scoring system named after him, originally used the term “adenosis” said Otis Brawley, MD, FACP, Chief Medical and Scientific Officer at the American Cancer Society. Brawley was not a panel member but said after the meeting that he agreed that a new term was needed.

“We need a molecular definition of cancer in general,” he said.

Others were concerned that using a different term might downplay the seriousness of the disease. Merel Nissenberg, an attorney from La Jolla, California, who is also President of the National Alliance of State Prostate Cancer Coalitions, said she worried that men could be misled into not getting curative treatment when they needed it. Dr. Col noted that the new term was not intended to replace all forms of prostate cancer, only the very early stages. “There is general agreement and firm evidence that men diagnosed with more serious forms of the disease are best served by receiving immediate treatment,” she said.

Quality of Life So far, results from cohort studies of active surveillance suggest that diseasefree and survival rates compare favorably to surgery and radiation. Also, the first results from a trial comparing watchful waiting to treatment, the Prostate Cancer Intervention or Observation Trial (PIVOT), presented at the conference, showed no difference in prostate cancer mortality after 10 years’ follow-up.

In the wake of such findings, quality-of-life endpoints become “the crux of the issue” said Mark Litwin, MD, MPH, of University of California, Los Angeles, who presented data from quality-of-life studies. If there is no difference in mortality, then quality of life is “the defining issue,” he said.

But he and others pointed out that active surveillance is not without its own risks. Repeat biopsies carry a risk of infection, and men may have many biopsies under current protocols. In its final statement, the panel noted, “we continued on page 25

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Proven clinical profile Efficacy comparable to tamoxifen in head to head trials

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Important safety information: FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively.

References: FARESTON® Prescribing Information, 2011. Data on file, GTx, Inc.

Please see brief summary of prescribing information including boxed warning on the following page.

For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

© 2011 GTx, Inc., Memphis, TN 38103. All rights reserved. FAR-P400-R0 October 2011

BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions].

INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side.

CONTRAINDICATIONS Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug.

QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia.

WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death.

Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology].

Hypercalcemia and Tumor Flare As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued.

Tumorigenicity Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available.

Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology].

General Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.

Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur.

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

Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment.

The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

North American Study FAR60 n = 221

TAM20 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below.

Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies].

Adverse Reactions Cardiac Cardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular* Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia Thromboembolic Pulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests** AST Alkaline Phosphatase Bilirubin Hypercalcemia

North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) 2 2 -

(1) (1)

1 (<1) 3 (1.5) -

1 1

22 20 8 4 3 -

(10) (9) (4) (2) (1.5)

16 (7.5) 16 (7.5) 10 (5) 2 (1) 2 (1) -

1 -

4 1

(2)

2 (1) 2 (1) 1 (<1) -

1 1 1 -

(<1) (<1) (<1)

4 24 4 6

30 16 2 1

(19) (10) (1) (<1)

(<1)

11 (5) 41 (19) 3 (1.5) 6 (3)

(2) (11) (2) (3)

(<1) (<1)

(<1)

1 (<1) 2 (1) -

2 (1) 3 (1.5) 1 (<1)

3 (1.5) 1 (<1) 1 (<1) 2 (1)

-

3 (1.5)

5 (3) 1 (<1) 1 (<1) -

(<1)

4 (2) 3 (1.5) 4 (2)

1 (<1) 3 (1.5) 4 (2) 4 (2)

22 (15) 13 (9) 1 (<1) -

32 (15) 18 (8) 2 (1) -

35 (17) 31 (15) 3 (1.5) -

1 1

(<1)

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea.

Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

Post-marketing Experience The following adverse reactions were identified during post approval use of FARESTON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge.

DRUG INTERACTIONS Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions].

Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum.

Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively.

N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively.

The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions].

Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%.

Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely.

Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies.

Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly.

Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis).

Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero.

Nursing Mothers It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use There is no indication for use of FARESTON in pediatric patients.

Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

Hepatic Impairment The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Race The pharmacokinetics of toremifene in patients of different races has not been studied.

Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted.

OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.

Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.

Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

CLINICALPHARMACOLOGY Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor.

Pharmacodynamics Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions].

Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions].

Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Toremifene 20 mg (N = 47) Toremifene 80 mg (N = 47) Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms 7 (0.9, 13.6) 26 (21.1, 31.2) 65 (60.1, 69.2)

ΔQTc > 60 ms (n, %) 0 2 (4.3%) 43 (89.6%)

QTc > 500 ms (n, %) 0 0 5 (10.4%)

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks.

Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin.

Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state.

Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies.

Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days.

Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function.

Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients.

Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food.

Race – The pharmacokinetics of toremifene in patients of different races has not been studied.

Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis).

Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests).

Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes).

Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks.

PATIENT COUNSELING INFORMATION Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs.

FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations].

Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions].

Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.

Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology].

Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment.

Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions].

Distributed by GTx, Inc. Memphis, TN 38103, USA Product covered by Orion Product Patents and related patent numbers. © 2011 GTx, Inc. All rights reserved.

2E Rev. 03/2011

ASCOPost.com | JANUARY 15, 2012

PAGE 25

NIH State-of-the-Science Conference Genitourinary Oncology

Data on Watchful Waiting for Low-risk Prostate Cancer May Swing Focus to Higher-risk Tumors and Quality of Life

By Caroline McNeil

S

urgery did not increase survival rates compared to watchful waiting in men with clinically localized prostate cancer. Results were particularly strong for men with prostate-specific antigen (PSA) levels of 10 ng/dL and under, and those who have low-risk disease, according to data from the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Watchful waiting, moreover, was associated with a significantly lower risk of urinary, sexual, and erectile dysfunction, and similar quality of life compared with surgery. There was little difference between treatment arms in terms of worry about prostate cancer or bother from cancer therapy.

The results “strongly support observation” for patients with low-risk and low-PSA disease and “will encourage future study” of observation in men with higher risk tumors, said Timothy J. Wilt, MD, MPH, from the Minneapolis VA Medical Center and the University of Minnesota School of Medicine, principal investigator of PIVOT. Dr Wilt spoke at the NIH State-of-the-Science Conference held in Bethesda, Maryland.

Role of Active Surveillance In the most detailed presentation of PIVOT results to date, Dr. Wilt reported the trial’s survival and quality-of-life data. The meeting considered the role of active surveillance, a more proactive version of watchful waiting, in management of localized prostate cancer.

PIVOT was the first large randomized trial since PSA screening became common to compare observation to immediate intervention. Its results played a role in the panel’s final conclusions in favor of observational strategies in general and active surveillance in particular. Dr. Wilt’s presentation contained detailed data on quality-of-life endpoints for the first time, as well as survival data report-

Active Surveillance continued from page 22

have a particular concern with the complications that result from image-guided, transrectal biopsies of the prostate.”

Standardized protocols need to be developed to minimize frequency and intervals of biopsies and to reduce pain and infection rates, the panel concluded. It also called for research on other indicators of disease progres-

ed briefly at a meeting of the American Urological Association earlier in 2011.

“The results of the PIVOT trial suggest that more conservative monitoring strategies may have the same outcomes as immediate treatment,” said Panel Chair Patricia Ganz, MD, Professor, UCLA Schools of Medicine and Public Health, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center. PIVOT completed follow-up in January 2010, and the first results have been submitted for publication, Dr. Wilt said.

Survival Data PIVOT’s survival data showed that all-cause and prostate cancer mortality differed little between the two arms of the trial. During a median follow-up of 10 years, the absolute risk reduction due to surgery was less than 3% for both all-cause and prostate cancer mortality (not statistically significant).

There were no differences by age, race, Gleason score, or health status.

However, men with PSAs above 10 ng/dL and those with high-risk tumors may benefit from surgery. Both overall and prostate cancer mortality in these groups were higher in the obeservation

they looked at patients with D’Amico intermediate-risk scores (see sidebar).

However, when using histologic classification of biopsy specimens based on central pathology lab, the differences were no longer statistically significant.

Quality of Life Urinary, erectile, and sexual function also showed differences between the two arms of the trial: At 2 years after randomization, 81% of men in the radical prostatectomy group reported erectile dysfunction vs 45% in the watchful waiting group; 61% reported sexual dissatisfaction vs 33% on watchful waiting; and 16% men who had surgery reported urinary incontinence vs 6% who had watchful waiting. The differences were statistically significant.

After 5 years, differences between the arms were smaller but still statistically significant for two criteria—erectile dysfunction (25% more men in the surgery group) and sexual dissatisfaction (14% more in the surgery group).

Reported bowel dysfunction was similar between the two groups.

There were no differences in overall, physical, or mental health status. Regarding “bother about prostate cancer

Observation vs Treatment in Prostate Cancer ■■ New data from the PIVOT trial of watchful waiting vs radical

prostatectomy show no difference in overall or prostate cancer mortality in men with clinically localized prostate cancer.

■■ The data suggest that the research focus should move to quality-of-life issues in men with low-risk prostate cancer.

D’Amico Risk Assessment for Prostate Cancer Low risk: PSA ≤ 10 ng/mL and Gleason ≤ 6 and the percentage of involved cores is < 50%; or intermediate risk with only 1 positive core Intermediate risk: Gleason score of 7 or PSA of 10–20 ng/mL; or low risk with > 50% of positive cores; or high risk and only 1 positive core High risk: Gleason ≥ 8 or PSA > 20 ng/mL and more than 1 positive core; or intermediate risk and more than 50% positive cores

to consistently favor observation over time, while “worry” slightly favored surgery at later but not early time periods.

The PIVOT trial was the first to focus on treatment in the early PSA era—the years when PSA screening became widespread. Between November 1994 and December 2002, 731 men with clinically localized disease (T1-T2NxM0) were randomly assigned to radical prostatectomy (n = 364) or observation (n = 367).

Half had T1C tumors. The mean age of participants was 67, and the median PSA was 7.8 ng/dL. An earlier Scandinavian trial found a survival benefit for surgery vs observation, but because it recruited patients in the pre-PSA era, participants had more advanced disease.

Crux of Issue group compared to the surgery group.

Differences remained significant when the blood samples were sent to a central, rather than local, PSA lab.

The researchers also found a borderline difference in survival when

or treatment” and “worry about prostate cancer,” there was little difference between arms at baseline. Dr. Wilt said he was just beginning to do the analyses with findings regarding “bother about prostate cancer or treatment” appearing

PIVOT’s findings suggest that the research focus may now turn to quality-of-life differences. “You’ve heard that outcomes are not different for low-risk disease, which brings us to the

sion, such as imaging, molecular classification of cancers, and biomarkers of a patient’s risk of progression.

The panel did not recommend randomized controlled trials of active surveillance vs immediate treatment for low-risk patients with a life expectancy shorter than 20 years. Asked why, Dr. Ganz said, “we are comfortable with the data” that show active surveillance is a viable option for this group.

But for people with longer life expectancies and those at intermediate risk, such as those with Gleason scores of 7 or 8, the panel did recommend trials. But it explicitly recommended against federal funding of single-institution studies and strongly endorsed the creation of registries to collect data on large numbers of patients.

Other research needs include examining what influences the offer

of, acceptance of, and adherence to active surveillance; determining optimal protocols for monitoring; and developing methods to enhance the decision-making process.

“There’s going to be a very dynamic set of investigations going forward,” Ganz said.

continued on page 26

■

Disclosure: Drs. Ganz, Kogan, Nissenberg, and Col reported no potential conflicts of interest.

The ASCO Post | JANUARY 15, 2012

PAGE 26

Chemotherapy Foundation Symposium XXIX Sipuleucel-T Should Be Used Early in Metastatic Castrate-resistant Prostate Cancer, before Chemotherapy

By Alice Goodman

W

hen sipuleucel-T (Provenge) was approved by FDA in April 2010, it was the first vaccine to be approved as a treatment for prostate cancer and was hailed as a major advance.

Although sipuleucel-T is now reimbursable by Medicare, some physicians are not clear about when to use it, and patients who are not ideal candidates for the vaccine may demand it. Current evidence suggests that the vaccine’s optimal use is early in the course of metastatic castrate-resistant prostate cancer and before chemotherapy is considered.

Simon J. Hall, MD

“Patient selection for sipuleucel-T should be based on data, not on instinct or financial consideration. Selection involves clinical judgment,” said Simon J. Hall, MD, Chair of Urology at the Mount Sinai School of Medicine, New York. He spoke at the 2011 Chemotherapy Foundation Symposium in New York.

Sipuleucel-T is a vaccine derived

from the patient’s own white blood cells following exposure to prostatic acid phosphatase (PAP), and it is designed to stimulate production of T-cell immunity against cells expressing PAP. The vaccine is approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. Treatment is administered three times every other week for a total of 5 weeks, and a course of treatment is estimated to cost about $93,000.

Demonstrating Effectiveness Dr. Hall reminded listeners that the vaccine is for treating established disease and the goal is disease control, not disease eradication. “We have little experience in humans with immunotherapy and how to determine whether it is effective,” he said.

Clinical trials and experience with the vaccine has shown that it takes time to demonstrate an effect on clinical endpoints. Even when induction of immunity can be seen on the ELISPOT assay of T cells, there is a lack of correlation with clinical endpoints, Dr. Hall explained.

The pivotal studies for FDA approval showed that the vaccine improves overall survival by a median of about 4 months. “It takes 6 to 9 months [from the time of treatment] to show a difference in survival,” he said. “Therefore, if a patient has a life expectancy less than

Optimal Use of Sipuleucel-T ■■ Sipuleucel-T is approved for asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer and a rising PSA level.

■■ It should not be used in patients with a life expectancy of < 6 to 9 months, and after chemotherapy should be considered only in select patients.

■■ Consider the vaccine early in the course of advanced prostate cancer.

Watchful Waiting continued from page 25

crux of the issue … which is quality of life,” said Mark Litwin, MD, MPH, of University of California, Los Angeles, who reviewed quality-of-life studies in prostate cancer patients following the PIVOT presentation.

Looking at data from several large studies, Dr. Litwin concluded that treatment—either radical prostatectomy or radiation—is unlikely to affect general health-related quality of life. However, it

may be associated with clinically significant changes in sexual, urinary, or bowel function compared to observation.

The Scandinavian trial, for instance, found that in the first 5 years after randomization, men undergoing prostatectomy had more erectile dysfunction (80% vs 45%) and more urinary leakage (49% vs 21%) compared to men on observation.

Surgery, however, was associated with a lower incidence of urinary obstruction (28% vs 44%). Dr. Litwin emphasized that subsequent observational trials have

EXPERT POINT OF VIEW

“T

he main message [from Dr. Hall’s presentation at the 2011 Chemotherapy Foundation Symposium] is that we need to think about using sipuleucel-T early in men with prostate cancer who are asymptomatic but are castration-resistant and metastatic. “If there is going to be a benefit [of the vaccine], it will be optimal in this group,” said William Oh, MD, Professor of Urology at the Mount Sinai School of Medicine, New York.

But many men in this state may not want to conWilliam Oh, MD sider another treatment. “These patients have a rising PSA but otherwise feel well. They often consider the vaccine a hassle and don’t want to have six or seven visits in a 5-week period,” he continued.

Another message from Dr. Hall’s presentation is that the vaccine theoretically does not work well with prednisone or chemotherapy, so use of the vaccine should be considered before chemotherapy, Dr. Oh stated.

■

Disclosure: Dr. Oh is on the scientific advisory board for and receives research funding from Dendreon.

6 to 9 months, the vaccine will not be of benefit,” he commented.

Issues with the vaccine that need to be resolved include timing, sequencing, and where the vaccine falls in the treatment paradigm. Several treatments for castrate-resistant prostate cancer have been shown to extend survival, including docetaxel, cabazitaxel ( Jevtana), abiraterone (Zytiga), sipuleucel-T, and radium-223 (not yet approved), and whether to combine these treatments—as well as the best sequencing for them—remains to be established.

Timing of Therapy Thus far, evidence suggests that the earlier a patient with castrate-resistant prostate cancer is treated with the vaccine, the better the outcome. No data are available about using the vaccine in patients before they have bone disease.

Dr. Hall said use of sipuleucel-T in this setting may be a good option, but more shown that nerve-sparing surgery has reduced the impact of prostatectomy on sexual function and urinary incontinence.

The NIH panel agreed that quality of life was the key issue: “Given that there are insignificant mortality differences between observational strategies and immediate curative treatment for men with low-risk prostate cancer, the focus of what we still need to learn about … should be on the impact of treatment morbidity and health-related quality of life,” they concluded.

studies are needed.

“The vaccine should be used only with caution in patients postchemotherapy, because these patients are usually quite sick,” he noted.

“Sipuleucel-T has minimal impact on reducing PSA levels and limited impact as seen on bone scans. The timing of treatment should be based on your judgment. It is not clear if abiraterone plus prednisone or chemotherapy plus prednisone blunt the immunity induced by the vaccine, so rethink using chemotherapy if you are considering sipuleucel-T,” Dr. Hall said.

■

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

Reference 1. Hall SJ: Optimizing patient selection for sipuleucel-T in prostate cancer. Chemotherapy Foundation Symposium XXIX: Innovative Cancer Therapy for Tomorrow.

Presented November 11, 2011.

The panel also recommended research on the comparative effectiveness of observational management vs curative therapy for low-risk patients with long life expectancy and for intermediate- and high-risk patients with limited life expectancy.

But the panel did not recommend trials of observational strategies for men with shorter life expectancy (less than 20 years).

■

Disclosure: Drs. Wilt, Litwin, and Ganz reported no potential conflicts of interest.

Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

1

Introducing the first and only personalized treatment for unresectable or metastatic melanoma with the BRAFV600E mutation1,2

DECODE

metastatic melanoma

Indication and Usage ZELBORAF™ (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.

ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.

Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7 to 8 weeks.

Potential risk factors included age ≥65 years, prior skin cancer, and chronic sun exposure.

All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care.

Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe reactions may include generalized rash and erythema or hypotension.

Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including 1 case of Stevens-Johnson syndrome and 1 case of toxic epidermal necrolysis in the Phase III study.

ZELBORAF treatment should be permanently discontinued in patients who experience a severe hypersensitivity or dermatologic reaction.

QT prolongation Exposure-dependent QT prolongation has been observed in patients treated with ZELBORAF, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes.

Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval.

ECG and electrolytes should be monitored before initiating treatment with ZELBORAF and after dose modification and routinely during treatment (15 days after treatment initiation then monthly for first 3 months of treatment and every 3 months thereafter or as clinically indicated). If the QTc exceeds 500 ms, ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values.

Liver laboratory abnormalities Liver laboratory abnormalities have occurred with ZELBORAF. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated.

Lab abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation.

Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials.

While taking ZELBORAF, all patients should be advised to avoid sun exposure and, when outdoors, to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30). For intolerable grade 2 or greater photosensitivity, dose modifications are recommended.

Ophthalmologic Reactions In the Phase III study, 5 cases of uveitis were reported in patients treated with ZELBORAF.

EXTEND

survival

56% reduction in risk of death from any cause with ZELBORAF (95% CI, 0.33-0.59)

P<0.0001

OS=overall survival HR=hazard ratio CI=confidence interval * Median follow-up was 6.2 months (95% CI, 0.4-13.9) for ZELBORAF patients vs 4.5 months (95% CI <0.1-11.7) for those taking dacarbazine. † There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms respectively at the time of analysis.3

~4-month improvement in median progression-free survival (5.3 vs 1.6 months; HR=0.26, P<0.0001, 95% CI, 4.9-6.6 vs 1.6-1.7) Significant improvement in best overall response rate (48.4% vs 5.5%; P<0.0001, 95% CI, 41.6%-55.2% vs 2.8%-9.3%) There were 2 complete responses (1%) and 104 partial responses (PRs) (47.4%) with ZELBORAF vs 12 PRs (5.5%) with dacarbazine

The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis.

Patients should be routinely monitored for signs and symptoms of uveitis.

Additionally, 5 cases each of blurry vision and iritis and 6 cases of photophobia were reported in the Phase III study. One case of retinal vein occlusion was reported in the Phase II study.

New Primary Malignant Melanoma Eight skin lesions in 7 patients were reported as new primary malignant melanoma in the Phase III study.

Cases were managed with excision and patients continued treatment without dose adjustment; monitoring for skin lesions should occur as outlined above [see cuSCC].

Use in Pregnancy: Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women.

If ZELBORAF is used during pregnancy or if the patient becomes pregnant while taking ZELBORAF, the patient should be apprised of the potential hazard to a fetus.

BRAF Testing Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for the selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma.

Most common adverse events The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event.

Please see Brief Summary of Prescribing Information on the following page.

References: 1. Smalley KS, Sondak VK. Melanoma—an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010;363:876-878. 2. Flaherty KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. 2011; 3:1-4. doi:10.3410/M3-8. 3. Data on file. Genentech, Inc.

© 2011 Genentech USA, Inc. All rights reserved. BRF0000653200 Printed in USA.

www.zelboraf.com

The ASCO Post | JANUARY 15, 2012

PAGE 30

Issues in Oncology

Estrogen for Vulvovaginal Atrophy in Breast Cancer: Debate Continues

By Caroline Helwick

V

ulvovaginal atrophy is a concern for the majority of patients with breast cancer, not only because of its physical and psychosexual consequences, but because the optimal

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information.

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

The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

But some women’s health experts maintain that, with ultra–low-dose estrogen products on the market, such fears are misguided. “In the absence of clinical trial data showing these products are

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.

Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

-

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm.

7 DRUG INTERACTIONS Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes with ZELBORAF* Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)].

Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug.

4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritis 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)].

Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action.

Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women.

Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus.

Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established.

Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly disorders patients (≥ 65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine.

Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC†# 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)].

8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. disorders Cough Injury, poisoning and procedural complications Sunburn

8

-

-

7

-

-

12

-

-

10

-

-

-

-

-

14

-

-

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

BRF0000422000 Initial U.S. Approval: August 2011 © 2011 Genentech, Inc

unsafe, the field has gone overboard and has deprived women of urogenital health, and unnecessarily so,” said James A. Simon, MD, of Women’s Health and Research Consultants in Washington, DC.

James A. Simon, MD

Dr. Simon delivered a lecture on vulvovaginal atrophy at the 2011 Breast Cancer Symposium in San Francisco.1 He also coauthored a recent article on the management of urogenital atrophy in women with breast cancer.2

Severity of the Problem Genitourinary atrophy involves the entire perineum, an area loaded with estrogen receptors. “After menopause, 100% of women are affected,” with about half of all women experiencing vaginal dryness, urinary incontinence, urinary tract infections, and sexual dysfunction, “but patients are not necessarily going to tell you about this,” he added.

The most bothersome symptoms are vaginal dryness and dyspareunia. “Vaginal dryness is not the need for lubricants to have sex; it’s the sensation of being dry between the legs regardless of whether you are having sex or not,” he pointed out.

Women with sexual dysfunction are four times more likely to have vulvovaginal atrophy.3 “Reducing symptoms of one condition may also relieve symptoms of the other,” he said.

Safety:10"

ZELBORAF™ (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about TRADENAME. Before prescribing, please refer to the full Prescribing Information.

1 INDICATIONS AND USAGE ZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment.

It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued.

5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued.

5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval.

ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values.

5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated.

Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)].

5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn.

For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)].

5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2.

5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)].

5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

treatment—estrogen replacement—is controversial. Patients and physicians alike remain concerned that external estradiol may contribute to the risk of cancer recurrence.

Safety:7"

Low-dose Estrogen Options Estrogen therapy promotes vaginal cell growth and cellular maturation, fosters recolonization with lactobacilli, enhances vaginal blood flow, augments muscle tension development, increases vibratory sensation, improves vaginal thickness and elasticity, decreases vaginal pH, and relieves vulvovaginal symptoms. Level I evidence supports the use of estrogen in treating not only vaginal atrophy but also overactive bladder and recurrent urinary tract infections (by normalizing vaginal pH). For each condition, local treatment is superior to systemic.

Products approved by the FDA include:

ASCOPost.com | JANUARY 15, 2012

PAGE 31

Issues in Oncology

■■ Estradiol vaginal cream ■■ Conjugated estrogens vaginal cream (also indicated for dyspareunia) ■■ Estradiol hemihydrates vaginal tablet (Vagifem) ■■ Estradiol vaginal rings (Estring for local delivery; FemRing for systemic delivery) The local delivery of estradiol is very low with both Vagifem tablets (10 µg twice a week; 25 µg no longer available in the United States) and the Estring vaginal ring (7.5 µg/d). Vaginal creams deliver a much higher amount of estradiol into the systemic circulation, which is a concern in breast cancer, Dr. Simon said (see Table 1).2 The estrogen products are considered equally effective at recommended doses.

“Physician experience, patient preference, and pharmacy coverage cost may drive the choice,” he said. “For patients with breast cancer, the focus should be on avoiding systemic exposure and reducing total estrogenic exposure.”

Results will not be felt for about 6 weeks, but thereafter 80% to 90% of patients report improvement with vaginal estrogen replacement, he said. In cases of extreme introital stenosis, vaginal agglutination, and insertional dyspareunia, vaginal dilators and physical therapy will probably be necessary. “For these women, no amount of estrogen will help without concomitant physical therapy. Intercourse becomes impossible, even with liberal use of lubricants,” he pointed out.

Dr. Simon emphasized that avoid-

ance of intercourse will only increase sexual dysfunction. “Use it or lose it,” he said. “Continued sexual activity via coitus or masturbation increases blood flow to the pelvic organs.” Moisturizers should also be used regularly and lubricants as needed (with intercourse).

Estradiol Preparations and Delivered Dose “For patients with breast cancer, we recommend the low-dose vaginal tablet and low-dose vaginal ring, even in patients undergoing estrogen deprivation therapy,” he said. With Vagifem and Estring, the typical serum level and maximum annual delivered doses are substantially lower than those of conventional estrogen products (Table 1).2 Dr. Simon added that part of the fear of estrogen arises from the package insert, which carries the same safety warning regardless of the product, and regardless of systemic absorption. The FDA is considering revision so as to differentiate between “local” and systemic therapies.

Counterpoint: Safety Not Proven Daniel F. Hayes, MD, of the University of Michigan, argued that even low-dose estrogen cannot be endorsed for patients with breast cancer.

“I would add a strong note of caution,” he commented. “I agree that vaginal atrophy is an enormous problem. It accounts for about 20% of my time in the clinic. On the other hand, the assumption that estrogen is not absorbed

is not entirely fair.”

According to Dr. Hayes, standard estrogen assays do not necessarily detect the levels of estrogen that may be of concern, especially in patients on aromatase inhibitors whose tissue estrogen levels are very low, he said.

In an assay specifically developed to measure low levels of estrogen in postmenopausal women, investigators from the Royal Marsden Hospital in London showed that vaginal estradiol tablets (Vagifem 25 µg) significantly raised systemic estradiol levels in women on aromatase inhibitors, at least in the short term.4 Mean levels rose from ≤ 5 pmol/L to 72 pmol/L at 2 weeks, then decreased to < 35 pmol/L by 4 weeks in most, but not all, women. The investigators concluded that Vagifem reverses the estradiol suppression achieved by aromatase inhibitors and is contraindicated. “If you don’t do high-tech assays, you won’t see this,” Dr. Hayes said.

Also, the assumption that low estrogen levels are safer than high estrogen levels “is exactly the opposite of what we know in breast cancer,” he continued. “Before tamoxifen, we gave pharmacologic doses of estrogen to patients because we saw tumors grow in the presence of small levels and stop growing when high doses were given.”

Answer Far from Certain Perhaps more relevantly, a randomized trial of tamoxifen with or without estrogen replacement in 434 women was

Table 1: Estradiol Preparations and Maximum Annual Delivered Dose Product

Route/Type of Administration

Typical Regimen

Normal Daily Delivery Ratea or Administered Lowest Approved Doseb

Typical Serum Level

Maximum Annual Delivered Dose

Vaginal estradiol Vagifem

Vaginal tablet

1 tablet daily × 14, then 2 × weekly

10 μg

4.6 pg/mL

1.14 mg

Estring

Vaginal ring

1 ring vaginally every 3 mo

7.5 μg

8.0 pg/mL

2.74 mg

Estrace

Vaginal cream

1 g cream vaginally every week

Variable

Variable

7.1 mg

FemRing

Vaginal ring

1 ring vaginally every 3 mo

0.05 mg

40.6 pg/mL

18.25 mg

Oral tablet

1 tablet daily

0.5 mg

55.4 pg/mL

182.5 mg

Oral estradiol Estrace tablets and generics

Transdermal estradiol Divigel

Gel

0.25 mg packet daily

0.003 mg/d

9.8 pg/mL

1.09 mg

Estrogel

Gel

0.75 mg/pump daily

0.035 mg/d

28.3 pg/mL

12.78 mg

Evamist

Spray

1.53 mg spray daily

0.021 mg/d

19.6 pg/mL

7.67 mg

Climara

Patch

1 patch weekly

0.025 mg/d

22 pg/mL

9.13 mg

Menostar

Patch

1 patch weekly

0.014 mg/d

13.7 pg/mL

5.11 mg

Vivelle-Dot

Patch

1 patch twice weekly

0.0375 mg/d

34 pg/mL

12.78 mg

b For vaginal and oral estradiol.

For transdermal estradiol.

Adapted, with permission, from, Pruthi S, Simon JA, Early AP: Current overview of the management of urogenital atrophy in women with breast cancer. Breast J 17(4): 403–408, 2011.

a

closed early due to more breast cancer events in the estrogen replacement arm: 26 in the estrogen replacement am vs 7 in the control arm at 2.1 years median follow-up.5 The authors felt the findings indicated an unacceptable risk for women exposed to estrogen replacement.

“While I wish intravaginal estrogen was the way to go, especially for women on aromatase inhibitors, I am quite concerned that we may be overcoming a small but real effect of aromatase inhibitors over tamoxifen by adding estrogen back in.

The answer is far from certain. Anyone recommending estrogen replacement for women on aromatase inhibitors should do so with great caution,” Dr. Hayes said.

Dr. Simon responded that his assay captures levels as low as 3 pg/mL. And studies performed in his laboratory showed that mean serum estradiol concentrations obtained with Vagifem 10 µg rose only on the first day of administration, then returned to baseline.6 He also noted that patients deprived of estrogen, then rechallenged, demonstrate renewed responsiveness to therapy and that estrogen-deprived breast cancer cells exposed to hormone-replacement therapy undergo apoptosis. “So the story is very complicated and needs to be studied,” he concluded. “These very tiny serum estrogen levels should offer some reassurance, so that we don’t totally disregard this part of a woman’s anatomy.”

■

Disclosure: Dr. Hayes reported no potential conflicts of interest. Dr. Simon has served as a consultant or on the advisory boards of Abbott, Agile Therapeutics, Ascend Therapeutics, Azur Pharma, BioSante, Boehringer Ingelheim, Depomed, Fabre‐Kramer, Laboratoire HRA Pharma, Meditrina Pharmaceuticals, Merck, Merrion Pharmaceuticals, NDA Partners LLC, Novo Nordisk, Novogyne, Pfizer, Shionogi, Slate Pharmaceuticals, Teva Pharmaceutical Industries, Trovis Pharmaceuticals, Warner Chilcott, and Watson Pharmaceutical. He has received grant/research support from BioSante, Boehringer Ingelheim, EndoCeutics, Novo Nordisk, Novogyne, and Teva Pharmaceutical Industries. He has also served on the speakers bureaus of Amgen, Ascend Therapeutics, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, Novogyne, Teva Pharmaceutical Industries, and Warner Chilcott.

References 1. Simon JA: 2011 Breast Cancer Symposium. General Session V: Survivorship.

Presented September 9, 2011.

2. Pruthi S, et al: Breast J 17:403-408, 2011.

3. Levine KB: Menopause 15:661-666, 2008.

4. Kendall A, et al: Ann Oncol 17:584587, 2006.

5. Holmberg L, et al: Lancet 363:453455, 2004.

6. Eugster-Hausmann M, et al: Climacteric 13:219-227, 2010.

The ASCO Post | JANUARY 15, 2012

PAGE 32

Eighth International SIO Conference ‘New Science, New Solutions’ Explored at Society for Integrative Oncology Conference

By Charlotte Bath

“I

nnovating Integrative Oncology: New Science, New Solutions” was the title of the Society for Integrative Oncology (SIO) Eighth International Conference. Topics ranged from

molecular biology to mitigation of treatment toxicity to mind-body medicine.

A total of 505 people attended the conference, which was jointly sponsored by the School of Medicine at

Case Western Reserve University. This represented a 50% increase over the previous year. In the multidisciplinary mix were 100 medical students who were provided scholarships to attend,

Oncotype DX reveals the underlying biology that changes treatment decisions 37% of the time ®

105 physicians, 33 nurses, 11 acupuncturists, 5 social workers, 2 dietitians, and 249 others.

“I am particularly thrilled about the 100 medical students who are here,” NIH Director Francis Collins, MD, PhD, stated in his keynote addresses.

“You are the future, and as you are finding out at this meeting, the future has never been more exciting than it is right now for advances and understanding in how to prevent and treat cancer. And certainly the integrative approach that this meeting focuses on is a critical part of that future.”

37%

changed

63% confirmed

Kara Kelly, MD

Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach • In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1

▸ 33% switched from CT + HT to HT alone ▸ 4% switched from HT only to CT + HT

‡

‡

• Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

Broadening Outreach New SIO President Kara Kelly, MD, said that plans for the upcoming year include efforts “to really broaden our outreach” and to get members more involved. “We want to develop strategic alliances with a broad range of different constituencies.” Dr. Kelly is Medical Director of the Integrative Therapies Program for Children with Cancer at the Children’s Hospital of New YorkPresbyterian and Associate Professor of Clinical Pediatrics at Columbia University in New York. “Especially for myself, as an oncologist, I would really love to see us tap more into the conventional oncology world, both in the community as well as in the academic institutions,” she said.

www.oncotypeDX.com *This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy.

Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010.

Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0112

Now available for patients with ductal carcinoma in situ (DCIS)

Barrie R. Cassileth, PhD

Major Priorities In an interview with The ASCO Post, Barrie R. Cassileth, PhD, continued on page 33

ASCOPost.com | JANUARY 15, 2012

PAGE 33

Eighth International SIO Conference NIH Director Calls for Rigorous Evaluation of Integrative Medicine to Provide Evidence of Efficacy

By Charlotte Bath

“M

any new frontiers exist in integrative medicine,” NIH Director Francis Collins, MD, PhD, stated in his keynote address at the Eighth International Conference of the Society for Integrative Oncology (SIO) in Cleveland. “The evidence is overwhelming that these approaches are being used by many individuals in the United States, including those with cancer,” he said. “For wellness, immune function, and pain-related symptoms, there is a significant increase in interest among cancer survivors compared to other people who use complementary and alternative medicine.”

Survey data show that over a lifetime, complementary and alternative medicine (CAM) is used by “65% of cancer survivors vs 53% of noncancer respondents,” he said. When questioned about motivations to use CAM, cancer survivors “are more likely to be using this because they are unhappy that medical treatments have not helped them or because it has been recommended by the provider,” he noted.

“We have always had concerns about possible interactions between CAM and other standard cancer therapies, and there are certainly patients who are not telling their providers about their CAM use,” Dr. Collins added. He cited a recently reported study from The University of Texas MD Anderson Cancer Center showing that 52% of cancer patients are using CAM during phase I trials, but that 23% don’t disclose that information to trialists. This finding, he said, should encourage researchers to continue to ask patients questions aimed at eliciting information about complementary and alternative medicine use.

Comparative Effectiveness Research Dr. Collins acknowledged that there are differences in opinion about the use of the terms complementary

New Solutions continued from page 32

founding President of the SIO and Chief of the Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center, said, “From my perspective, the major priorities of the

and alternative, as in NIH’s National Center for Complementary and Alternative Medicine (NCCAM), vs the term integrative, as in the Society for Integrative Oncology (SIO), but said that the strategy of NCCAM is “very much aligned” with that of the SIO. He stressed the need for “rigorous evaluation” of complementary and alternative medicine and well-designed clinical trials “so you have evidence that can be shared with the public about whether or not a particular approach is going to help them.” One way to do that is through comparative effectiveness research, which is something NIH has been doing for many decades, although it was not always known by

1990s, those trials showed that “not only is beta-carotene not protective, it actually increased lung cancer risk— 16% in one study and 28% in another—and so the studies were halted.” A follow-up study in 2004 corroborated those results.

A more recent example concerned the use of vitamin E for the prevention of prostate cancer, again based on indirect evidence. When tested in a controlled trial, the results indicated that “vitamin E actually increased the likelihood of prostate cancer by about 17% in the men who took this over a course of a number of years,” Dr. Collins explained. “That’s the kind of data we need if we are going to be giving

tor of the National Human Genome Research Institute at the NIH from 1993 to 2008.

Due to technologic advances over the past few years, we can now “look at the DNA of a cancer cell and catalogue all of the things that have gone awry,” Dr. Collins noted. “You don’t have to guess which of the 20,000 genes in a particular cancer cell might be driving the malignant behavior.”

The challenge is to figure out “which mutations are actually drivers of the malignant phenotype and which of them are what we would call passengers—just mutations that that cell has taken on, with no real biologic consequences,” he explained.

‘You Need Big Numbers’

We need to do this research, not only to find out what works, but to find out what interventions actually may be harmful.

— Francis Collins, MD, PhD

that term, he said. This is an important issue for the Patient-Centered Outcomes Research Institute (founded under the Patient Protection and Affordable Care Act), which is starting to support this kind of research “with a particular focus on patient-centered concerns,” he continued.

“We need to do this research, not only to find out what works, but to find out what interventions actually may be harmful,” no matter how unlikely that may seem, Dr. Collins commented.

For example, he pointed to the story of beta-carotene in cancer prevention.

In the 1980s, epidemiologic evidence suggested that beta-carotene might decrease lung cancer risk. Double-blind clinical trials were initiated, and in the organization now have to be to grow in two separate areas.” First, SIO needs to expand in geographic scope, getting representatives from more countries to attend the international conference. But the more important priority, she said, is to have more on-

rational recommendations to patients and providers about how to practice better prevention and treatment,” he said.

Rocketing Science “The science of understanding what causes a good cell to go bad— what causes malignancy to appear— has rocketed forwarded in the course of the past few years,” Dr. Collins stated. “Genomics has become a major driver of research in cancer because cancer is a disease of the genome.”

Dr. Collins is noted for his leadership of the international Human Genome Project, which culminated with the completion of a finished sequence of human DNA, and he served as Direccologists and oncology nurses actively involved in the organization.

The concept of integrative oncology continues to gain recognition and acceptance in the oncology community. “Here is the proof of the pudding,” Dr. Cassileth said. “There is virtually no major

“You need big numbers to sort out what’s a driver and what’s a passenger,” he said. “You need hundreds of tumors of each type, and for each of those tumors you need matched DNA for that same individual, and then you can begin to see if there are in fact recurrent molecular changes that appear frequently in that particular class of tumors.” That is what The Cancer Genome Atlas is doing as a joint effort between the NCI and the National Human Genome Research Institute—systematically mapping genomic changes in the major types and subtypes of cancer.

Having already focused extensively on glioblastoma multiforme, ovarian cancer, and lung cancer, The Cancer Genome Atlas researchers are attempting to characterize all of the recurrent genomic changes for at least 20 of the most common cancers in the next 3 years, Dr. Collins reported. Once validated, the data will become immediately available to other investigators. This project “undoubtedly is going to revolutionize the field,” he said, particularly in stimulating the development of a new generation of targeted therapeutics. continued on page 34

cancer conference in the world, including ASCO’s Annual Meeting, that does not have some integrative medicine or integrative oncology involved.”

■

Disclosure: Drs. Collins, Kelly, and Cassileth reported no potential conflicts of interest.

The ASCO Post | JANUARY 15, 2012

PAGE 34

Eighth International SIO Conference Francis Collins, MD, PhD continued from page 33

Projects currently underway are posted on The Cancer Genome Atlas website (cancergenome.nih.gov).

“The colon cancer project is well along, and I think they are in the middle of the data analysis right now.…

There will be a publication on what they’ve found within half a year,” Dr. Collins said.

“It’s a major undertaking and it does involve really big numbers,” he said. “For each of these tumor types, they aim to identify 500 tumors that are highly characterized, very pure

without much stroma, and for which the DNA is available and full consent has been given to make the data accessible. It’s quite a challenge,” he said.

“That’s 500 tumors and 500 blood samples, all of which have to have complete genome sequencing done.

That’s 1,000 samples for each of those

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Dramatic Examples As “a dramatic example” of the new targeted, personalized approach to cancer treatment, Dr. Collins described the case of a woman, a nonsmoker who was diagnosed with very aggressive, stage IV non–small cell lung cancer in both lungs about 4 years ago. Following standard chemotherapy, she participated in a clinical trial with crizotinib (Xalkori). Prominent lung metastases shown on x-ray in July 2009 “were essentially gone by November 2009,” Dr. Collins reported. “So she has had a dramatic response, and she continues to do extremely well,” he added.

“Of course this drug doesn’t work for everybody with this kind of lung cancer. So what’s the difference? It depends on whether the particular cancer has a fusion involving the ALK gene,” Dr. Collins explained. “Crizotinib was not developed with that particular target in mind, but it turned out after the fact that this was going to be a very responsive situation.”

The success of crizotinib when used in a targeted personalized approach led to its approval by the FDA several months ago. Yet the drug may not have been approved if it “had been tried on thousands of people with lung cancer without having stratified them by the specific molecular findings,” Dr. Collins said.

Harnessing the Immune System

mckessonspecialtyhealth.com/oncology or contact us at: 800.482.6700, Option 4

Another advance, and “one that I am sure resonates” with SIO members, Dr. Collins said, is harnessing the immune system to search out and destroy malignant cells. He cited two papers published last summer in The New England Journal of Medicine1 and Science Translational Medicine,2 describing three patients with chronic lymphocytic leukemia (CLL) in an effort to activate the patients’ own T cells to attack the leukemic cells. The result was an “unprecedented success,” he said, and two of the three patients achieved sustained remissions with no evidence of disease. Based on this success, a similar strategy is being considered for other cancers. While “immune therapies for cancer have been around for a long time,” Dr. Collins said that the success with CLL is a significant advance that “gives us all the sense that we are on the right path.”

“We also have great excitement

© 2011 McKesson Specialty Health. All rights reserved.

USO173_Technology_MSH_ASCO_7x10.indd 1

20 tumor types, or 20,000 human genome projects. It’s amazing.”

11/8/11 2:38 PM

ASCOPost.com | JANUARY 15, 2012

PAGE 35

Eighth International SIO Conference about a new era in therapeutics based on natural remedies,” Dr. Collins said.

The NCI has an ongoing program looking for anticancer activity in extracts from plants, marine invertebrates, and microbes. “We are also seeking opportunities by looking at traditional medicines, many of them from China, for how we can decrease the side effects of treatment.”

Research Funding Threatened While NCCAM is an important focus of efforts at NIH, other institutes within NIH also have initiatives in complementary and alternative medicine, Dr. Collins noted. “The NCI has the largest one by far,” he

said, and “the budget for CAM in the NCI is actually slightly larger than the entire budget of NCCAM. The total investment that NIH makes in complementary and alternative medicine research in 1 year is about a halfbillion dollars. I wish it was more, but I wish everything we are doing in biomedical research could be more,” he said.

“The opportunities for medical research have never been greater than they are right now, and yet the threat to the support of biomedical research has—in the memories of anybody who is currently working in the field—never been greater either,” Dr. Collins stated. He noted that in

fiscal year 2011, “for only the second time in 40 years, the NIH budget sustained a real cut.” If the failure of the Joint Select Committee on Deficit Reduction (the so-called supercommittee) to cut $1.2 trillion from the budget results in sequestering of discretionary budgets, “a dramatic downturn in support for biomedical research” could occur in fiscal year 2013, Dr. Collins said.

“I am optimistic because it seems to me our case is so strong,” he said. “The value of what we do for transforming human health has been well proven and is more promising now than ever. The opportunity we have to contribute to a turnaround of the economy, consider-

ing the return on investment for what NIH does, is extremely compelling.

But these are difficult times, and it is up to all of us to effectively make that case and ensure that it is being heard.”

■

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

References 1. Porter DL, Levine BL, Kalos M, et al: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:735-733, 2011.

2. Kalos M, Levine BL, Porter DL, et al: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3:95ra73, 2011.

Acupuncture Continues to Secure Position within Integrative Oncology

By Charlotte Bath

M

ore than 14 years after an NIH Consensus Panel finding of “efficacy of acupuncture in adult postoperative and chemotherapy nausea and vomiting,” an informal show-of-hands poll at the Eighth International Society for Integrative Oncology (SIO) Conference indicated acupuncture was not yet fully integrated into the care provided at participants’ institutions. Results of some acupuncture studies presented at the SIO conference, however, showed the contributions acupuncture can make to integrative oncology care.

derson Cancer Center Departments of General Oncology and Behavioral Science, and Director of the Integrative Medicine Program there.

Profound Medical Implications The published study involved 86 patients with nasopharyngeal carcinoma, treated at Fudan University Shanghai Cancer Center, 40 randomized to

control group were still reporting symptoms of xerostomia. Saliva flow rates were also greater in the acupuncture group, starting at 3 weeks into radiotherapy and persisting through the 1- and 6-month follow-up.

“The medical implications are quite profound in terms of quality of life, because while chronic dry mouth may sound benign, it has a significant impact on sleeping, eating, and speak-

Physicians working collaboratively with acupuncturists could foster better research, better ideas, and better results.

—Jennifer Stone, LAc

Lorenzo Cohen, PhD

Two studies—a small placebocontrolled study reported at the SIO meeting and another recently published in the journal Cancer1— showed for the first time that acupuncture given alongside radiation therapy for head and neck cancer reduced the debilitating side effect of xerostomia. Most current treatments for xerostomia are palliative and offer limited benefit, according to Lorenzo Cohen, PhD, Professor at The University of Texas MD An-

acupuncture and 46 to the standard of care. Those in the treatment arm received acupuncture therapy three times per week during the 7-week course of radiotherapy. The results were based on data derived from two self-report questionnaires and measuring actual saliva flow.

At 1 month after the end of radiotherapy, 54.3% of the acupuncture group reported xerostomia questionnaire scores greater than 30, compared to the control group at 86.1%. (The xerostomia questionnaire includes eight questions about oral dryness and discomfort, each rated on a scale from 0 to 10; the higher the score, the worse the xerostomia.) At 6 months after radiotherapy, 24.1% in the acupuncture group and 63.6% of the

ing,” Dr. Cohen said. “Without saliva, there can be an increase in microbial growth, possible bone infection, and irreversible nutritional deficits.”

Encouraging Acupuncturists and MDs to Work Together Dr. Cohen is also a Past President of the SIO and moderated a panel discussion about acupuncture at this year’s conference. One of the panelists at that session, Jennifer Stone, a licensed acupuncturist (LAc) from Indiana University School of Medicine in Indianapolis, encouraged physicians to work more collaboratively with acupuncturists to foster “better research, better ideas, and better results.”

Physicians would benefit from this

Jennifer Stone, LAc

collaboration, she said, because the clinical experience of acupuncturists could help in designing treatment plan and research design options. In addition, the generally lower salaries of acupuncturists compared to physicians could help stretch research dollars.

LAcs would benefit, she said, by increasing their opportunities to publish in MEDLINE-indexed journals, developing university affiliations, and gaining access to research resources, animal and human subjects, and data from pilot studies to help secure funding.

As the overall benefit of collaboration, Ms. Stone said, “We end up having better results because we have a more informed team.”

■

Disclosure: Dr. Cohen and Ms. Stone reported no potential conflicts of interest.

Reference 1. Meng Z, Garcia MK, Hu C, et al: Randomized controlled trial of acupuncture for prevention of radiation-induced xerostomia among patients with nasopharyngeal carcinoma. Cancer. November 9, 2011 (early release online).

In HER2+ breast cancer

HER2 dimerization activates downstream signaling.

What if you could inhibit HER2 dimerization and further disrupt the oncogenic cascade?

Š 2011 Genentech USA, Inc. All rights reserved. BIO0000647200 Printed in USA.

The potential of HER2 Dimerization Inhibitors (HDIs) HER2 dimerization: an important driver of HER2+ disease Despite significant treatment advances, HER2+ breast cancer continues to be a challenging disease requiring aggressive intervention.

HER dimerization, or receptor pairing, is a critical driver of tumor growth in HER2+ disease.1,2 The HER family of receptors is composed of 4 receptors that must pair, or dimerize, in order to activate downstream signaling.3 When HER2 receptors are overexpressed, as in HER2+ breast cancer, excessive dimerization is thought to lead to abnormal activation of signaling, which results in tumor growth.1,3

The HER2:HER3 dimer: the most potent oncogenic HER dimer Although HER2 can dimerize with any HER family member, preclinical studies suggest that the HER2:HER3 dimer is the most potent oncogenic HER receptor pair,1 as it activates 2 key pathways.2,4 While HER2 activates the MAPK pathway, HER3 is the only receptor that can directly activate the PI3K pathway.2,5 The HER2:HER3 dimer may be crucial for the aggressive tumor growth seen in HER2+ breast cancer.2,4

HER2 Causes cell proliferation by activating the MAPK (mitogen-activated protein kinase) pathway2,5 HER3 Leads to cell survival signaling by activating the Pl3K (phosphatidylinositol 3-kinase) pathway2,5

HER2 Dimerization Inhibitors (HDIs): the potential for a more comprehensive blockade Preclinical studies demonstrate that inhibiting HER2 dimerization, including the HER2:HER3 dimer, interrupts both the MAPK and PI3K pathways and, ultimately, tumor growth.6 Inhibition of ligand-induced HER2 dimerization while administering other HER2-targeted agents may offer a more comprehensive blockade of signaling in HER2+ disease.7

Learn more about the potential of HDIs in HER2+ breast cancer Scan to visit ResearchHDIs.com to explore more and view a narrated video.

References: 1. Jones KL, Buzdar AU. Evolving novel anti-HER2 strategies. Lancet Oncol. 2009;10:1179-1187. 2. Rosen LS, Ashurst HL, Chap L. Targeting signal transduction pathways in metastatic breast cancer: a comprehensive review. Oncologist. 2010;15:216-235. 3. Arpino G, Gutierrez C, Weiss H, et al. Treatment of human epidermal growth factor receptor 2â&#x20AC;&#x201D;overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst. 2007;99:694-705. 4. Amin DN, Sergina N, Ahuja D, et al. Resiliency and vulnerability in the HER2-HER3 tumorigenic driver. Sci Transl Med. 2010;2:16ra7. 5. 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. 6. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127-137. 7. Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006;3:269-280.

The ASCO Post | JANUARY 15, 2012

PAGE 38

Direct from ASCO

ASCO Launches FASCO Designation To replace the Statesman Award

A

SCO has announced the designation of Fellow of the American Society of Clinical Oncology, otherwise known as FASCO. Formerly called the ASCO Statesman Award and launched in 2007, the distinction is designed to honor ASCO’s most active volunteer members.

“The FASCO status represents recognition for the most dedicated and active volunteer members inside the organization,” said Allen S. Lichter, MD, CEO of ASCO. “These are people who have given of themselves tirelessly over a long period of time. They represent the very best of our organization.”

Entry at 20 Points To qualify, ASCO members must have accumulated 20 or more points in volunteer service to ASCO. The point system assigns a number value to various lengths and levels of volunteer service.

For example, serving as President of ASCO earns 4 points; serving as a Board Member, a Committee Chair, or Editor-in-Chief of the Journal of Clinical Oncology ( JCO), the Journal of Oncology Practice ( JOP), or Can-

Allen S. Lichter, MD

cer.Net earns 2 points; and members get 0.3 points for serving on an editorial board or being a member of a task force, a working group, or an advisory group.

“Getting 20 points is not easy to do,” said Dr. Lichter, adding that of the approximately 20,000 active ASCO members, only 205 have thus far earned 20 or more points and received FASCO’s predecessor honor, the Statesman Award.

Only active members of the Society are eligible to earn points.

‘Fellow’ Speaks Volumes Why the name change? Dr. Lichter said members let the board know that fellow status meant more to them than being dubbed a statesman.

“The term ‘statesman’ is just something that’s foreign enough and outside the main sphere of the medical lexicon that it wasn’t getting the attention that we think this important honor should get,” he explained. “So we’ve joined our many sister organizations in making our most dedicated members fellows of our Society.”

FASCO status will be conferred on members at the widely attended opening session of the ASCO Annual Meeting, starting in 2012.

ASCO members who earn fellowship may add FASCO after their name.

Fellowship Designation and Benefits Once conferred, the fellow status is a lifetime recognition. ASCO members who earn fellowship may use the designation “Fellow of the American Society of Clinical Oncology,” and may add FASCO after

their name. Each new fellow will receive a certificate of fellowship and will wear a special ribbon at the Annual Meeting. Each year, fellows will get a reduced registration rate at one ASCO meeting, an invitation to the President’s reception at the Annual Meeting, and advanced access to members-only housing, and each fellow’s name will be published in appropriate ASCO publications.

Previous recipients of the Statesman Award will be grandfathered in and will have the FASCO status.

The purpose of the award, besides honoring those who have dedicated themselves to volunteering for ASCO—sometimes serving on multiple committees at once—in order to advance the field of oncology and to benefit patients, is to encourage more members to become involved in volunteer activities, Dr. Lichter said.

To learn more about the FASCO award, go to www.asco.org/specialawards.

■

© 2012. American Society of Clinical Oncology. All rights reserved.

Joining ASCO’s ACT Network Offers Variety of Advocacy Opportunities

A

re you looking for ways to discuss the issues that impact the oncology community with members of Congress? Doing so is easier than you think. ASCO’s ACT Network provides many different opportunities to contact your policymakers, including the ability to draft your own message to your member of Congress, find phone numbers and mailing addresses for your elected officials, and see how your member of Congress votes on the key issues.

Policymakers, both local and national, make decisions every day that directly influence cancer treatment and research. Oncologists are uniquely qualified to communicate with Congress and the White House about effective policies for

providing the best quality care to cancer patients. Most importantly, oncologists’ perspectives are a necessity to the development of sound cancer policy.

of ASCO’s Government Relations Committee. “It is very important that we educate them on the problems faced by patients with cancer and the challenges in trying to move cancer

Members of Congress make frequent decisions that affect cancer care and research, but they do not have the experience of an oncologist or oncology professional.

“Members of Congress make frequent decisions that affect cancer care and research, but they do not have the experience of an oncologist or oncology professional,” said Richard L. Schilsky, MD, Chair

research and treatment forward.”

By joining the ACT Network, you will become part of a team that is dedicated to shaping the future of oncology by influencing Congress and other policymakers on

important legislation. No legislative advocacy experience is necessary, ASCO will provide the tools necessary to create and sustain these relationships. Once you sign up, you will receive timely updates on the latest congressional and regulatory activity and updates on emerging policy issues that interest you. Recent alerts have focused on research funding, reimbursement, and drug shortages.

If you are interested in learning more about ASCO’s ACT Network or would like to join, please go to: http://ascoaction.asco.org/AdvocacyTools.aspx.

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© 2012. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | JANUARY 15, 2012

PAGE 39

Direct from ASCO

Renewing Our Commitment to Conquering Cancer

C

ongress passed a resolution in December recognizing the 40th anniversary of the National Cancer Act of 1971 and the more than 12 million cancer survivors who are alive as a result of the nation’s commitment to cancer research and advances in cancer prevention, detection, diagnosis, and treatment.

ASCO and other cancer organizations supported the resolution that was introduced by Senators Sherrod Brown (D-Ohio), John Kerry (DMass), and Jerry Moran (R-Kan).

“It’s refreshing that in this difficult budgetary time, this Senate resolution reaffirms that support for cancer research continues to be a national priority,” said ASCO CEO Allen S. Lichter, MD. “We have made significant progress against cancer in the past 40 years, and we believe that with sustained support and bold action as outlined in ASCO’s research blueprint, ‘Accelerating Progress Against Cancer,’ we can make new advances against even the most difficult cancers in the years ahead.”

Historical Background The National Cancer Act, signed in December 1971, led to the establishment of the National Cancer Program, which significantly expanded the authorities and responsibilities of the National Cancer Institute, a component of the National Institutes of Health. Through the research, training, and infrastructure programs of the NCI, cancer patient care expanded from a few pioneering research institutions to cancer centers, community hospitals, and oncology practices around the nation.

NCI-funded Research Project Grants fueled the development of new therapies and diagnostic ap-

proaches. The NCI Clinical Trials Cooperative Groups developed procedures for testing the effectiveness of new treatments through collaborative clinical research studies.

The NCI Cancer Centers Program encouraged the establishment of research-driven cancer centers around the country to deliver state-of-theart care. The NCI Community Clinical Oncology Program provided access to clinical research studies in the community setting, and spread knowledge to community hospitals and oncology practices.

Thanks to these and other federally funded programs, cancer patients in the United States can usually receive the majority of their care, with the most effective treatments available, in their local communities or nearby.

This national commitment to research and patient care has saved millions of lives and billions of dollars. It is estimated that every 1% decline in cancer mortality saves the U.S. economy $500 billion annually.

From 1990 to 2007, the death rate from all cancers combined declined by 22% for men and 14% for women, resulting in 900,000 fewer deaths during that time. In 1971, the 5-year survival rate for all cancers combined was 50% for adults and 52% for children. Today, 68% of adults and 80% of children survive at least 5 years after a cancer diagnosis.

As we enter an era in which cancer treatment is becoming more personalized for patients based on unique molecular profiles, the nation’s cancer research system urgently needs modernization to gear up for the task.

ASCO Report “Accelerating Progress Against

Give Your Patients the Latest GI Research News

O

n January 19, direct your patients to www.cancer.net/gisymposium, where they can get up-to-theminute research highlights from the

3-day 2012 Gastrointestinal Cancers Symposium. Also, your patients can listen to a podcast of the symposium highlights online or download it free of charge at www.cancer.net/podcasts.

■

© 2012. American Society of Clinical Oncology. All rights reserved.

Cancer: ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research,” lays out a vision for a cancer research system that delivers on the potential for more personalized, effective cancer care. The report recommends concrete changes in three main areas: (1) establishing a new approach to developing cancer therapies, driven by our more thorough understanding of cancer’s biology (2) designing “smarter” clinical trials that provide answers about new treatments more quickly, with smaller groups of patients defined more by molecular characteristics of cancer, and not as much by the location of cancer in the body

Volume 29, Issue 15

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

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

■

© 2012. American Society of Clinical Oncology. All rights reserved.

What’s Hot in

May 20, 2011

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

(3) harnessing information technology to seamlessly integrate clinical research and patient care data, ensuring that every patient’s experience can inform research and improve care “On this 40th anniversary of the National Cancer Act, ASCO renews our commitment to conquering cancer,” Dr. Lichter said. “ASCO will continue to work closely with others in the cancer research community to carry out the recommendations of the research blueprint, and we hope that policymakers in Washington will play an active role.”

JCO

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

JCO.org

1. Positive Sentinel Nodes Without Axillary Dissection: Implications for the Radiation Oncologist Bruce G. Haffty, et al 29(34): 4479

6. Is There an Ideal Way to Combine Trastuzumab With Chemotherapy?

Ana M. Gonzalez-Angulo, et al 29(34): 4474

2. More Is Not Necessarily Better When Treating Hodgkin’s Lymphoma Joseph M. Connors 29(32): 4215

7. Anatomy and Biology: Two Complementary Sides of Breast Cancer Prognostication Lajos Pusztai 29(33): 4347

3. Challenges to the Development of New Agents for Molecularly Defined Patient Subsets: Lessons From BRCA1/2Associated Breast Cancer Susan M. Domchek, et al 29(32): 4224

8. The Sad Smile Richard M. Boulay 29(33): 4462

4. Gastric Cancer: Nagoya Is Not New York John S. Macdonald 29(33): 4348

9. Quantitative Reverse Transcriptase Polymerase Chain Reaction and the Oncotype DX Test for Assessment of Human Epidermal Growth Factor Receptor 2 Status: Time to Reflect Again?

John M.S. Bartlett, et al 29(32): 4219

5. Determining the Best Dose for the Individual Patient Ron H.J. Mathijssen, et al 29(33): 4345

10. Implications of the Oropharyngeal Cancer Epidemic Edmund A. Mroz, et al 29(32): 4222

The ASCO Post | JANUARY 15, 2012

PAGE 40

Direct from ASCO

Conquer Cancer Foundation Grantees Advance Cancer Care

E

ach year, the Conquer Cancer Foundation of ASCO funds Young Investigator Awards (YIAs) and Career Development Awards (CDAs). These research grants provide start-up funding for

young physician-scientists as they embark on cancer research careers. Clearly, the programs are working: Six of the top research advances of 2011, as published in ASCO’s Clinical Cancer Advances, were

spearheaded by former YIA and CDA grantees.

■■ Paul Chapman, MD (1989 YIA) and Antoni Ribas, MD (2000 CDA) led research on the new melanoma

Now Enrolling

AMG 386: Phase III Clinical Trials in Ovarian Cancer

TRINOVA-1: A Phase 3, Randomized, Double-Blind Trial of Weekly Paclitaxel Plus AMG 386 or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer Primary Endpoint: • Progression-free survival (PFS) Key Secondary Endpoint: • Overall survival (OS)

R A N D O M I Z A T I O N

AMG 386 15 mg/kg IV QW + Paclitaxel 80 mg/m2 IV QW (3 on/1 off)

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + Paclitaxel 80 mg/m2 IV QW (3 on/1 off)

OS

AMG 386 is an investigational agent that has not been approved by the FDA for the use under investigation for this trial.

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com (20090508) • www.ClinicalTrials.gov (NCT01204749)

© 2012 Amgen Inc. All rights reserved.

drug vemurafenib (Zelboraf). Their research was presented at the 2011 ASCO Annual Meeting, and the FDA subsequently approved vemurafenib for use in the United States.

■■ Carol Aghajanian, MD (1995 YIA and 1996 CDA) led research showing that patients with recurrent gynecologic cancers who received a combination of bevacizumab (Avastin) and a chemotherapy regimen lived significantly longer before the cancer progressed, and had more tumor shrinkage, than patients who were given chemotherapy alone.

■■ Apostolia Tsimberidou, MD, PhD (2007 CDA) was principal investigator of the IMPACT trial, which showed that studying the genetics of an individual’s tumor and choosing therapy based on this information yielded better response rates and increased survival compared with the standard approach.

■■ A 2009 YIA funded by Susan G. Komen for the Cure® supported, in part, work on end-of-life care by Alexi Wright, MD. Her research showed that patients who died in a hospital or intensive care unit, rather than at home with hospice care, experienced diminished quality of life.

■■ Leslie Boyd, MD (2008 YIA), published research revealing disparities in cancer care for patients treated in New York public hospitals. These findings could have important implications for the future of patient care.

■■ Bryan P. Schneider, MD, received a second grant from the Foundation in 2011. His study was the first to identify a marker of neuropathy caused by chemotherapy treatment.

The follow-up study to replicate and confirm these findings is being funded through a 2011 Conquer Cancer Foundation of ASCO Advanced Clinical Research Award in Breast Cancer, supported by The Breast Cancer Research Foundation.

To support early-career researchers, please visit www.conquercancerfoundation.org/donate.

■

© 2012. American Society of Clinical Oncology.

All rights reserved.

ASCOPost.com | JANUARY 15, 2012

PAGE 41

Direct from ASCO

JOP Content Now Available Online before Print

J

ournal of Oncology Practice ( JOP) recently began publishing the majority of its articles online ahead of print. This exciting initiative benefits both JOP’s authors and readers by making practice-changing content readily available online in a timely manner.

With the launch of the publishahead-of-print (PAP) program, JOP joins ASCO’s sister journal, Journal of Clinical Oncology ( JCO), in offering rapid and convenient online access to journal content on a weekly basis.

John V. Cox, DO, MBA, FACP

Authors and readers now have the opportunity to access JOP’s important articles continuously on the Early Release page at jop. ascopubs.org/content/early/recent. JOP Early Release content is updated as often as once a week.

JOP’s authors value the increased online exposure their articles receive with the PAP format, and readers benefit from the frequently updated online presence of articles covering topics across multiple disciplines.

JOP Editor-in-Chief John V. Cox, DO, MBA, FACP, is enthusiastic about the new process. “The continuous publish-ahead-of-print process lets authors see their work published more rapidly,” he notes.

“This new workflow will help us to improve our time-to-publication

metrics.” Dr. Cox also highlights the enhanced online experience for JOP readers. “The PAP initiative allows our content online to be refreshed on a near-weekly basis, so that readers who use our electronic RSS feeds and visit the Early Release page regularly will have access to a variety of articles online well ahead of the print publication date.”

Keeping Updated With this transition to a publish-ahead-of-print model, the publication event of record for the PubMed indexing service has shifted from the date of print publication to the date an article appears on the Early Release page. This means articles will be searchable via PubMed within days after the PAP event.

The introduction of the PAP format makes it easy for readers to keep updated with the most current information available. “PAP is a win-win for authors who see their work move faster through our editorial process to publication, and a win for readers, who can be exposed to content without having to wait for the print issue,” Dr. Cox explains. JOP content encompasses research into all aspects of the provision of oncology care, including outcomes research, health service research, data informing practice of efficiencies in care, models of practice, and analyses of the effects of changing health policy on practice. JOP is a valuable resource to keep practicing oncologists current on changes and challenges inherent in delivering quality oncology care.

■

© 2012. American Society of Clinical Oncology. All rights reserved.

Save the Date Genitourinary Cancers Symposium February 2-4, 2012 San Francisco Marriott Marquis San Francisco, California

ASCO’12 Annual Meeting June 1-5, 2012 McCormick Place Chicago, Illinois

Best of ASCO® Chicago July 12-13, 2012 Hyatt Regency Chicago Chicago, Illinois

Best of ASCO® Boston August 3-4, 2012 Renaissance Boston Waterfront Hotel Boston, Massachusetts

Best of ASCO® San Diego August 10-11, 2012 Manchester Grand Hyatt San Diego, California

The ASCO Post | JANUARY 15, 2012

PAGE 42

News Breast Cancer

Neoadjuvant Chemotherapy or Surgery First: Outcome Not Affected

By Caroline Helwick

C

hemotherapy can be delivered before breast-conserving therapy or after surgery, without influencing long-term local-regional recurrence, a large study from The University of Texas MD Anderson Cancer Center confirmed. The data were presented at the 2011 Breast Cancer Symposium in San Francisco.1 “A woman can have chemotherapy or surgery first, and the choice will not affect her outcome,” said Elizabeth Ann Mittendorf, MD, a surgical oncologist at MD Anderson.

Elizabeth Ann Mittendorf, MD

The findings suggest that treatment success is due more to biologic factors than chemotherapy timing, she said.

“The molecular characteristics of the tumor and other factors have an impact on treatment success, but not the order in which chemotherapy and surgery are given.”

The retrospective study included 2,984 women treated between 1987 and 2005 with segmental mastectomy and whole-breast irradiation, including 78% who underwent surgery before chemotherapy and 22% who had neoadjuvant chemotherapy, then surgery. Women with worse prognostic factors were more likely to have preoperative chemotherapy.

Approaches Have Similar Outcomes The 5- and 10-year local-regional recurrence-free survival rates were excellent for both groups: 97% and 94%, respectively, for those who had surgery first, and 93% and 90%, respectively, for those who had neoadjuvant chemotherapy. When patients were evaluated by presenting clinical stage, there were no differences with respect to local-regional recurrence-free survival rates. Even in patients who had one or more adverse features, such as later disease stage and higher tumor grade or estrogen receptor–negative status, no survival differences emerged when

a number of adverse features were controlled for.

Neoadjuvant chemotherapy resulted in complete pathologic responses in 20% of patients, and allowed for cancer stage

to be downgraded in almost half the patients with stage II or III disease. Neoadjuvant chemotherapy, therefore, made breast-conserving therapy (vs mastectomy) more likely among clinical stage

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 • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • 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 • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. 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) 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%),

II and III patients. Breast-conserving therapy was performed in 69% of stage II patients who underwent neoadjuvant chemotherapy compared with 19% who had surgery first, and in 24% and 1%, re-

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.

ISTODAX® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation 10/11 IST11038

ASCOPost.com | JANUARY 15, 2012

PAGE 43

News

spectively, of stage III patients (P < .001).

“Even women who present with clinical stage II or III disease may have good results with [breast-conserving therapy] after chemotherapy and not need a mastectomy,” Dr. Mittendorf said.

The group plans to extend the study to include MD Anderson pa-

tients treated after 2005. “Since 2005, treatment techniques have improved, including the ability to add targeted therapies to chemotherapy,” she said.

“In the future we will look at the effects of newer agents, and we anticipate the results will be even more favorable for women who received

these treatments before surgery.”

‘Apples and Oranges’ But Barbara Fowble, MD, of the University of California School of Medicine, San Francisco, the invited discussant of the abstract, expressed concern about the imbalance in pa-

INDICATIONS THE FIRST AND ONLY • Treatment of peripheral T-cell lymphoma (PTCL) in patients DRUG APPROVED IN BOTH who have received at least one prior therapy PTCL AND CTCL • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

RECHARGE THE POSSIBILITIES

www.istodax.com Please see Important Safety Information on adjacent page.

Please see Brief Summary of full Prescribing Information on following pages.

tient numbers between the arms, making this a comparison of “apples and oranges,” she told The ASCO Post.

Among stage III patients, 157 underwent neoadjuvant chemotherapy, while just 18 had surgery first. Among stage I patients, 45 had neoadjuvant continued on page 44

The ASCO Post | JANUARY 15, 2012

PAGE 44

News

Timing of Chemotherapy in Breast Cancer continued from page 43

chemotherapy and 1,854 had surgery first. “So the only things we can really say from the data pertain to the stage II patients, who had about 450 patients per arm,” she suggested.

Essentially, she added, the study supports what has already been established by randomized controlled trials: that the two approaches provide comparable outcomes in appropriately selected patients.

■

Disclosure: Drs. Mittendorf and Fowble reported no potential conflicts of interest.

Reference 1. Mittendorf EA, Buchholz TA, Tucker SL, et al: Impact of chemotherapy timing on local-regional failures in patients with breast cancer undergoing breast-conserving therapy. 2011 Breast Cancer Symposium. Abstract 82. Presented September 8, 2011.

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 drug.

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.

Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

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

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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 and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. 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)].

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) 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) Cosmos Communications 718.482.1800

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News Breast Cancer

Single-agent Lapatinib Arm Discontinued in ALTTO

By Caroline Helwick

T

he Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) study, which is evaluating various anti-HER2 therapy approaches in breast cancer, has dis-

continued the single-agent lapatinib (Tykerb) arm, according to study sponsor GlaxoSmithKline.

Following a preplanned interim analysis based on 256 events, the

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 hypomagnesmia.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted 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) 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

study’s data safety and monitoring committee (DSMB) indicated that “the lapatinib-alone arm is unlikely to meet the prespecified criteria to demonstrate noninferiority

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 of 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) 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 and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. 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.

Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures Cosmos Communications 718.482.1800

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to trastuzumab (Herceptin)-alone with respect to disease-free survival,” according to a recenty issued company statement. continued on page 46

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PAGE 46

News

Lapatinib Discontinued in ALTTO Study continued from page 45

Other Study Arms

The three other arms of the ALTTO trial, which involves more than 8,000 patients in 50 countries, will continue uninterrupted. This includes trastu-

zumab monotherapy (52 weeks), trastuzumab (12–18 weeks) followed by lapatinib (28–34 weeks) and trastuzumab in combination with lapatinib (52 weeks). Patients also receive chemotherapy (anthracyclines, taxane, or docetaxel/carboplatin) during the first 12 or 18 weeks of treatment.

(AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.

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 end-stage 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.

“Preliminary data showed that lapatinib appeared to be inferior to singleagent trastuzumab for disease-free survival, as it crossed the boundary for noninferiority. The patients on lapatinib alone appeared not to be doing as well as the control treatment,” said Edith A. Perez, MD, coprincipal in-

vestigator of ALTTO, in a presentation at the 2011 Breast Cancer Symposium in San Francisco that coincided with the announcement.1 “Based on the information provided by the DSMB, the leadership of ALTTO concluded that the rest of the study remains as written,” she added.

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 published1-4 [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, flu-like 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 Pregnancy If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling.

[See Warnings and Precautions (5.5)].

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

Edith A. Perez, MD

“Patients receiving single-agent lapatinib should discuss their options to receive adjuvant trastuzumab, which will be provided free of charge to patients if there are problems with insurance coverage,” she said.

Dr. Perez noted that these findings differ from what was observed in the NeoALTTO trial, which found no statistically significant difference for single-agent lapatinib and trastuzumab (plus chemotherapy) and neoadjuvant treatment. “Importantly, this calls into question whether we can use comparisons in the neoadjuvant setting to predict what we will see in the adjuvant setting,” she said.

■

Disclosure: Dr. Perez receives research funding from Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Novartis, and Sanofi-Oncology.

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146

Reference 1. Perez E: HER2-directed therapy.

2011 Breast Cancer Symposium. Welcome and General Session VII: Advances in Molecular Classification of Breast Cancer and Clinical Implications. Presented September 10, 2011.

ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBVPI.003/PPI.003 09/11

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 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.

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News

Changes in Receptor Status during Breast Cancer Progression Warrant Rebiopsies at Relapse and Metastasis

By Alice Goodman

O

ncologists should be aware that common clinical tumor markers (denoting hormonal and HER2 status) change as breast cancer progresses, because these changes can affect treatment selection. Estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor status was changed from the time of the primary tumor diagnosis to relapse diagnosis in tumor tissue from the same individual, according to a study presented at the 2011 European Multidisciplinary Cancer Congress in Stockholm.

Linda Lindström, MSc, PhD

“At present, clinical management of metastatic breast cancer patients is frequently based on primary tumor marker status. Importantly, our study showed that at least one in three breast cancer patients have altered ER or PR receptor status, and 15% of patients changed HER2 status during the course of disease,” said Linda Lindström, MSc, PhD, Department of Oncology-Pathology, Karolinska Institutet, Stockholm.

“These findings suggest the need for clinical rebiopsy at relapse and metastasis, to enable optimized treatment decisions for each patient,” she stated.

Study Specifics The study was based on a cohort of 1,010 patients with breast cancer in the Stockholm health-care region

who relapsed between January 1, 1997, and December 1, 2007. Biochemical or immunohistochemical/ immunocytochemical (IHC/ICC) assays were used to determine ER, PR, and HER2 status, which was also confirmed by fluorescence in situ hybridization (FISH) for HER2 +2 and +3 patients.

In 459, 430, and 104 patients, ER, PR, and HER2 information was assessed from both primary tumor and first relapse, revealing a change in 32.4%, 40.7%, and 14.5% of patients, respectively. In addition, ER status was assessed in 119 patients and PR status in 116 patients in multiple relapse sites. These markers were unstable throughout tumor progression as well as during advanced-stage disease. One-third of patients had discordant ER status between different relapse sites, whereas 36.1% were classified as stable ER-positive and 30.3% were stable ER-negative; 16% of patients changed from ER-positive to ERnegative, 12.6% changed from ERnegative to ER-positive, and 5% went back and forth throughout tumor progression.

“Loss of ER status generally means that the tumor is resistant to endocrine therapy, whereas a gain in ER expression in the relapse setting would introduce an additional choice of therapy that could affect survival,” Dr. Lindström pointed out. “Women with ER-positive primary tumors changing to ER-negative compared with women with stable ER-positive disease had a significantly increased (by almost 50%) risk of dying,” she added.

Further, she said that the findings suggest that hormonal therapy promotes loss of ER expression during disease progression.

Receptor Status Changes as Breast Cancer Progresses ■■ Hormone receptor status and HER2 status change throughout the course of progressive breast cancer.

■■ About one-third of patients have altered ER or PR status, and about 15% have changes in HER2 status at relapse and metastasis.

■■ These findings argue for the need to rebiopsy at disease progression in order to ensure that patients are receiving the appropriate therapy.

EXPERT POINT OF VIEW: U.S. Perspective

“T

he practice of rebiopsy at relapse and metastasis is becoming increasingly common in the United States,” said Hope Rugo, MD, Professor at the University of California, San Francisco.

“More than 20% of patients have differing results from the primary tumor to rebiopsy at disease progression. It could be that diagnostic tests are faulty, but we believe there is some shift in the tumor characteristics as the disease progresses,” she noted.

Hope Rugo, MD A good reason to rebiopsy would be disease progression with different characteristics than those from the presentation at primary diagnosis, she continued. Biopsy is not needed in a patient who has a primary tumor and then 15 years later develops bone metastasis, she said.

■

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

EXPERT POINT OF VIEW: European Perspective

E

CCO President Michael Baumann, MD, said that the findings on changes in receptor status throughout breast cancer progression were of major importance, “because many patients do not receive optimal treatment for their disease. The price of regular biopsies may seem high, but in the long run they may avoid inappropriate and costly treatment, and, even more importantly, may be the basis for selecting more effective treatments for an indiFabrice André, MD vidual patient.”

According to Fabrice André, MD, Institut Gustave-Roussy, Villejuif, France, “The study further underlines the importance of taking regular biopsies in patients who relapse so that they can be sure of getting the most appropriate treatment, and of running trials looking at the relationship between the profiles of metastatic lesions and new specifically targeted agents.”

■

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

Future Research Dr. Lindström and coauthors are planning a prospective trial following a group of patients with breast cancer and assessing standard clinical markers throughout disease progression.

“It is important in this era of new and targeted therapies to make sure that the correct treatment is given throughout the disease,” she commented. “An additional advantage of rebiopsies at relapse and metastasis is that they could detect other primary cancers, or benign lesions, which could spare patients inappropriate or unnecessary therapies.”

Dr. Lindström said that tumor in-

stability is a promising area of research, not just for breast cancer but perhaps other cancers as well. She added that choice of therapy, patient characteristics, and inherent behavior of tumors may be shared by different tumor types.

■

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

Reference 1. Lindström LS, Karlsson E, Wilking U, et al: Clinically used breast cancer markers are heterogeneous throughout tumour progression. 2011 European Multidisciplinary Cancer Congress. Abstract 5024. Presented September 25, 2011.

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In the Clinic

What You Should Know about Denosumab (Prolia) for Increasing Bone Mass during Breast and Prostate Cancer Therapies

By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indications

I

n September 2011, the monoclonal antibody RANKL inhibitor denosumab (Prolia) was approved for use in increasing bone mass in patients at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer or aromatase inhibitor therapy for breast cancer.1 Under the trade name Xgeva, denosumab has an indication for prevention of skeletal-related events in patients with bone metastases from solid tumors at a different dose (120 mg subcutaneously every 4 weeks) than in the current indications. Denosumab (as Prolia) also has a nononcologic indication for treatment of postmenopausal women with osteoporosis at high risk for fracture.2 Approval of denosumab in the nonmetastatic breast cancer setting was based on a 2-year trial comparing every-6-month subcutaneous injections (total of four doses) of denosumab (n = 127) vs placebo (n = 125) in 252 women (median age 59 years) receiving aromatase inhibitor therapy (62% for > 6 months).3 Patients had to have bone mineral density (BMD) T-scores of –1.0 to

Of Note Marketed as Xgeva, denosumab is approved for prevention of skeletal-related events in patients with bone metastases from solid tumors at 120 mg every 4 weeks—a different dose than used for the indications approved for Prolia.

–2.5 at the lumbar spine, total hip, or femoral neck and could not have had a fracture after age 25. Changes in lumbar spine BMD at 12 months, the primary endpoint of the trial, were +4.8% with denosumab and –0.7% with placebo, a treatment difference of 5.5% (P < .0001).

Approval in the nonmetastatic prostate cancer setting was based on a 3-year trial comparing every-6-month subcutaneous injections (total of six doses) of denosumab (n = 734) vs placebo (n = 734) in 1,468 men (median age 76 years) receiving androgen deprivation therapy (79% > 6 months).4 Men younger than age 70 had to have a BMD T-score between –1.0 and –4.0 at the lumbar spine, total hip, or femoral neck or history of osteoporotic fracture. Changes in lumbar spine BMD T-scores at 24

Of Note Denosumab inhibits bone loss by binding to RANKL, a protein involved in the formation, function, and survival of osteoclasts, the cells responsible for bone resorption.

months, the primary endpoint of the trial, were +5.6% with denosumab and –1.0% with placebo, a treatment difference of 6.7% (P < .0001). Denosumab treatment also resulted in a 66% relative risk reduction (1.5% vs 3.9%, P = .0125) for new vertebral fracture at 36 months, a secondary endpoint of the trial.

How It Works Both androgen deprivation therapy and aromatase inhibitor therapy are associated with bone loss and risk of fracture. Denosumab is a monoclonal antibody that binds to RANKL, a protein involved in the formation, function, and survival of osteoclasts, the cells responsible for bone resorption.5 By inhibiting resorption, denosumab inhibits bone loss.

Denosumab to Prevent Bone Loss from Cancer Treatments ■■ Previously approved in the osteoporosis setting, denosumab (Prolia) is

now cleared for use in increasing bone mass in patients at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer or aromatase inhibitor therapy for breast cancer.

■■ The drug is administered subcutaneously in the upper arm, upper thigh, or abdomen at 60 mg every 6 months.

How It Is Given Denosumab should be administered by a health-care professional.

The recommended dose is 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen. Patients should take 1,000 mg of calcium and at least 400 IU of vitamin D daily. Hypocalcemia must be corrected prior to starting denosumab; it may worsen, particularly in patients with renal impairment. Patients receiving denosumab as Xgeva should not receive denosumab as Prolia (same active ingredient). The dose of denosumab (Prolia) in the prostate and breast cancer settings is the same as that for postmenopausal women with osteoporosis.

Safety Profile In the trials supporting approval of denosumab, adverse events reported in at least 10% of denosumab patients and seen more frequently than in placebo patients were arthralgia and back pain. Pain in extremities and musculoskeletal pain were also observed more frequently with denosumab treatment.

In men receiving androgen deprivation therapy, denosumab was associated with a greater frequency of cataracts (4.7% vs 1.2%). Hypocalcemia was observed only in denosumab patients (2.4%) at 1 month after the first dose.

Warnings and precautions for denosumab include hypocalcemia, serious infections including skin infections, osteonecrosis of the jaw, and oversuppression of bone turnover.

Cost The drug cost for denosumab is ap-

proximately $825 per 60-mg injection, or $1,650 for two injections per year.

■

References 1. U.S. Food and Drug Administration: What’s New from the Office of Hematology Oncology Products: Denosumab (Prolia).

Available at http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm272420.htm.

Accessed December 9, 2011.

2. PROLIA® (denosumab) injection for subcutaneous use prescribing information.

Amgen Inc, September 2011. Available at http://pi.amgen.com/united_states/prolia/prolia_pi.pdf. Accessed December 9, 2011.

3. Ellis GK, Bone HG, Chlebowski R, et al: Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 26:4875-4882, 2008.

4. Smith MR, Egerdie B, Hernández Toriz N, et al: Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361:745755, 2009.

5. Muir VJ, Scott LJ: Denosumab: In cancer treatment-induced bone loss. BioDrugs 24:379-386, 2010.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1800-FDA-1088).

Solutions that can help your patients

stay ahead of access barriers What your patients need for access—from benefits investigations through patient assistance options— is available through Genentech BioOncologyTM Access Solutions®.

Our Specialists can help you navigate the process.

To find out more, contact our Specialists at (888) 249-4918 or visit BioOncologyAccessSolutions.com/resources

© 2011 Genentech USA, Inc. All rights reserved. ACS0000716800 Printed in USA.

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Expert’s Corner

Advances in Gynecologic Cancer Surgery Continue to Improve Outcomes A Conversation with Ginger Gardner, MD

By Ronald Piana

Ginger Gardner, MD

O

ver the past several decades, advances in chemotherapy and surgery have begun to translate into improved survival in gynecologic malignancies. The ASCO Post recently spoke with Ginger Gardner, MD, a surgical oncologist at Memorial SloanKettering Cancer Center, who specializes in the management of gynecologic malignancies, predominantly ovarian, uterine, and cervical cancers.

Challenges and Controversies Despite the potential for cure in early ovarian cancer, the disease kills more women in the United States than all gynecologic malignancies combined. What challenges does this bring to you as a surgeon?

We realize that optimal management for ovarian cancer is a two-part strategy of surgical resection and combination chemotherapy. From a surgical standpoint, the spread of ovarian cancer with its route of peritoneal dissemination means that the disease can invade other pelvic structures, but it can also metastasize readily to the upper abdomen, involving the omentum, diaphragm, liver surface, spleen, and a variety of upper abdominal structures.

Given that clinical situation, there has been an increased emphasis from a surgical perspective to expand our armamentarium in order to fully resect ovarian cancer when we encounter bulky disease in the upper abdomen.

What are the current controversial areas in ovarian cancer management?

There is some controversy regarding the appropriate candidates for neoadjuvant chemotherapy, defined as giving chemotherapy first to shrink the tumor, and then performing surgery at a later time. There is concern about the development of chemotherapy

resistance prior to surgical resection with this approach, and this is weighed against the surgical risks of a large-scale tumor debulking at initial diagnosis.

A recent randomized controlled trial in Europe demonstrated an equivalent overall survival outcome with either approach, but the overall survival for both arms was only 30 months, similar to the survival outcome for suboptimal debulking in prior reports.

Interestingly, there was no benefit in quality-of-life indices with neoadjuvant treatment.

In contrast, decades of experience in the U.S. have demonstrated a benefit of a primary optimal tumor debulking for ovarian cancer followed by chemotherapy, with overall survival greater than 5 years in many studies. Further, the use of intraperitoneal chemotherapy is associated with improved survival outcomes in randomized controlled trials and is most appropriate for patients who have completed an optimal tumor debulking first. As such, many oncologists support primary tumor

identified to have a pelvic mass. The results of this test serve as a triage point to help determine the likelihood of ovarian malignancy, and whether the woman should be referred to a gynecologic oncologist or can be managed by a general gynecologist for her surgery.

We are seeing progress in various markers that will one day give us better screening and diagnostic tools, but there is still much work to be done in this area. Screening for early disease is difficult given that we’re looking at a relatively low-incidence cancer, and the probability of false-positive results if applied as general population-based screening. Certainly, the risk-to-reward ratio needs to be factored into the development and widespread use of any screening tool.

extent, cervical cancer. A smaller role exists in ovarian cancer, where it is mostly used for staging or for resecting an isolated recurrence of disease.

The main advantage of robotic surgery is the amount of control the primary surgeon has. At our institution, we have also identified a decreased need for postop pain medication with robotic surgery compared with standard laparoscopy.

Given today’s economic stress, it’s important to mention that the upfront costs of this equipment are very expensive. I was trained in robotics in 2004, and there have been several equipment iterations since then. While the current system is much more streamlined, the platform still involves bulky, costly equipment.

Robotic Surgery

Cervical Cancer

As an expert in robotic surgery, please give the readers a better understanding of this relatively new and highly touted surgical tool.

Robotics is one of the newest tools

With the advent of Pap, advanced cervical cancer rates in the United States have dropped drastically. What do you see for this disease at Memorial SloanKettering?

Unfortunately, I continue to see cases of advanced cervical cancer. It’s a tragedy that these women, sometimes relocated to the U.S. from other countries, did not have proper screening opportunities either in their home country or after relocation here and then present with advanced-stage cervical cancer.

On the other end of the spectrum are younger women who have not completed fertility when they receive the diagnosis of early-stage cervical cancer. In this setting, we have made a lot of progress by being able to offer fertility-sparing surgery, such as radical trachelectomy for uterine preservation in women with early-stage cervical cancer. In fact, at Memorial Sloan-Kettering we just celebrated our 10-year anniversary in doing these procedures. We had a big event with mothers and their babies, a joyful recognition of how advances in specialized surgical procedures can impact survivorship and quality of life. It was very rewarding to see these women all together, successful survivors of early-stage cervical cancer, and the babies that have been born as a result of innovative surgical techniques designed for fertility preservation.

Decades of experience in the U.S. have demonstrated a benefit of a primary optimal tumor debulking for ovarian cancer followed by chemotherapy, with overall survival greater than 5 years in many studies.

—Ginger Gardner, MD

debulking for the majority of patients.

The most appropriate selection criteria for neoadjuvant treatment is yet to be standardized.

Progress in Biomarkers Managing advanced disease presents difficult challenges, is there any light at the end of the tunnel concerning early detection in gynecologic malignancies, especially ovarian cancer?

We’ve learned more in gynecologic oncology about surveillance markers, one of which is CA-125 level. Recent data show promise for a disease surveillance marker that measures the serum concentration of the protein HE4, which is overexpressed in women with ovarian cancer. A new test called OVA1, which is a composite of several tumor markers, is now used for patients

for performing minimally invasive surgery. The procedure on the inside is the same, whether it is a standard laparoscopic procedure or a robotic procedure. The major difference with robotics is that the camera has threedimensional optic image acquisition with high-definition display. The instrument tips have a 360������������� °������������ fluid rotational range. The primary surgeon maintains control of more instruments—the camera, two operative hands, plus a retracting instrument— all at the same time. Foot pedals toggle the instruments. This is in contrast to standard laparoscopy, during which the surgeon and first assistant each have two instruments.

The biggest expansion of robotic surgery for gynecologic malignancies is in uterine cancer and, to some

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Expert’s Corner

Current Outlook Where do we stand with regard to the management of gynecologic cancers?

There has been a lot of progress in the management of ovarian cancer, in terms of surgical management, newer chemotherapy agents, and targeted molecular therapeutics. In fact, we are now looking at a median survival of 5 years in many of our clinical trials, which really runs counter to the recurring phrase about ovarian cancer being the silent killer of women and the lack of progress in ovarian cancer outcomes.

Any last thoughts about the direction of health care in this country?

Despite some concerns, I think the new initiatives toward cost-effectiveness research are a positive trend. However, despite the pressure to reduce costs, we need to keep an open mind and realize that while new treatments

or procedures may not initially be costeffective, costs decline with increasing use. Moreover, the long-term benefits derived from positive outcomes tend to mitigate initial costs.

Scientific and technologic advances have brought us to an exciting juncture where we can improve health-

care access and outcomes across the full spectrum of patients facing gynecologic malignancies. And in some ways, I think we are becoming smarter in the way we decide how we use our precious resources.

■

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

CMYK

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

Act before febrile neutropenia strikes

For young women with early-stage cervical cancer, fertility-sparing procedures are feasible.

Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved:

In uterine cancer, surgery is the mainstay of treatment, and there are a growing number of cases performed via a minimally invasive approach with decreased postoperative pain in part due to the introduction of robotics. In addition, the recognition that symptoms of postmenopausal bleeding or vaginal spotting can be an early sign of uterine cancer and should be followed with a prompt visit to the gynecologist is central to the identification of earlystage disease and improved outcomes.

Of the predominant gynecologic cancers, cervical cancer is the least common in the U.S. However, for young women with early-stage disease, fertilitysparing procedures are feasible and several centers are now accepting patients for this procedure on a selected basis.

Several thousand American women die annually of this preventable disease, and many of those deaths are among women with poor access to routine medical care and screening. So that’s an area we can improve on with patient education and outreach services.

Send Us Your News Send your news of new appointments, awards, or significant events to The ASCO Post.

Write to editor@ASCOPost.com.

All submissions will be considered for publication.

�

94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2

�

93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2

�

80% reduction in febrile neutropenia– related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®.

Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions.

Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

Bone pain and pain in extremity occurred at a higher incidence in Neulasta ®-treated patients as compared with placebotreated patients.

Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with ≥ 17% risk of febrile neutropenia.

References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2011 Amgen. All rights reserved.

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08-11

www.neulastaHCP.com

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Special Report

Therapy for Hodgkin Lymphoma in the Elderly Remains Undefined

By Matthew Stenger

A

t the 2011 Pan-Pacific Lymphoma Conference held recently in Kauai, Hawaii, Andrew M. Evens, DO, MSc, Director of the Lymphoma Program at the University of Massa-

BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta.

Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

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

chusetts Medical School in Worcester, discussed Hodgkin lymphoma in elderly patients.

Event-free survival and overall survival rates in older patients with

(n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other.

Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients.

Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2 (N = 467)

Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9%

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies.

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of 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 Neulasta with the incidence of antibodies to other products may be misleading.

Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) ADVERSE REACTIONS reported frequency of the reaction, or (3) strength of causal The following serious adverse reactions are discussed in relationship to Neulasta. greater detail in other sections of the Brief Summary: Gastro-intestinal disorders: Splenic rupture [see Warnings • Splenic Rupture [See Warnings and Precautions] and Precautions] • Acute Respiratory Distress Syndrome [See Warnings Blood and lymphatic system disorder: Sickle cell crisis and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] [see Warnings and Precautions] Hypersensitivity reactions: Allergic reactions/hypersensitivity, • Use in Patients with Sickle Cell Disorders [See Warnings including anaphylaxis, skin rash, and urticaria, generalized and Precautions] erythema and flushing [see Warnings and Precautions] • Potential for Tumor Growth Stimulatory Effects on Malignant Respiratory, thoracic, and mediastinal disorder: ARDS Cells [See Warnings and Precautions] [see Warnings and Precautions] The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: Injection site reactions in the pegfilgrastim arm in placebo controlled clinical trials Skin and subcutaneous tissue disorders: Sweet’s syndrome, are bone pain and pain in extremity.

Cutaneous vasculitis Clinical Trials Experience DRUG INTERACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials No formal drug interaction studies between Neulasta and other of a drug cannot be directly compared with rates in the clinical drugs have been performed. Increased hematopoietic activity trials of another drug and may not reflect the rates observed in of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider clinical practice.

Neulasta clinical trials safety data are based upon 932 patients these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The USE IN SPECIFIC POPULATIONS population was 21 to 88 years of age and 92% female. The Pregnancy ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy Category C 1% Asian. Patients with breast (n = 823), lung and thoracic There are no adequate and well-controlled studies in pregnant tumors (n = 53) and lymphoma (n = 56) received Neulasta women. Pegfilgrastim was embryotoxic and increased after nonmyeloablative cytotoxic chemotherapy. Most patients pregnancy loss in pregnant rabbits that received cumulative received a single 100 mcg/kg (n = 259) or a single 6 mg doses approximately 4 times the recommended human dose (n = 546) dose per chemotherapy cycle over 4 cycles. (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta

Hodgkin disease have been reported at 40% to 50% lower than rates in younger patients. This difference in outcome may be related to several factors. The disease may have a different

K

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred.

Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area).

Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk.

Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.

Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11).

The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.

DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.

NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.

This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2011 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

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biology in older patients, who have a greater frequency of mixed cell disease and Epstein-Barr virus–related disease.

Older patients have a greater frequency of comorbidities that preclude appropriate treatment and thus frequently have inadequate treatment duration and intensity. They also have an increased frequency of treatmentrelated toxicities—especially bleomycin lung toxicity.

Currently, there is no standard treatment for older patients with Hodgkin disease—ie, those aged 60 years or older. Further, these patients are underrepresented in clinical trials, typically accounting for less than 5% to 10% of most clinical trial populations, compared with 15% to 20% of the Hodgkin disease population.

Chicago Cohort A recent retrospective analysis defined characteristics and outcomes among 95 Chicago area Hodgkin lymphoma patients over 60 years old seen between 2000 and 2010.1 Patients had a median age of 67 years, with 33% older than 70 years and 7% older than 80 years.

Disease types were nodular sclerosis in 47%, mixed cell in 31%, not otherwise specified in 16%, lymphocyte predominant in 5%, and lymphocyte depleted in 1%.

Prior malignancy was present in 27% of patients, B symptoms in 54% (> 10% weight loss in 35%), ECOG performance status > 1 in 27%, stage III/IV disease in 65% (with bone marrow involvement in 25%), bulky disease in only 4%, and International Prognostic Score of 4 to 7 in 58%. With regard to functional status, 61% had a grade 3 or 4 comorbidity on the Cumulative Illness Rating Scale-Geriatrics, 26% were categorized as “not fit,” 13% had loss of activities of daily living, and 17% had a documented geriatric syndrome.

The overall response rate to treatment in this cohort of patients was 85%, with 73% having complete response. However, the 5-year eventfree survival rate was 47% and 5-year overall survival rate was 58%, with rates being significantly lower in patients with stage III/IV disease than in those with stage I/II disease (37% vs 65%, respectively, for 5-year event-

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Special Report

free survival, P = .007; 46% vs 79%, respectively, for 5-year overall survival, P = .001).

Bleomycin lung toxicity occurred in 32% of patients, which had a mortality rate of 25%. On univariate analysis, predictors of inferior event-free and overall survival were age greater than 70 years, B symptoms, weight loss, performance status > 1, low serum albumin, history of coronary artery disease, stage III/IV disease, any comorbidity of grade 3 or 4, and loss of activities of daily living. On multivariate analysis, predictors of poorer outcome were age greater than 70 years (HR = 2.24; P = .02), loss of activities of daily living (HR = 2.71, P = .04), and lack of complete response (HR = 8.1, P < .0001).

Another study has indicated some “catch up” in 10-year relative survival among elderly patients over the past 30 years.2 Compared with the period of 1980 to 1984, 10-year relative survival during 2000 to 2004 has increased by 23% among patients aged 60 years or older and by 25% in those aged 45 to 59 years. However, the gap between older and younger patients still persists, with a strong age gradient in 10-year relative survival during the 2000 to 2004 period being observed: 93% for the 15 to 24 year age group, 89% for the 25 to 34 year group, 85% for the 35 to 44 year group, 76% for the 45 to 54 year group, and 45% for the 60 year and older group.

ABVD and Stanford V in Intergroup E2496 The recent Intergroup E2496 trial compared standard Hodgkin lymphoma treatment consisting of six to eight cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine; n = 404) vs 12 weeks of the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine [Mustargen], etoposide, bleomycin, vincristine, and prednisone; n = 408) in patients with advanced-stage Hodgkin lymphoma.3 Modified involved-field radiation therapy of 36 Gy was given to patients in the ABVD group with massive mediastinal disease and to patients in the Stanford V group with affected sites > 5 cm.

A total of 43 patients aged 60 years or older were included in the trial. Compared with younger patients, these older patients were significantly less likely to have a performance status of 0 vs 1 to 2 (odds ratio = 2.58, P = .004) and significantly more likely to have the mixed cell disease type (odds ratio = 3.51, P = .0004).

Overall response rate was 70% in older patients vs 78% in younger patients (P = .19). Rates of complete response plus clinical complete response were 65% vs 71% (P = .49).

Among elderly subjects, there were no significant differences between ABVD and Stanford V in failure-free survival or overall survival. Overall, survival was significantly poorer for elderly vs younger patients (Fig. 1): 3-year

Failure-free survival

1.0

survival rates, compared with younger patients. This may be related to differences in biology, increased comorbidities, or treatment-related toxicities.

■■ There is no standard treatment for older patients with Hodgkin

lymphoma, and this population is underrepresented in clinical trials.

■■ The UK SHIELD program (for which data analysis is forthcoming)

has enabled the treatment of older Hodgkin patients with VEPEMB in a phase II protocol. A U.S. phase II study is assessing the use of brentuximab vedotin in this population.

failure-free survival was 55% vs 76% (P = .0014) and 5-year failure-free survival was 46% vs 74% (P < .0001); 3-year overall survival was 69% vs 93% (P < .0001) and 5-year overall survival was 56% vs 90% (P < .0001).

Among older patients, grade 3 nonhematologic toxicity with ABVD occurring in more than 5% of patients consisted of fatigue in 17% and dehydration, vomiting, hyperglycemia, and myalgia in 9% each; grade 4 toxicities consisted of motor neuropathy and sensory neuropathy in 9% each and neutropenic fever in 4%. Grade 3 toxicities occurring in more than 5% of patients receiving Stanford V consisted of motor neuropathy in 15% and muscle weakness, hyperglycemia, and neutropenic fever in 10%; grade 4 toxicities consisted of constipation and myalgia in 5% each.

Overall treatment-related mortality was significantly greater in older vs younger patients (9.3% vs 0.3%, Overall survival P < .001

0.9

0.8

0.8

P = .001

0.7

Probability

Probability

■■ Older patients with Hodgkin lymphoma have up to 50% lower

1.0

0.9

0.6 0.5 0.4 0.3

0

1

2

3

0.6 0.5 0.4 ≥ 60 yr

0.1 4

5

6

7

8

0.0

9

0

1

2

3

Year

Failure-free survival

Overall survival

4

5

6

7

8

9

Year

< 60 yr

P < .001). Bleomycin lung toxicity occurred in 26% of older patients (n = 11), with a fatality rate of 18%. Of these 11 cases, 10 were in the ABVD group.

Analysis of German Hodgkin Study Group Trials Similar disparity in outcome was observed in the analysis of elderly patients who were treated in the German Hodgkin Study Group trials for early-stage Hodgkin lymphoma. The HD10 trial comparing two vs four cycles of ABVD plus radiotherapy of 20 or 30 Gy included 68 elderly patients, and the HD11 trial comparing ABVD vs BEACOPP-baseline (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], and prednisone) plus radiotherapy of 20 or 30 Gy included 49 elderly patients (median ages of 65 and 64 years, respectively).

WHO grade 3/4 toxicities occurred in 67% of these patients in HD10 and in 69% in HD11. Treatment-related mortality was 5%. Furthermore, the 5-year progression-free survival rates for elderly vs younger patients with Hodgkin lymphoma were 79% vs 96% in HD10 and 69% vs 86% in HD11.4

Current and Future Directions < 60 yr

0.2

≥ 60 yr

0.1

0.7

0.3

< 60 yr

0.2 0.0

Hodgkin Lymphoma in Elderly Patients

≥ 60 yr

3-yr

76%

55%

5-yr

74%

46%

3-yr

93%

69%

5-yr

90%

56%

P .0014

< .0001

Fig. 1: Failure-free and overall survival in patients aged < 60 years vs those aged ≥ 60 years in Intergroup Trial E2498. Adapted with permission from Evens AM, et al.3

The UK SHIELD (Study of Hodgkin lymphoma In the Elderly/Lymphoma Database) program has allowed physicians to treat elderly patients through a phase II study protocol using VEPEMB therapy (vinblastine, cyclophosphamide, procarbazine, etoposide, mitoxantrone, and bleomycin) or to collect data from elderly patients otherwise under treatment. More than 200 patients were registered in the program.

Data collection included comorbidity and functional scales and quality-of-life assessments. Analyses of these data are expected in the near future.

In the United States, a phase II continued on page 54

The ASCO Post | JANUARY 15, 2012

PAGE 54

Special Report

Hodgkin Lymphoma in the Elderly

Expert Point of View

continued from page 53

By Andrew M. Evens, DO, MSc

study is underway to examine incorporation of brentuximab vedotin (Adcetris) and positron-emission tomography (PET) into front-line treatment of advanced disease in patients aged 60 years or older.5 Brentuximab vedotin is a CD30-directed antibody-drug conjugate that was recently approved for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplantation or after failure of at least two prior multiagent chemotherapy regimens in patients who are not stem cell transplant candidates.

Following PET and computed tomography (CT) staging, patients will receive two cycles of brentuximab vedotin at 1.8 mg/kg every 3 weeks, followed by PET in the first 22 patients.

Patients with complete response, partial response, or stable disease will then receive six cycles of AVD (doxorubicin, vinblastine, dacarbazine). Those with complete or partial response on subsequent PET and CT are to receive consolidation treatment with brentuximab vedotin at the same dose for four cycles.

■

Disclosure: Dr. Evens has received research funding from Seattle Genetics.

References 1. Evens AM, Helenowski I, Ramsdale E, et al: A retrospective multicenter analysis of elderly Hodgkin lymphoma: Outcomes and prognostic factors in the modern era. Blood November 23, 2011 (early release online).

2. Brenner H, Gondos A, Pulte D: Ongoing improvement in long-term survival of patients with Hodgkin disease at all ages and recent catch-up of older patients.

Blood 111:2977-2983, 2008.

3. Evens AM, Hong F, Gordon LI, et al: Efficacy and tolerability of ABVD and Stanford V for elderly advancedstage Hodgkin lymphoma (HL): Analysis from the phase III randomized U.S. Intergroup Trial E2496. J Clin Oncol 29(suppl):Abstract 8035, 2011.

4. Böll B, Görgen H, Fuchs M, et al: Feasibility and efficacy of ABVD in elderly Hodgkin lymphoma patients: Analysis of two randomized prospective multicenter trials of the German Hodgkin Study Group (HD10 and HD11). Blood 116(21):Abstract 418, 2010.

5. ClinicalTrials.gov: Brentuximab vedotin and combination chemotherapy in treating older patients with previously untreated stage II-IV Hodgkin lymphoma.

Available at: http://www.clinicaltrials. gov/ct2/show/NCT01476410.

E

lderly ����������������������� Hodgkin lymphoma������� , typically defined as affecting individuals ≥ 60 years of age, remains a disease for which no standard treatment recommendation exists. This population is underrepresented in clinical studies, and survival rates in older patients with Hodgkin lymphoma are significantly and disproportionately inferior compared with younger patients.

Surveillance, Epidemiology and End Results (SEER) data reported by Brenner et al showed that Hodgkin lymphoma outcomes in elderly patients improved from 1980 to 2004.1 However, that study and others reported 5‑year progression-free survival and freedom from treatment failure rates of 30% to 45%, with 5-year overall survival rates of 40% to 55% for elderly patients.2,3 This compares with 5-year overall survival rates of > 80% to 90% for Hodgkin lymphoma populations under age 45 years.

mixed-cellularity subtype, EBV positivity, advanced-stage disease, and low incidence of bulky disease. Additionally, a paucity of prognostic data exists for elderly Hodgkin lymphoma, while the potential impact of functional status on survival is largely unexplored.20 The most commonly used prognostic tool in Hodgkin lymphoma is the���� International Prognostic Score (IPS), which utilizes seven adverse clinical prognostic factors (including age ≥ 45 years) to predict outcome. However, only 9% of patients in that pivotal analysis were over age 55, and none were over 65 years.21

Andrew M. Evens, DO, MSc

rates were good, with a complete remission rate of 73%; however, the incidence of bleomycin lung toxicity was 32%, which had an associated mortality rate of 25%. Moreover, the incidence of bleomycin lung toxicity Recent Analyses was 38% vs 0% among patients who We recently conducted a multi- received G‑CSF (filgrastim, Neupocenter retrospective analysis of elderly gen) vs not, respectively (P = .0001). patients consecutively diagnosed and G-CSF may induce bleomycin lung treated with Hodgkin lymphoma be- toxicity in part through recruitment tween 1999 and 2009 at five medical of pulmonary neutrophils with associcenters.22 We documented that that ated free radical–induced pulmonary the majority of patients had a severe damage.25 Other series have reported (ie, grade 3 or 4) comorbidity in at an increased incidence of bleomycin Prior Studies least one category (as scored by the lung toxicity when G-CSF was used A number of analyduring bleomycinses conducted in the containing chemoOlder patients with Hodgkin lymphoma 1970s to 1990s examtherapy, with an assoined a variety of checiated mortality rate are underrepresented in clinical studies, motherapy regimens, of 40% in patients and survival rates in this population are documenting modest ≥ age 40 years.26 significantly and disproportionately inferior With a median foloutcomes for elderly low-up of 66 months, patients with Hodgkin compared with younger patients.

4-14 These the 5-year overall surlymphoma. treatments included vival for advancedless intensive regimens as well as Cumulative Illness Rating Scale–Ge- stage Hodgkin lymphoma in our setherapy tailored to individual patients riatric system),23,24 while a significant ries of elderly patients with Hodgkin based on comorbidities. More intense minority of subjects had a geriatric lymphoma was < 50%. Further, most regimens, such as BEACOPP-baseline syndrome and/or loss of activities of IPS factors (eg, anemia, WBC, sex, (bleomycin, etoposide, doxorubi- daily living at diagnosis. lymphopenia) were not significant The presence of comorbidity as a on univariate analysis. On multivaricin, cyclophosphamide, vincristine, procarbazine [Matulane], and pred- prognostic factor is particularly rel- ate Cox regression analysis, only two nisone), have been studied in elderly evant for older patients. In a popula- factors were associated with inferior patients with Hodgkin lymphoma tion-based study, van Spronsen et al survival: (1) age ≥ 70 years and (2) and shown to be too toxic.10,15,16 In- reported that among elderly patients loss of activities of daily living. Furadequate treatment delivery for older with Hodgkin lymphoma, 56% had a thermore, we created a new survival patients may compromise the rate of serious comorbid condition vs 13% model based on the number of these cure, while comorbidities may pre- in younger patients (P < .0001).18 Ad- risk factors present at initial diagnoclude the delivery of standard chemo- ditionally, Levis et al reported results sis (0, 1, or 2), showing a differential of elderly patients with Hodgkin lym- 2-year overall survival of 83%, 70%, therapy.13,17,18 Treatment delivery and comorbid- phoma who received lower-intensity 13%, respectively (P < .0001), and ity, however, do not appear to com- chemotherapy6; the presence of co- 5-year overall survival of 73%, 51%, pletely explain the observed differenc- morbidity independently correlated 0%, respectively (P < .0001). es in the outcome of elderly patients with lower disease-specific and overall We also recently presented data with Hodgkin lymphoma, implicating survival. among the subset of elderly patients The most common treatment in with Hodgkin lymphoma (n = 43) in part a different disease biology.19 Indeed, elderly subjects with Hodgkin our series was ABVD-based therapy. who were treated on the E2496 Intercontinued on page 59 lymphoma frequently present with The overall and complete remission

To confront a

Common Threat in the 2 leading causes of cancer death1...

Indications Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Think Avastin Percentage Surviving

First-line metastatic non-squamous NSCLC: 19% increase in median OS in combination with PC (Study E4599)2

100

1-year survival: 51% vs 44%2

80

2-year survival: 23% vs 15%2

60 40

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

20 0

10

20

30

40

50

OS (Months)

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

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)2 Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%)3

Indications Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention

©2011 Genentech USA, Inc. All rights reserved. AVA0000488101 Printed in USA. (11/11)

Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.4%) — Proteinuria including nephrotic syndrome (<1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Because overall survival matters Proven to extend overall survival (OS) in the 2 cancers with the highest mortalities1 First-line MCRC in combination with IV 5-FU–based chemotherapy: 30% increase in median OS in combination with IFL (Study 2107)2,4,5

Percentage Surviving

100

First-line median OS: 20.3 vs 15.6 months (HR=0.66 [95% CI, 0.54–0.81], P<0.001)

80 60 40 20

Avastin + IFL (n=402) Placebo + IFL (n=411)

0 6

18 12 OS (Months)

24

30

MCRC=metastatic colorectal cancer; IV=intravenous; 5-FU=5-fluorouracil; IFL=5-FU/leucovorin (LV)/irinotecan.

OS in second-line MCRC Study E3200: Median OS of 13.0 months with Avastin plus 5-FU/LV/oxaliplatin (FOLFOX4) vs 10.8 months with FOLFOX4 alone (HR=0.75 [95% CI, 0.63–0.89], P=0.001)2,6

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

Pregnancy warning Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

References: 1. American Cancer Society. Cancer Facts and Figures 2010. http://www. cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Accessed April 21, 2011. 2. Avastin Prescribing Information. Genentech, Inc. September 2011.

3. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550. 4. Data on file. Genentech, Inc. 5. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 6. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol.

2007;25:1539-1544.

www.avastin.com

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), Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

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.

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

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).]

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued.

Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL+Avastin vs. IFL)

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%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).

[See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

• Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

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

The data below reflect exposure to Avastin in 4024 patients with CRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18-88 years (median 59), 41% male and 85.1% white. The population included 1783 firstand second-line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 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

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra-abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone.

In a second, randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

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.

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥30 mIU/mL and a negative serum β-HCG pregnancy test)was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n=84 or with Avastin (n=95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% (7/32) of the Avastin-treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post-treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1.

Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

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

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

Arm 2 IFL + Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5-FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs.

9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs.

1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs.

0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥ 2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs.

0.3%) and proteinuria (3% vs. 0%).

Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.

Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/ hypotension (2).

Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥ 5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Body as a Whole Asthenia Headache Pain Cardiovascular Hypertension Digestive Stomatitis Metabolic/Nutrition Weight loss Musculoskeletal Myalgia Respiratory Dyspnea Epistaxis Skin/Appendages Exfoliative dermatitis Urogenital Albuminuria

Capecitabine (n = 215)

Capecitabine + Avastin (n = 229)

47% 13% 25%

57% 33% 31%

2%

24%

19%

25%

4%

9%

8%

14%

18% 1%

27% 16%

75%

84%

7%

22%

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study

ASCOPost.com | JAUNARY 15, 2012 AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

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 compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN-α plus Avastin compared to the IFN-α plus placebo arm are presented in Table 4.

Table 4 NCI-CTC Grades 1−5 Adverse Events in Study 9 (Occurring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo) System Organ Class/ IFN-α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

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

Adverse events were encoded using MedDRA, Version 10.1.

a

The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Avastin arm compared to IFN-α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs.

0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

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

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.

Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs.

1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin-treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (reported from unapproved use for treatment of various ocular disorders): Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual disturbances; Ocular hyperemia; Ocular pain and/or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis,Anastomotic ulceration Hemic and lymphatic: Pancytopenia Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/ carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/ carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions.

[See Nonclinical Toxicology (13.3).]

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is

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

11/11 AVA0000764000 10127309 Initial U.S.Approval: February 2004 Code Revision Date: September 2011 Avastin® is a registered trademark of Genentech, Inc. ©2011 Genentech, Inc.

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Special Report

Expert Point of View continued from page 54

group trial that randomly assigned patients with advanced-stage disease to six to eight cycles ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) vs Stanford V (doxorubicin, vinblastine, mechlorethamine [Mustargen], etoposide, bleomycin, vincristine, and prednisone).27 Not surprisingly, the failure-free and overall survival rates were significantly inferior for elderly patients compared with those under 60 years old, with survival rates > 30% to 35% lower for the former. Further, treatmentrelated mortality was comparatively higher for the elderly Hodgkin lymphoma population. The incidence rate of bleomycin lung toxicity in this prospective trial (26%) was remarkably consistent with the aforementioned retrospective series, while the bleomycin lung toxicity–related mortality rate in E2496 was 18%.

Treatment Toxicities and Alternatives Hodgkin lymphoma is a malignancy that does not have an expected appreciable rate of treatment-related mortality. However, due in part to bleomycin and other chemotherapy-related toxicities, treatmentassociated mortality is likely more common than suggested, despite the contemporary era of supportive care measures. In fact, use of granulocyte growth factors concurrently with bleomycin may exacerbate pulmonary toxicity, as noted before.

Outside of a clinical trial, I typically advocate treatment with AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) for elderly Hodgkin lymphoma, withholding bleomycin a priori in most subjects over ages 60 to 65 years old. Retrospective data from Cancer and Leukemia Group B (CALGB) research suggests that bleomycin may not be needed as a component of ABVD therapy.28 If bleomycin is not administered, G‑CSF may then be used with impunity.

Another systemic therapeutic option for elderly Hodgkin lymphoma includes CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone). In a small study, Kolstad et al reported encouraging results with CHOP in this setting.29 Additionally, with respect to

number of cycles of chemotherapy and use of radiotherapy (ie, for earlystage disease), I follow stage-based guidelines similar to those applied for younger patients.30

Ongoing Research New therapeutic options, including biologically based strategies, are actively being investigated in Hodgkin lymphoma. This includes brentuximab vedotin (Adcetris), the antibody-drug conjugate, which has shown significant single-agent activity in relapsed/refractory disease.31 This and other novel agents should be explored in front-line therapy of elderly Hodgkin lymphoma through prospective clinical trials.

In addition, continued examination of the biology of the disease in elderly patients, especially the impact of Epstein-Barr virus, is warranted. Finally, results from the recently completed SHIELD study conducted by Proctor and colleagues, which included analysis of a large cohort of elderly Hodgkin patients (with functional assessments) in addition to completion of a prospective clinical trial, are eagerly awaited.32

■

Disclosure: Dr. Evens has received research funding from Seattle Genetics.

References 1. Brenner H, Gondos A, Pulte D: Ongoing improvement in long-term survival of patients with Hodgkin disease at all ages and recent catch-up of older patients. Blood 111:2977-2983, 2008.

2. Proctor SJ, Rueffer JU, Angus B, et al: Hodgkin’s disease in the elderly: Current status and future directions. Ann Oncol 13(suppl 1):133-137, 2002.

3. Evens AM, Sweetenham JW, Horning SJ: Hodgkin lymphoma in older patients: An uncommon disease in need of study. Oncology (Williston Park) 22:1369-1379, 2008.

4. Enblad G, Glimelius B, Sundstrom C: Treatment outcome in Hodgkin’s disease in patients above the age of 60: A population-based study. Ann Oncol 2:297-302, 1991.

5. Enblad G, Gustavsson A, Sundstrom C, et al: Patients above sixty years of age with Hodgkin’s lymphoma treated with a new strategy. Acta Oncol 41:659667, 2002.

6. Levis A, Anselmo AP, Ambrosetti A, et al: VEPEMB in elderly Hodgkin’s lymphoma patients. Results from an Intergruppo Italiano Linfomi (IIL) study.

Ann Oncol 15:123-128, 2004.

7. Levis A, Depaoli L, Bertini M, et al: continued on page 60

The ASCO Post | JANUARY 15, 2012

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Health IT/EHR Symposium Shortening the Learning Curve of the U.S. Health-care System

A novel health information technology initiative seeks to enable our health-care system to educate itself and accelerate clinical progress.

By Ronald Piana

I

f we are able to harness the full potential of digital technologies, computerized registries, databases, and the Web, could we solve many of the current woes of our sluggish and costly health-care system? Yes, according to Lynn Etheredge, a consultant with the Rapid Learning Project at the George

Lynn Etheredge

Washington University in Washington, DC, who presented a session titled, “A Rapid-Learning Healthcare System” at the recent ASCO Health IT/EHR

Expert Point of View continued from page 59

Results of a low aggressivity chemotherapy regimen (CVP/CEB) in elderly Hodgkin’s disease patients. Haematologica 81:450456, 1996.

8. Weekes CD, Vose JM, Lynch JC, et al: Hodgkin’s disease in the elderly: Improved treatment outcome with a doxorubicin-containing regimen. J Clin Oncol 20:1087-1093, 2002.

9. Zinzani PL, Magagnoli M, Bendandi M, et al: Efficacy of the VBM regimen in the treatment of elderly patients with Hodgkin’s disease. Haematologica 85:729732, 2000.

10. Mir R, Anderson J, Strauchen J, et al: Hodgkin disease in patients 60 years of age or older. Histologic and clinical features of advanced-stage disease. The Cancer and Leukemia Group B. Cancer 71:1857-1866, 1993.

11. Stark GL, Wood KM, Jack F, et al: Hodgkin’s disease in the elderly: A population-based study. Br J Haematol 119:432440, 2002.

12. Engert A, Ballova V, Haverkamp H, et al: Hodgkin’s lymphoma in elderly patients: A comprehensive retrospective analysis from the German Hodgkin’s Study Group. J Clin Oncol 23:5052-5060, 2005.

13. Erdkamp FL, Breed WP, Bosch LJ, et al: Hodgkin disease in the elderly.

A registry-based analysis. Cancer 70:830-

[Health Information Technology/ Electronic Health Records] Symposium in Atlanta.

What Is a Rapid-learning Health-care System?

According to Mr. Etheredge, we have the technologies at hand to build a rapid-learning health-care system that would accelerate our clinical research and trial system. “The objective of a rapid-learning health-care system is simply to learn as fast as possible about what is the best treatment for each patient—and deliver it,” Mr. Etheredge commented.

Conceptually, a rapid-learning system speaks to some of the major problems in our current system: clinical practice variations, poor quality, lack of comparative effectiveness research, rising costs, ineffective markets, and an inefficient regulatory body. “In short, a fully implemented rapid-learning

834, 1992.

14. Roy P, Vaughan Hudson G, Vaughan Hudson B, et al: Long-term survival in Hodgkin’s disease patients. A comparison of relative survival in patients in trials and those recorded in population-based cancer registries. Eur J Cancer 36:384-389, 2000.

15. Ballova V, Ruffer JU, Haverkamp H, et al: A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin’s disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol 16:124131, 2005.

16. Levis A, Depaoli L, Urgesi A, et al: Probability of cure in elderly Hodgkin’s disease patients. Haematologica 79:46-54, 1994.

17. Janssen-Heijnen ML, van Spronsen DJ, Lemmens VE, et al: A populationbased study of severity of comorbidity among patients with non-Hodgkin’s lymphoma: Prognostic impact independent of International Prognostic Index. Br J Haematol 129:597-606, 2005.

18. van Spronsen DJ, Janssen-Heijnen ML, Lemmens VE, et al: Independent prognostic effect of co-morbidity in lymphoma patients: Results of the population-based Eindhoven Cancer Registry.

Eur J Cancer 41:1051-1057, 2005.

19. Klimm B, Diehl V, Engert A: Hodgkin’s lymphoma in the elderly: A differ-

Toward a Rapid-learning Health-care System ■■ Rapid-learning health care uses information technologies to determine,

as quickly as possible, best practices that can be adopted throughout the health-care system.

■■ Oncology models of rapid-learning systems are currently open for

discussion, with innovators and researchers encouraged to offer input.

■■ ASCO can have a key role in creating a rapid-learning system for cancer care.

system addresses the issue of delivering personalized therapy by advancing translational science and evidencebased medicine,” Mr. Etheredge said.

A key concept in this initiative is “in silico” research—using massive computerized databases and research networks for cutting-edge science that compliments in vivo and in vitro methods. “In silico research gives us the potential to learn much faster. Using this approach, we’ll be able to study many more patients than allowed by our cur-

ent disease in patients over 60. Oncology (Williston Park) 21:982-990, 2007.

20. Boll B, Bredenfeld H, Gorgen H, et al: Phase II study of PVAG (prednisone, vinblastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma. Blood September 13, 2011 (early release online).

21. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease: International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339:1506-1514, 1998.

22. Evens AM, Helenowski I, Ramsdale E, et al: A retrospective multicenter analysis of elderly Hodgkin lymphoma: Outcomes and prognostic factors in the modern era. Blood November 23, 2011 (early release online).

23. Mistry R, Gokhman I, Bastani R, et al: Measuring medical burden using CIRS in older veterans enrolled in UPBEAT, a psychogeriatric treatment program: A pilot study. J Gerontol A Biol Sci Med Sci 59:1068-1075, 2004.

24. Parmelee PA, Thuras PD, Katz IR, et al: Validation of the Cumulative Illness Rating Scale in a geriatric residential population. J Am Geriatr Soc 43:130-137, 1995.

25. Azoulay E, Herigault S, Levame M, et al: Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and pulmonary fibrosis. Crit

rent clinical trial system,” Mr. Etheredge explained.

Incomplete Equation Having access to large databases with richer and longitudinal data creates an atmosphere in which many more researchers can conduct different and faster studies. “Today, researchers who want to test an idea must apply for a grant and do preliminary data collection. It is a multiyear process. Howevcontinued on page 61

Care Med 31:1442-1448, 2003.

26. Martin WG, Ristow KM, Habermann TM, et al: Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin’s lymphoma. J Clin Oncol 23:7614-7620, 2005.

27. Evens AM, Hong F, Gordon LI, et al: Efficacy and tolerability of ABVD and Stanford V for elderly advancedstage Hodgkin lymphoma (HL): Analysis from the phase III randomized U.S. Intergroup Trial E2496. J Clin Oncol 29(suppl):Abstract 8035, 2011.

28. Canellos GP, Duggan D, Johnson J, et al: How important is bleomycin in the adriamycin + bleomycin + vinblastine + dacarbazine regimen? J Clin Oncol 22:1532-1533, 2004.

29. Kolstad A, Nome O, Delabie J, et al: Standard CHOP-21 as first line therapy for elderly patients with Hodgkin’s lymphoma. Leuk Lymphoma 48:570-576, 2007.

30. Hoppe RT, Advani RH, Ai WZ, et al: Hodgkin lymphoma. J Natl Compr Canc Netw 9:1020-1058, 2011.

31. Younes A, Bartlett NL, Leonard JP, et al: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363:1812-1821, 2010.

32. Proctor SJ, White J, Jones GL: An international approach to the treatment of Hodgkin’s disease in the elderly: Launch of the SHIELD study programme. Eur J Haematol 75(suppl 66):63-67, 2005.

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Health IT/EHR Symposium Shortening the Health-care Learning Curve continued from page 60

er, many researchers, such as astronomers, log onto their computer in the morning and access evidence-based data that has already been predigested by high-speed computer programs,” Mr. Etheredge said.

The end result: Linking high-speed computer systems to robust databases would allow researchers to test multiple hypotheses—in what now takes years to get results—in a matter of a few days.

Mr. Etheredge uses a fairly straightforward model to capture the essence of a rapid-learning health-care system: RL = R + C + D + Apps. “R is for great researchers and C is for very fast computers. We have both of those. D is for databases. We don’t have a national system of high-quality clinical research registries and databases that are predesigned, prebuilt, and prepopulated for answering the questions we’re likely to ask in a rapid learning system,” Mr. Etheredge noted.

Mr. Etheredge continued, “Most rapid-learning questions are applied research—in other words, treatment A vs treatment B for subpopulation C. We need specific data that will answer the questions and electronic health records to enable the researcher to access the new, data-rich environment in a computable world of clinical evidence.”

“Finally,” Mr. Etheredge concluded, “I’ve come to realize that we need a whole new world of apps: user-friendly software to acquire, share, analyze, and use computable data in a quick and efficient manner, to develop the neces-

sary clinical tools such as predictive modeling. That is the broad concept of a rapid-learning health-care system in a nutshell.”

Oncology Rapid-learning System The session’s second presenter, Peter Paul Yu, MD, of Palo Alto Medical Foundation, distilled the rapidlearning health-care system concept into two oncology models. “The principles of a rapid-learning health-care system are learning from every patient experience, identifying the useful data within the tsunami of data out there, then using the “extract, transform, and load” process to mine and aggregate the data for knowledge creation that ultimately is applied at the point of oncology care. From there, we iterate and innovate,” Dr. Yu commented.

Model A: Clinical Practice Quality and Guidelines “Our guidelines condense knowledge into clinical recommendations. In an ideal world, the guidelines would be linked to outcomes measures to determine not only how one should proceed in a certain situation, but to establish whether following this recommendation would achieve an outcome that will improve clinical results,” Dr. Yu said, explaining that a computerized clinical decision support instrument is necessary to get full value from the guidelines.

“We should not expect a busy clinician to go to the ASCO site and open a 100-page guideline document, breeze through it and return to the patient with a treatment decision. It needs to be a

Peter Paul Yu, MD

seamless computerized process, in which the EHR has the software to instantly mine the data and guidelines and make the recommendation,” Dr. Yu said.

The outcomes from that individual patient would then be uploaded into a knowledge-based registry such as the Quality Oncology Practice Initiative (QOPI ®), where we can perform analytics that in turn would feed the digested data back into the guidelines, creating an organic system of continual updates. “We’re a long way off from a seamless guidelines-to-patient process,” he conceded.

Dr. Yu reviewed challenges to the existing ASCO Guidelines process, many of which relate to the time and resources required to conduct a systematic review of the literature. He cited the need for future efforts to integrate outcomes measurement and identify and fill knowledge gaps, along with a development process that ensures that recommendations are integrated into EHRs to most successfully inform daily cancer care. Moreover, he pointed out that the QOPI quality assessment process is constrained by a number of factors, such as being chart abstraction–based and retrospective, rather than real-time.

“To rework cancer care delivery into a rapid-learning system will take sociotechnologic change, with an emphasis on the societal arm. We need greater precision, and that means developing computer-based clinical decision support tools that can help us analyze, measure, and deliver much better health and economic outcomes,” Dr. Yu stressed.

Model B: Clinical Trials and Personalized Medicine “The core principle of model B is that we learn from every patient on trial. However, clinical trials are not patient-centric, they are not rapid, and nonresponders and rare responders are ignored. In short, trials are more about the drugs than the patients,” Dr. Yu commented.

To move toward a personalized health model, Dr. Yu said it is incumbent to learn from complex molecular data, and we need to make randomized clinical trials rapid-learning. “EHRs that can access molecular data and are certified for clinical research are an essential component in reshaping our clinical trial system. We also need more pragmatic trial design and health information exchanges,” Dr. Yu said.

Dr. Yu emphasized that to develop a rapid-learning health-care system, we need to follow and learn from individual patients; those experiences generate population data that inform health and economic outcomes. “Simply put, rapid-learning conflates high-grade research and routine health-care delivery,” Dr. Yu concluded.

■

Disclosure: Dr. Yu and Mr. Etheredge reported no potential conflicts of interest.

First Genomic-based Pediatric Trials Launched in Neuroblastoma

Dell donates funding and supercomputing technology to expedite personalized medicine trials for children with neuroblastoma.

By Jo Cavallo

L

ast November, Dell announced it was donating an initial $4 million including cloud-computing technology to speed up development of personalized medicine trials for children with neuroblastoma and other pediatric cancers. According to the American Cancer Society, about 650 children under the age of 15 are diagnosed with neuroblastoma each year. It is the second most common tumor in children and the most common cancer in babies less than 1 year old. Although

5-year survival rates for children with low- and intermediate-risk neuroblastoma is higher than 95%, only between 40% and 50% of children with highrisk neuroblastoma survive long-term.

The disease is responsible for one in seven pediatric cancer deaths.

To increase survival rates, researchers need the ability to analyze a patient’s genomic profile quickly and then determine highly targeted, effective therapies for that patient’s tumor type, said Giselle Sholler, MD, Chair

Consortium (NMTRC); Co-director of the Van Andel Research Institute (VARI) Pediatric Cancer Translational Research Program; and Director of the Haworth Family Pediatric Oncology Innovative Therapeutics Clinic at the Helen DeVos Children’s Hospital in Grand Rapids, Michigan.

Giselle Sholler, MD

of the Neuroblastoma and Medulloblastoma Translational Research

Pilot Study To accomplish that goal, last spring, Dr. Sholler launched the first genomiccontinued on page 64

In Advanced Renal Cell Carcinoma...

Indication VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Important Safety Information WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

• Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

• QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of

electrolytes within the normal range should be performed.

• Hemorrhagic Events: Fatal hemorrhagic events have been reported (all Grades [16%] and Grades 3 to 5 [2%]). VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients.

• Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all Grades [3%] and Grades 3 to 5 [2%]) were observed. Use with caution in patients who are at increased risk for these events.

• Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula.

• Hypertension: Hypertension, including hypertensive crisis, has been observed. Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed.

Hypertension was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite

Move Forward With VOTRIENT In a phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1,3

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines® Category 1 recommendation4 • As a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology . These Guidelines also include therapies other than VOTRIENT as first-line treatment options

WARNING: HEPATOTOXICITY

Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

VOTRIENT: Safety Profile Summary1 • Most common adverse events observed with VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% of patients — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14% of patients • For any individual adverse reaction in the VOTRIENT arm, the rate of Grade 3/4 adverse events is ≤4%

Most common laboratory abnormalities were ALT and AST increases1 • Grade 3 ALT increases occurred in 10% of patients; grade 4, 2% of patients • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the first 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated.

Periodic monitoring should then continue after this time period

anti-hypertensive therapy and dose reduction of VOTRIENT. • Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence.

• Hypothyroidism: Hypothyroidism was reported as an adverse reaction in 26/586 (4%). Monitoring of thyroid function tests is recommended.

• Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria.

• Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors.

• CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. • CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

• Adverse Reactions: The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs. 9%), hypertension (40% vs. 10%), hair color changes (depigmentation) (38% vs. 3%), nausea (26% vs. 9%), anorexia (22% vs. 10%), and vomiting (21% vs. 8%).

• Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in the VOTRIENT arm versus placebo included increases in ALT (53% vs. 22%), AST (53% vs. 19%), glucose (41% vs. 33%), and total bilirubin (36% vs. 10%); decreases in phosphorus (34% vs. 11%), sodium (31% vs. 24%), magnesium (26% vs. 14%), and glucose (17% vs. 3%); and leukopenia (37% vs. 6%), neutropenia (34% vs. 6%), thrombocytopenia (32% vs. 5%), and lymphocytopenia (31% vs. 24%).

• VOTRIENT has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (<1%).

Please see Brief Summary of Prescribing Information on adjacent pages.

References: 1. VOTRIENT Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061–1068. 3. Data on file, GlaxoSmithKline.

4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.1.2012. © National Comprehensive Cancer Network, Inc 2011. All rights reserved. Accessed November 17, 2011. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

www.VOTRIENT.com

The ASCO Post | JANUARY 15, 2012

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News

Genomic-based Pediatric Trials continued from page 61

based personalized medicine pediatric cancer trial in neuroblastoma. “The program developed over the past 5 years while we were profiling all of our neuroblastoma patients by isolat-

ing the neruoblastoma cells from their bone marrow and noticing that they had very different tumor profiles,” says Dr. Sholler.

Dr. Sholler worked with Craig Webb, PhD, Co-director of VARI’s Pediatric Cancer Translational Research Program, who developed the com-

puter algorithms to analyze the RNA expression of the tumors of each of the five patients in a pilot study, completed in 2010, and then found drugs that targeted each tumor type. All of the children had relapsed from front-line therapy and had no other therapeutic options.

BRIEF SUMMARY VOTRIENT (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information.

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies.

Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).]

1 INDICATIONS AND USAGE VOTRIENT™ is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information].

The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. [See Clinical Pharmacology (12.3) of full prescribing information.]

If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. The dose of VOTRIENT should not exceed 800 mg. Hepatic Impairment: The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day. There are no data in patients with severe hepatic impairment; therefore, use of VOTRIENT is not recommended in these patients. [See Use in Specific Populations (8.6).] Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. [See Drug Interactions (7.1).] Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided.

VOTRIENT should not be used in patients who can not avoid chronic use of strong CYP3A4 inducers. [See Drug Interactions (7.1).]

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed [see Adverse Reactions (6.1)]. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Across all monotherapy studies with VOTRIENT, ALT >3 X upper limit of normal (ULN) was reported in 138/977 (14%) and ALT >8 X ULN was reported in 40/977 (4%) of patients who received VOTRIENT. Concurrent elevations in ALT >3 X ULN and bilirubin >2 X ULN regardless of alkaline phosphatase levels were detected in 13/977 (1%) of patients.

Four of the 13 patients had no other explanation for these elevations. Two of 977 (0.2%) patients died with disease progression and hepatic failure.

Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information].

Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. The safety of VOTRIENT in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT, is unknown. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment.

[See Dosage and Administration (2.2) and Use in Specific Populations (8.6).]

“The Institutional Review Board wanted us to be able to get the data back in real time because neuroblastoma tumors grow so quickly. Our goal was to be able to do a biopsy of each patient’s tumor, analyze the data from the gene-expression profile, generate a report, and then bring together mem-

5.2 QT Prolongation and Torsades de Pointes: In clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the monotherapy studies. In the randomized clinical trial, 3 of the 290 patients receiving VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) [see Adverse Reactions (6.1)]. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients.

5.4 Arterial Thrombotic Events: In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been observed in 2/586 (0.3%). In the randomized study, these events were observed more frequently with VOTRIENT compared to placebo [see Adverse Reactions (6.1)]. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months and should not be used in those patients. 5.5 Gastrointestinal Perforation and Fistula: In clinical RCC studies of VOTRIENT, gastrointestinal perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal perforation or fistula.

5.6 Hypertension : In clinical studies, events of hypertension including hypertensive crisis have occurred. Blood pressure should be well-controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension and treated as needed with anti-hypertensive therapy. Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). [See Adverse Reactions (6.1).] In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see Dosage and Administration (2.2)].

VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. 5.7 Wound Healing: No formal studies on the effect of VOTRIENT on wound healing have been conducted.

Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.8 Hypothyroidism: In clinical RCC studies of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 (4%) [see Adverse Reactions (6.1)]. Proactive monitoring of thyroid function tests is recommended. 5.9 Proteinuria: In clinical RCC studies with VOTRIENT, proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 (<1%) and Grade 4, 1/586 (<1%)] [see Adverse Reactions (6.1)]. Baseline and periodic urinalysis during treatment is recommended. VOTRIENT should be discontinued if the patient develops Grade 4 proteinuria. 5.10 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman.

Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. [See Use in Specific Populations (8.1).]

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

Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, hemorrhagic events, arterial thrombotic events, gastrointestinal perforation and fistula, and hypertensive crisis [see Warnings and Precautions (5.1-5.5)]. The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and

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bers of our molecular tumor board, which includes researchers, oncologists, pharmacists, bioinformaticians, pathologists, and radiologists. The board would discuss each patient’s clinical care so far, the status of the patient, and, based on the report, the list of drugs that target the patient’s

tumor, so that we could create an individual treatment plan. All of this would be done in less than 2 weeks,” said Dr. Sholler.

Larger Trial A larger 14-patient trial opened last summer at five centers by the NMTRC

vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebocontrolled study [see Clinical Studies (14) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received VOTRIENT

Adverse Reactions Diarrhea Hypertension Hair color changes Nausea Anorexia Vomiting Fatigue Asthenia Abdominal pain Headache a

VOTRIENT

Placebo

(N = 290)

(N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 52 3 <1 9 <1 0 40 4 0 10 <1 0 38 <1 0 3 0 0 26 <1 0 9 0 0 22 2 0 10 <1 0 21 2 <1 8 2 0 19 2 0 8 1 1 14 3 0 8 0 0 11 2 0 1 0 0 10 0 0 5 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N = 290)

Parameters Hematologic Leukopenia Neutropenia Thrombocytopenia Lymphocytopenia Chemistry ALT increased AST increased Glucose increased Total bilirubin increased Phosphorus decreased Sodium decreased Magnesium decreased Glucose decreased a

Placebo (N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 37 34 32 31

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53

10 7

2 <1

22 19

1 <1

0 0

41

<1

0

33

1

0

36

3

<1

10

1

<1

34

4

0

11

0

0

31

4

1

24

4

0

26

<1

1

14

0

0

17

0

<1

3

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

in collaboration with Intervention Insights—there are 11 clinical trial sites nationwide and 7 more are expected to open this year—and three neuroblastoma patients have enrolled so far.

Implementation of Dell’s cloud supercomputer, which is 1,200% faster than the current technology in use at

Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo.

Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration (2.2) of full prescribing information and Warnings and Precautions (5.1).]

Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo. The majority of cases of hypertension were manageable with anti-hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. VOTRIENT has been associated with hypertensive crisis in patients with various cancer types including RCC. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions (5.6).] QT Prolongation and Torsades de Pointes: In a controlled clinical study with VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings and Precautions (5.2).] Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions (5.4).] Hemorrhagic Events: In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions (5.3).] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with VOTRIENT. Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any post-baseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively).

Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See Warnings and Precautions (5.8).] Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. [See Warnings and Precautions (5.9).] Lipase Elevations: In a single-arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%). Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%).

7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations. A dose reduction for VOTRIENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and Administration (2.2)].

the Translational Genomics Research Institute (TGen), where the data is stored, will allow Dr. Sholler to not only sequence each patient’s RNA expression profile, but his DNA expression profile as well, in less time.

“Sequencing itself takes about 2 continued on page 66

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; JANUARY 15, 2012

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Genomic-based Pediatric Trials continued from page 65

weeks, but the analysis that takes time too. Right now, 2Â months is the quickest we can get good data to make clinical decisions. The supercomputer will shorten that time to about 2 weeks

for RNA sequencing and 1 month for DNA sequencing. We will make clinical decisions based on the RNA sequencing and expression and go through a cycle or two of therapy and then have our second molecular tumor board meeting, when we will have the DNA information as well and we can

7.2 Effects of Pazopanib on CYP Substrates Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing information.]

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.10)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of â&#x2030;Ľ3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossiďŹ cation. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses â&#x2030;Ľ3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses â&#x2030;Ľ30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses â&#x2030;Ľ100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses â&#x2030;Ľ3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses â&#x2030;Ľ3 mg/ kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses.

Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged â&#x2030;Ľ65 years, and 34 subjects (6%) were aged >75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identiďŹ ed differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established. In clinical studies for VOTRIENT, patients with total bilirubin â&#x2030;¤1.5 X ULN and AST and ALT â&#x2030;¤2 X ULN were included [see Warnings and Precautions (5.1)]. An interim analysis of data from 12 patients with normal hepatic function and 9 with moderate hepatic impairment showed that the maximum tolerated dose in patients with moderate hepatic impairment was 200 mg per day [see Clinical Pharmacology (12.3) of full prescribing information]. There are no data on patients with severe hepatic impairment [see Dosage and Administration (2.2)]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/ moderate renal impairment (creatinine clearance â&#x2030;Ľ30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to signiďŹ cantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/ min) did not inďŹ&#x201A;uence clearance of pazopanib. Therefore, renal impairment is not expected to inďŹ&#x201A;uence pazopanib exposure, and dose adjustment is not necessary.

reassess treatment options,â&#x20AC;? said Dr. Sholler.

Future of Personalized Medicine â&#x20AC;&#x153;We choose to fund the personalized medicine trials of the NMTRC because neuroblastoma is such a

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials.

Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no speciďŹ c antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not signiďŹ cantly renally excreted and is highly bound to plasma proteins.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages â&#x2030;Ľ30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses â&#x2030;Ľ10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given â&#x2030;Ľ100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given â&#x2030;Ľ300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC).

Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses â&#x2030;Ľ3 mg/kg/day, epididymal sperm concentrations at doses â&#x2030;Ľ30 mg/kg/ day, and sperm motility at â&#x2030;Ľ100 mg/kg/day following 15 weeks of dosing.

Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaďŹ&#x201A;et that accompanies the product. However, inform patients of the following: t 5IFSBQZ XJUI 7053*&/5 NBZ SFTVMU JO IFQBUPCJMJBSZ MBCPSBUPSZ abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the ďŹ rst 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away. t ZFMMPXJOH PG UIF TLJO PS UIF XIJUFT PG UIF FZFT KBVOEJDF

t VOVTVBM EBSLFOJOH PG UIF VSJOF t VOVTVBM UJSFEOFTT t SJHIU VQQFS TUPNBDI BSFB QBJO t (BTUSPJOUFTUJOBM BEWFSTF SFBDUJPOT TVDI BT EJBSSIFB OBVTFB BOE WPNJUJOH have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. t 8PNFO PG DIJMECFBSJOH QPUFOUJBM TIPVME CF BEWJTFE PG UIF QPUFOUJBM IB[BSE to the fetus and to avoid becoming pregnant. t 1BUJFOUT TIPVME CF BEWJTFE UP JOGPSN UIFJS IFBMUIDBSF QSPWJEFST PG BMM concomitant medications, vitamins, or dietary and herbal supplements. t 1BUJFOUT TIPVME CF BEWJTFE UIBU EFQJHNFOUBUJPO PG UIF IBJS PS TLJO NBZ occur during treatment with VOTRIENT. t 1BUJFOUT TIPVME CF BEWJTFE UP UBLF 7053*&/5 XJUIPVU GPPE BU MFBTU IPVS before or 2 hours after a meal).

VOTRIENT is a trademark of GlaxoSmithKline.

deadly cancer and we wanted to take the cancer and use it as the first model for how we will do this kind of pediatric research going forward,â&#x20AC;? said James M. Coffin, PhD, Vice President and General Manager of Dell Healthcare and Life Sciences. â&#x20AC;&#x153;This model of personalized medicine is transferable to every kind of cancer, and we expect to build one of the largest supercomputing platforms in the genomic field.â&#x20AC;?

Analysis of the genomic profiling will be done using software developed by VARIâ&#x20AC;&#x2122;s Pediatric Cancer Translational Research Program and TGen, which Dr. Sholler can then use to create a treatment plan for each patient, using FDA-approved drugs with known pediatric dosing for the specific tumor type. For this study, the FDA has approved the use of a combination of up to four drugs from any drug classification. â&#x20AC;&#x153;Our goal is to offer these children a good quality of life, and we are not leaning toward the use of high-dose chemotherapies. Instead, weâ&#x20AC;&#x2122;re looking at lower-dose targeted therapies in combination with maybe one or two chemotherapies,â&#x20AC;? said Dr. Sholler.

Although Dr. Shollerâ&#x20AC;&#x2122;s trials are the first attempt in personalized medicine for children with relapsed disease, if successful, genomic-based medicine for pediatric patients with cancer may eventually be used in the front-line setting, where the greatest chance for cure may be possible.

Improving Cure Rates â&#x20AC;&#x153;Once a child with neuroblastoma has relapsed, there is no curative therapy. We have been able with lowerdose therapies to extend the lives of these children over the past 5Â years. If we can understand whatâ&#x20AC;&#x2122;s driving the tumors, stop them from growing, and ultimately kill them, thatâ&#x20AC;&#x2122;s a cure,â&#x20AC;? Dr. Sholler said. â&#x20AC;&#x153;Iâ&#x20AC;&#x2122;m hoping that as we validate this type of methodology and bring this to upfront therapy, thatâ&#x20AC;&#x2122;s when weâ&#x20AC;&#x2122;re going to see the cure rates change.

Right now we treat all the kids with the same high-dose therapy, but only 50% are responding. Weâ&#x20AC;&#x2122;re not serving the other 50% very well,â&#x20AC;? she concluded.

â&#x2013;

Š2011, GlaxoSmithKline. All rights reserved.

Revised 10/2011 VTR:4BRS Š2011 The GlaxoSmithKline Group of Companies All rights reserved.

Printed in USA. VOT274R0 November 2011

For information about the Neuroblastoma & Medulloblastoma Translational Research Consortium (NMTRC) and a listing of clinical trial sites, visit NMTRC.org.

ASCOPost.com | JANUARY 15, 2012

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Calendar

2012 Oncology Meetings JANUARY 2012 Gastrointestinal Cancers Symposium January 19-21 • San Francisco, California For more information: www.asco.org

16th Annual International Congress on Hematologic Malignancies February 23-26 • Snowbird, Utah For more information: cancerlearning.onclive.com Fifth Annual Symposium on Personalized Therapies and Best Clinical Practices for Breast Cancer February 25 • Orlando, Florida For more information: www.bmli.com

Multidisciplinary Head and Neck Cancer Symposium January 26-28 • Phoenia, Arizona For more information: http:// headandnecksymposium.org

FEBRUARY American Society for Blood and Marrow Transplantation (ASBMT) and the Center for International Blood & Marrow Transplant Research (CIBMTR) February 1-5 • San Diego, California For more information: www.asbmt.org 14th International Symposium on AntiAngiogenic Therapy: Recent Advances and Future Directions February 2-4 • San Diego, California For more information: www.mdanderson.org 2012 Genitourinary Cancers Symposium February 2-4 • San Francisco, California For more information: www.asco.org 17th Annual Multidisciplinary Symposium on Breast Disease February 10-12 • Amelia Island, Florida For more information: http://cme.ufl.edu/msbd2012 4th Annual American College of Radiology Meeting: Leadership Strategies for Radiology 2012 February 12-17 • Vail, Colorado For more information: www.edusymp.com 12th Annual Targeted Therapies of the Treatment of Lung Cancer Meeting February 22-25 • Santa Monica, California For more information: http://iaslc.org

International Conference on Translational Research in RadioOncology and Physics for Health in Europe February 27-March 2 • Geneva, Switzerland For more information: http://ictr-phe12.web.cern.ch

MARCH ACR 5th Annual PET/CT Symposium March 1-4 • Stowe, Vermont For more information: www.acr.org 3rd Asian Breast Cancer Congress March 3-4 • Bangalore, India For more information: http://abcconline.net TAT 2012 (International Congress on Targeted AntiCancer Therapies) March 8-10 • Amsterdam, The Netherlands For more information: www.tatcongress.org 4th ESMO Sarcoma and GIST Conference March 9-10 • Milan, Italy For more information: www.esmo.org Society for Thoracic Radiology Thoracic Imaging Meeting March 11-14 • Huntington Beach, California For more information: www.thoracicrad.org ACCC 38th Annual National Meeting March 12–14 • Baltimore, Maryland For more information: http://accc-cancer.org 29th Annual Miami Breast Cancer Conference March 14-17 • Miami, Florida For more information: cancerlearning.onclive.com

NCCN 17th Annual Conference March 14-18 • Hollywood, Florida For more information: www.nccn.org

3rd European Lung Cancer Conference April 18-21 • Geneva, Switzerland For more information: www.esmo.org

Hematology/Oncology Pharmacy Association 8th Annual Meeting March 21-24 • Orlando, Florida For more information: www.hoparx.org

American Radium Society Annual Meeting April 28-May 2 • Las Vegas, Nevada For more information: www. americanradiumsociety.org

65th SSO Annual Meeting March 21-24 • Orlando, Florida For more information: www.surgonc.org Society of Interventional Radiology 37th Annual Meeting March 24-29.San Francisco, California For more information: www.sirmeeting.org Eighth International Symposium on Ovarian Cancer and Gynecologic Malignancies March 25-26 • New York, New York For more information: http:// cancerlearning.onclive.com 9th International Symposium on Ovarian Cancer and Other Gynecologic Malignancies March 30-31 • New York, New York For more information: http:// cancerlearning.onclive.com 5th Annual Interdisciplinary Prostate Cancer Congress March 31 • New York, New York For more information: http:// cancerlearning.onclive.com AACR 103rd Annual Meeting March 31-April 4 • Chicago, Illinois For more information: www.aacr.org

APRIL ASTRO Spring Refresher Course April 13-15 • Chicago, Illinois For more information: www.astro.org

American Roentgen Ray Society Annual Meeting April 29-May 4 • Vancouver, Canada For more information: www.arrs.org

MAY 4th IMPAKT Breast Cancer Conference May 3-5 • Brussels, Belgium For more information: www.esmo.org ONS 37th Annual Congress May 3-6 • New Orleans, Louisiana For more information: www.ons.org State of the Art Techniques in IMRT, IGRT, SBRT, Proton and Brachytherapy May 4-6 • Las Vegas, Nevada For more information: www.astro.org Accelerating Anticancer Agent Development and Validation Workshop May 16-18 • Bethesda, Maryland For more information: www. acceleratingworkshop.org AUA Annual Meeting May 19-23 • Atlanta, Georgia For more information: www.aua2012.org

JUNE ASCO Annual ’12 Meeting June 1-5 • Chicago, Illinois For more information: chicago2012.asco.org

35th National Conference on Breast Cancer April 13-15 • Hollywood, Florida For more information: www.acr.org

continued on page 68

The ASCO Post | JANUARY 15, 2012

PAGE 68

Calendar 2012 Oncology Calendar continued from page 67

AUGUST

ASHP 2012 Summer Meeting June 9-13 • Baltimore, Maryland For more information: www.ashpmedia.org

Best of ASCO® Boston August 3-4 • Boston, Massachusetts For more information: http://boa2012.asco.org

JULY Best of ASCO® Chicago July 12-13 • Chicago, Illinois For more information: http://boa2012.asco.org

Best of ASCO® San Diego August 10-11 • San Diego, California For more information: http://boa2012.asco.org

Pan Pacific Lymphoma Conference July 17-20 • Lahaina, Maui, Hawaii For more information: unmc.edu/panpacififlymphoma

10th International Coress on Targeted Therapies in Cancer August 10-12 • Washington, DC For more information: http://cancerlearning.onclive.com

13th International Lung Cancer Congress July 19-22 • Huntington Beach, California For more information: http://cancerlearning.onclive.com 5th Latin American Lung Cancer Conference July 25-27 • Rio De Janeiro, Brazil For more information: www.lalca2012.org 11th International Congress on the Future of Breast Cancer July 26-28 • Coronado, California For more information: http://cancerlearning.onclive.com

2012 Breast Cancer Symposium September 13-15 • San Francisco, California For more information: http://breastcasym.org

ASTRO’s 54th Annual Meeting October 28-31 • Boston, Massachusetts For more information: www.astro.org

8th Annual Symposium on Controversies and Clinical Challenges in Myeloma, Lymphoma, and Leukemia September 21-23 • Pasadena, California For more information: http://cancerlearning.onclive.com

NOVEMBER

37th ESMO Congress September 28-October2 • Vienna, Austria For more information: www.esmo.org

OCTOBER ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: http://accc-cancer.org

SEPTEMBER Multidisciplinary Symposium in Thoracic Oncology September 6-8 • Chicago, Illinois For more information: http://thoracicsymposium.org 9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

2012

Lymphoma Conference

Hyatt Regency Maui Resort & Spa Lahaina, Maui, Hawaii

A comprehensive conference by internationally recognized speakers presenting the most recent developments in lymphoma and transplantation.

Conference Directors James O. Armitage, MD

Joe Shapiro Professor of Medicine Division of Oncology and Hematology Department of Internal Medicine University of Nebraska Medical Center

32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org

CALL FOR ABSTRACTS: April 16, 2012

Scan code with your smartphone to learn more!

Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org American College of Gastroenterology Annual Scientific Meeting October 19-24 • Las Vegas, Nevada For more information: http://gi.org

Julie M. Vose, MD, MBA

Chief, Division of Oncology and Hematology Neumann M. and Mildred E. Harris Professor Department of Internal Medicine University of Nebraska Medical Center

unmc.edu/panpacificlymphoma

AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org

American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org

Tuesday-Friday

July 17-20, 2012

7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com

Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http:// chemotherapyfoundationsymposium.org

14th Annual Lynn Sage Breast Cancer Symposium October 4-7 • Chicago, Illinois For more information: www.lynnsagebreastcancer

Pan Pacific

8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, UK For more information: www.siog.org 9th Annual School of Breast Oncology October 25-28 • Atlanta, Georgia For more information: http://cancerlearning.onclive.com

Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/ 5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp

DECEMBER 35th Annual San Antonio Breast Cancer Symposium December 4-8 • San Antonio, Texas For more information: www.sabcs.org 2012 ASH Annual Meeting December 8-11 • Atlanta, Georgia For more information: www.hematology.org

Now Approved

Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1 • Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1 These indications are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

A new therapeutic alternative for relapsed patients

73% objective response rate (95% CI: 65%-83%) in HL1 86% objective response rate (95% CI: 77%-95%) in sALCL1 Peripheral neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for neuropathy and institute dose modifications accordingly.1

Infusion reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be discontinued immediately and appropriate medical management instituted.1

Please see Brief Summary of full Prescribing Information on the last page of this ad.

Please see full Prescribing Information at ADCETRIS.com.

ADCETRIS is the first approved CD30-directed antibody-drug conjugate (ADC)

Antibody The antibody, brentuximab, specific for CD301

Cytotoxic agent

Linker A synthetic protease-cleavable linker that covalently attaches MMAE to the CD30-directed antibody and releases the agent within the target cell1

The synthetic microtubuledisrupting agent, monomethyl auristatin E (MMAE, vedotin), that induces target cell death1

CD30 is prevalent in both HL and sALCL2 • ADCETRIS is an ADC designed to target cells expressing CD301 • Binding of ADCETRIS to CD30 on the cell surface initiates internalization of the ADC-CD30 complex1 • Inside the cell, MMAE is released via proteolytic cleavage1 • Binding of released MMAE to tubulin disrupts the microtubule network, inducing apoptotic cell death1

Neutropenia Single-agent ADCETRIS was evaluated in two pivotal, phase 2, open-label, single-arm, multicenter trials:

Monitor complete blood counts prior to each dose of ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.1

• 102 patients with HL who relapsed after ASCT1

Tumor lysis syndrome

• 58 patients with relapsed sALCL1 ADCETRIS 1.8 mg/kg was administered intravenously over 30 minutes every 3 weeks.1 Assessment of efficacy included objective response rate (complete remission plus partial remission) and duration of response evaluated by an independent review facility based on measures defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).1,3

Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.1

Stevens-Johnson syndrome Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.1

Progressive multifocal leukoencephalopathy (PML) A fatal case of PML has been reported in a patient who received four chemotherapy regimens prior to receiving ADCETRIS.1

Please see Brief Summary of full Prescribing Information on the last page of this ad.

Please see full Prescribing Information at ADCETRIS.com.

ADCETRIS induced complete and partial remissions in clinical trials1 Efficacy and safety in relapsed patients1 Relapsed HL

Relapsed sALCL

Median treatment duration: 27 weeks

Median treatment duration: 24 weeks

(N = 102)

Duration of response in months

Response, % (95% CI)

Range

32

20.5

1.4-21.9+

(23-42)

(12.0-NE*)

Partial remission (PR)

*Median duration of treatment.

40

3.5

(32-49)

(2.2-4.1)

1.3-18.7

73

6.7

(65-83)

(4.0-14.8)

Duration of response in months

Response, % (95% CI)

Median (95% CI)

Complete remission (CR)

Objective response rate (ORR)

(N = 58)

1.3-21.9+

Median (95% CI)

Range

57

13.2

0.7-15.9+

(44-70)

(10.8-NE*)

29

2.1

(18-41)

(1.3-5.7)

86

12.6

(77-95)

(5.7-NE*)

0.1-15.8+ 0.1-15.9+

*Not estimable. +Follow-up was ongoing at the time of data submission.

• ADCETRIS demonstrated efficacy in sALCL patients with poor prognosis1 – 72% of sALCL patients had anaplastic lymphoma kinase (ALK)-negative disease, which has a worse prognosis than ALK-positive disease1,4

Adverse reactions occurring in ≥20% of patients regardless of causality1

Adverse Reaction

Neutropenia Peripheral sensory neuropathy Fatigue Nausea Anemia Upper respiratory tract infection Diarrhea Pyrexia Rash Thrombocytopenia Cough Vomiting

HL (N = 102)

sALCL (N = 58)

% of patients

% of patients

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3

Grade 4

54 52 49 42 33 47 36 29 27 28 25 22

15 8 3 8 1 2 7 -

6 2 2 -

55 53 41 38 52 12 29 38 31 16 17 17

12 10 2 2 2 3 2 5 3

9 2 5 -

• 21% of patients discontinued therapy due to treatment-emergent adverse reactions1

Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity1 Recommended dose is 1.8 mg/kg administered only as an IV infusion over 30 minutes every 3 weeks1 • Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions1 • Complete blood counts should be monitored prior to each dose of ADCETRIS1

Most PN was Grade 1 or 2—no Grade 4 PN events were observed1 • 54% of patients experienced peripheral neuropathy (PN) in the pivotal trials1 • Grade 3 PN (sensory) was reported by 8% and 10% of patients in the HL and sALCL trials, respectively1 – 8% discontinued due to peripheral sensory neuropathy1 • Grade 3 PN (motor) was reported by 4% and 3% of patients in the HL and sALCL trials, respectively1 – 3% discontinued due to peripheral motor neuropathy1

Monitor patients for PN and institute dose modification accordingly1 New or worsening Grade 2 or 3

• Hold dose until PN improves to Grade 1 or baseline and then restart at 1.2 mg/kg

Grade 4

• Discontinue ADCETRIS

Improvement or resolution of PN symptoms was observed in the majority of patients during follow-up1: • 49% had complete resolution • 51% had residual PN at time of last evaluation (31% partial improvement, 20% no improvement)

Neutropenia should be managed by dose delay and reduction1 Grade 3 or 4 Recurrent Grade 4 despite use of growth factors

• Hold dose until resolution to baseline or Grade 2 or lower • Consider growth factor support for subsequent cycles • Discontinue or reduce dose to 1.2 mg/kg

Please see Brief Summary of full Prescribing Information on adjacent page.

Please see full Prescribing Information at ADCETRIS.com.

REFERENCES: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2011. 2. Haluska FG, Brufsky AM, Canellos GP. The cellular biology of the Reed-Sternberg cell.

Blood. 1994;84(4):1005-1019. 3. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol.

2007;25(5):579-586. 4. Savage KJ, Harris NL, Vose JM, et al; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496-5504.

855.4SEAGEN (855.473.2436) SeaGenSecure.com

ASCOPost.com | JANUARY 15, 2012

PAGE 73

Opinion

Thin Melanomas continued from page 2

set (which itself is a leap of faith), one would have to perform well over 300 sentinel lymph node biopsies to benefit one patient. As the addition of sentinel lymph node biopsy to wide excision significantly increases both the

melanoma—those patients most likely to benefit from the procedure.4,5 At this time, our efforts and resources are better spent addressing the utilization of sentinel lymph node biopsy among this population. In addition, we should continue our attempts to identify clinical, molecular, or proteomic markers

costs and the morbidity, it is difficult to justify this approach.

Conclusions Data from large national databases suggest that sentinel lymph node biopsy is only being used in a fraction of patients with intermediate-thickness

associated with a sufficient risk of regional metastases among patients with melanomas < 0.75 mm so as to identify a subset of those who should be offered the procedure. Until that time, the standard recommendations for sentinel lymph node biopsy (melanoma ≥ 1 mm or 0.76–0.99 mm with adverse features) should not be extended to include all T1b patients.

■

Disclosure: Dr. Sabel reported no potential conflicts of interest

Brief Summary of Prescribing Information

Drug interactions

(see Package Insert for full Prescribing Information)

In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Indications and usage

Effect of other drugs on ADCETRIS

These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.

ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications: None.

Warnings and precautions Peripheral neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions.

Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia

Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Stevens-Johnson syndrome

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Progressive multifocal leukoencephalopathy

A fatal case of progressive multifocal leukoencephalopathy (PML) has been reported in a patient who received 4 chemotherapy regimens prior to receiving ADCETRIS.

Use in pregnancy

There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritis, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased.

ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting.

The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specific populations Pregnancy

Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

References 1. Balch CM, Gershenwald JE, Sengjaw S, et al: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199-6206, 2009.

2. Morton DL, Thompson JF, Cochran AJ, et al: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355:1307-1317, 2006.

3. Andtbacka RH, Gershenwald JE: Role of sentinel lymph node biopsy in patients with thin melanoma. J Natl Compr Canc Netw 7:307-317, 2009.

4. Lane K, Kempf A, Magno C, et al: Regional differences in the use of sentinel lymph node biopsy for melanoma: A potential quality measure. Am Surg 74:981984, 2008.

5. Bilimoria KY, Balch CM, Wayne JD, et al: Health care system and socioeconomic factors associated with variance in use of sentinel lymph node biopsy for melanoma in the United States. J Clin Oncol 27:1857-1863, 2009.

Nursing mothers It is not known whether brentuximab vedotin 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 ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

The safety and effectiveness of ADCETRIS have not been established in the pediatric population.

Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal impairment

The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment

The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Dosage and administration

The ASCO Post Wants to Hear from You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com.

General dosing information

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

Dose modification

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued.

Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2011 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA

US/BV/2011/0029

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

The ASCO Post | JANUARY 15, 2012

PAGE 74

Spotlight on Research Thoracic Oncology

Studies Reveal that Hormonal Factors Influence Lung Cancer Risk in Women A Conversation with Christina S. Baik, MD, MPH

By Jo Cavallo

Basis for Research

Christina S. Baik, MD, MPH

I

n an effort to understand lung cancer risk factors and develop prevention strategies for the disease, Christina S. Baik, MD, MPH, thoracic oncologist and staff scientist at the Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center, has examined epidemiologic trends in lung cancer, including the role that hormones may play in making women more vulnerable to the disease. She is particularly interested in lung cancer development among women who have never smoked.

Three years ago, with support from the Lung Cancer Research Foundation, Dr. Baik studied the associations among reproductive factors, the use of hormone replacement therapy, and lung cancer incidence in women participating in the Nurses’ Health Study. Dr. Baik assessed a number of factors, including age at menopause, age at menarche, age at first birth, postmenopausal use of hormone replacement therapy, and past oral contraceptive use, as well as smoking history. The results from her study demonstrated that female hormones may influence lung carcinogenesis.1 Although the effect appeared to be small, the results correspond to the findings of other studies showing a potential link between hormones and lung cancer in women.

The ASCO Post spoke with Dr. Baik about her work in identifying the risk factors for lung cancer in women and the need to continue research in this area.

What compelled you to study the role hormones may play in the development of lung cancer?

For many years, researchers have suspected that the causes of lung cancer in women may be different from the causes of lung cancer in men. And that suspicion is based on epidemiologic data showing that the proportion of lung cancer in women in the United States who have never smoked is between 15% and 20%, compared to 10% in men who have never smoked. Some reports even suggest that as much as 50% of lung cancers in women globally, especially in East Asia, could be

laboratory studies, it looks like estrogen does affect lung cancer, so there is some biologic explanation.

We know that female hormones and some reproductive factors are associated with breast cancer. I was curious to find out whether there was a similar association in lung cancer in women. who were followed for nearly 22 years as part of the Nurses’ Health Study, we found that among neversmokers, the more children a woman had, the less risk she had for developing lung cancer. That finding is actually similar to what we see in breast cancer incidence, but we don’t know whether the mechanism is the same.

Based on the analysis of about 100,000 postmenopausal women, we found that among never-smokers, the more children a woman had, the less risk she had for developing lung cancer. coming from never-smokers. These are rough estimates, but we certainly see a lot of Asian women coming into our clinic with lung cancer who have never smoked.

Based on these observations, many researchers began to ask the question, is there a relationship between the female hormones estrogen and progesterone and lung cancer? That’s when I started to become interested in studying the possible connection as well.

Underlying Mechanism Is there a theory about why estrogen and progesterone potentially raise a woman’s risk for lung cancer?

Researchers have looked into estrogen and progesterone receptors in lung cancer in both lung cancer–derived human cell lines and in actual tumor specimens from patients and found estrogen receptor expression in the lung cancers.

In mouse studies where ovariectomized mice were treated with estradiol, the mice also developed lung cancer, and when they were given antiestrogens it reversed the process. Based on the data from the mouse studies and early

Hormone Replacement Therapy Did you find an increase in risk for lung cancer among women taking hormone replacement therapy as well?

We were interested in looking into the effect of hormone replacement therapy on lung cancer within the Nurses’ Health Study cohort, and we found that there is likely an increased risk of developing the disease—especially the adenocarcinoma subtype— but the findings were not statistically significant. Data from the Women’s Health Initiative (WHI), which looked at the role of hormone replacememt therapy in older postmenopausal women, also showed some increase in lung cancer incidence, although, similar to our study, it was not statistically significant. The WHI study did find, however, that hormone replacement use increased lung cancer mortality.

So, it looks like estrogen alone or estrogen and progesterone together have some effect in lung cancer development and progression, but there is a lot more we need to understand about the role of female hormones in lung

cancer. One interesting finding from the WHI study was that there was no increase in lung cancer rates—or in breast cancer rates—in the estrogenonly arm.

Role of Progesterone Is progesterone, then, the potential culprit in the development of these cancers?

It is a possibility. Progesterone has been shown to promote angiogenesis in cancers, and maybe that is what makes cancers more aggressive, or there may be a synergistic effect with estrogen. We still have to sort all this out.

Something about lung cancer makes it behave like a hormone-driven cancer. Of course, smoking is the main cause of lung cancer, but it appears that there are other factors that play a big part in its development as well.

Much to Clarify According to the American Cancer Society, lung cancer affects slightly more men than women [115,060 vs 106,070 new cases annually], but research may be showing that women are at greater risk for developing the disease. Does that add more credence to the theory that lung cancer is hormone-driven?

Possibly. Some studies show that women may be more sensitive to tobacco, but other studies dispute that, so it is unclear whether women are at higher risk from cigarettes or from other factors in addition to cigarettes. Also, whether women actually have a higher risk of developing lung cancer than men is not clear. I think the important thing is to recognize that there are risk factors that are specific in women and in men and develop specific preventative strategies that address those risk factors.

■

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

Reference 1. Baik CS, Strauss GM, Speizer FE, et al: Reproductive factors, hormone use, and risk for lung cancer in postmenopausal women, the Nurses’ Health Study. Cancer Epidemiol Biomarkers Prev 19:25252533, 2010.

NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia.

A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • It has been observed that patients with platelet counts <200 X 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment.

Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions.

Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections.

Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration].

Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother Please see Brief Summary of Full Prescribing Information on the following page.

Jakafi is a trademark of Incyte Corporation. © 2011, Incyte Corporation. All rights reserved.

RUX-1004C

11/11

The ASCO Post | JANUARY 15, 2012

PAGE 76

In the News Supportive Care

Outpatients Need to Be Aware of High Risk of Developing Venous Thromboembolism

By Charlotte Bath

M

ost

patients

who

develop

venous thromboembolisms 7 JK0 BS 12P_Layout 1 11/16/11 9:16 AM Page 1 (VTE) while being treated for can-

cer, do so as outpatients, according to results of a retrospective, observational study comparing the incidence

of VTE among inpatients and outpatients with cancer. Yet many outpatients do not even realize that they are

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.

A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Issued: November 2011 RUX-1040

a risk for venous thromboembolism, noted the study’s lead investigator, Alok Khorana, MD, Associate Professor of Medicine and Vice-Chief, Division of Hematology/Oncology, James P. Wilmot Cancer Center, University of Rochester Medical Center in Rochester, New York. By educating patients about the risks of venous thromboembolism and encouraging them to alert their treatment team if signs or symptoms develop, physicians can help reduce related morbidity and even mortality, while answering the Surgeon General’s Call to Action to reduce the public health burden of VTEs. Of the 17,784 patients with cancer identified using a linked database, 996 (5.6%) developed blood clots. A much higher proportion of venous thromboembolism was diagnosed in outpatients than in inpatients (78.3% vs 21.7%). The results were presented in abstract form at the American Society of Hematology 2011 Annual Meeting.

Dr. Khorana and his research team are now working on the full study report, which they hope to complete in mid2012 and submit for publication.

Life-threatening Complication “It’s really important to make sure patients are aware that VTE is a problem,” Dr. Khorana said. “Right now, most patients don’t even understand that this is a complication that they could develop. And it’s a life-threatening complication. About 1 in 10 patients with cancer will die of a venous or arterial blood clot.”

Acknowledging that physicians are doing a good job educating patients about other possible complications of treatment, such as nausea, vomiting, infections, and fever, Dr. Khorana said that venous thromboembolism also needs “to enter the discussion and be more firmly rooted in the patient education program.” This should include the risk of VTE, the warning signs and symptoms, and “when to call us if any of those signs or symptoms occur,” he explained (see sidebar, Expect Questions from Your Patients).

The risk factors for blood clots among outpatients appear to differ from those among inpatients, Dr. Khorana said. “Typically, we thought our inpatients—who were sicker, less mobile, and laying in bed all the time—

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In the News were more susceptible to blood clots.

But the patients I typically see in the clinic who get blood clots are just as active as the rest of my patients with cancer,” Dr. Khorana noted.

“It is a whole different set of risk factors,” he continued. “Certain patients with cancer are much more likely to get clots, regardless of their mobility. We think it’s really a combination of the type of cancer and the types of chemotherapy and other systemic therapeutics that we are using.” These include agents like thalidomide (Thalomid), lenalidomide (Revlimid), and bevacizumab (Avastin), Dr. Khorana said. In addition, the study identified the use of doxorubicin as a significant predictor of venous thromboembolism.

Patients whose primary site of cancer is the stomach, pancreas, brain, or testicles were shown by the study to be at higher risk of developing VTE. In an interview with The ASCO Post, Dr. Khorana said that there is also an increased risk of venous thromboembolism among patients with hematologic malignancies.

“We typically think of blood clots as occurring in patients with solid tumors, but patients with hematologic malignancies, especially lymphoma

and myeloma, also have a high rate of clots,” Dr. Khorana noted. “Patients with cancer who develop blood clots are more likely to get another one,” he added.

The study also identified a history of pulmonary disease as a predictor of venous thromboembolism. “Patients who have other medical problems are more likely to get clots, and that includes lung disease, for example, having chronic obstructive pulmonary disease, emphysema, or asthma. Those types of pulmonary illnesses increase the risk, not just for pulmonary embolism, but for any clot,” Dr. Khorana said.

Prophylaxis Not Recommended Patients who have signs and symptoms of venous thromboembolism, such as swelling in one leg, a sudden onset of chest pain, or shortness of breath, should be encouraged to report and discuss these symptoms with a member of their cancer treatment team as soon as possible, Dr. Khorana advised.

Most patients who develop these symptoms as outpatients will not be receiving anticoagulants. “And it is not clear that everybody should,” Dr. Kho-

Clinical Trials of VTE Prophylaxis for Outpatients

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everal studies are investigating low-molecularweight heparins to reduce the risk of venous thromboembolism (VTE) among patients with cancer. “I enrolled patients in SAVE-ONCO,” Alok Khorana, MD, said, “but that trial used drug called semuloparin, which is not currently available in the United States.”

Two European studies involve patients with pancreatic cancer and are testing the low-molecAlok Khorana, MD ular-weight heparins enoxoparin (Lovenox) and dalteparin (Fragmin). Both of these agents are available in the United States. “Once we have full information from these studies, I think the guideline committees are going to take a look at the results and make some new recommendations on outpatient prophylaxis,” Dr. Khorana said.

University of Rochester Study Dr. Khorana’s research group at the University of Rochester is funded by the NIH to study outpatient prophylaxis. They use a risk score system to identify outpatients at higher risk of venous thromboembolism.

“It’s based not just on the type of cancer, but also on other leveraging factors, like white cell count, platelet count, and hemoglobin, as well as body mass index,” Dr. Khorana explained. “If you reach 3 points, either by having a high-risk type of cancer or a combination of these factors, you are at high risk for VTE,” he said.

“In our study, we are randomly assigning just the high-risk patients to observation vs dalteparin, which is a low-molecular-weight heparin. The study is ongoing, and we won’t have results until the end of 2013,” he said. “Right now, the study is open at our institution and at Duke, and we expect more centers to be added in the next month or so.” Total anticipated enrollment is 229.

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Expect Questions from Your Patients

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he current lack of awareness about the high risk of venous thromboembolism (VTE) among people being treated for cancer as outpatients means “there’s a great role for provider education,” Alok Khorana, MD, told The ASCO Post. Here are Dr. Khorana’s answers to some likely questions from patients.

Who is at high risk for developing blot clots?

The study reported at the 2011 ASH Annual Meeting showed that almost 80% of blood clots that occur in patients with cancer develop among those being treated as outpatients. Some outpatients, however, are at higher risk than others—those whose primary site of cancer is the stomach, pancreas, brain, or testicles, and those with lymphoma and myeloma. Outpatients with lower risk of developing venous thromboembolism include those with breast or head and neck cancers.

What are signs and symptoms of VTE that need to be reported?

If a patient gets pain and swelling in one leg, which is asymmetrical compared to the other leg, if there is sudden onset of chest pain or shortness of breath, or if the patient has cough or blood streaks in the sputum, these are all signs of either a deep vein thrombosis or a pulmonary embolism. That is something they should report and discuss with their provider as soon as possible.

Is there anything outpatients can do to reduce the risk of developing blood clots?

No, there is not. In general, we want patients to be conditioned and be mobile as much as possible, and that’s a good preventive measure in the inpatient setting. It is not clear that that works in the outpatient setting because the risk factors are so different. There really are no lifestyle factors that you could change to ameliorate that risk. Because outpatients are often out and about, it is not practical for them to wear compression stockings and use various mechanical devices suggested for inpatients to reduce the risk of venous thromboembolism. But a heightened awareness of the symptoms is very important.

What happens if outpatients are diagnosed with a blood clot?

If outpatients do have a clot, they usually do not need to be hospitalized.

With the low-molecular-weight heparin, it is now very easy to treat these patients as outpatients. Exceptions would include patients who are medically unstable or have a big pulmonary embolism that is causing strain on the heart.

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rana said. “Although patients with cancer are at high risk, the risk is unevenly distributed. Certain types of cancer have much higher risk than others, but for head and neck cancer and breast cancer, for instance, the risk is pretty low.”

“At this point, none of the guidelines are recommending outpatient prophylaxis,” Dr. Khorana said. This could change, however, depending on the results of “two or three very large studies that were just completed,” he added (see sidebar, Clinical Trials of VTE Prophylaxis for Outpatients).

The exception for now would be patients with myeloma. “Almost all myeloma patients will receive some form of prophylaxis, such as aspirin, warfarin, or low-molecular-weight heparin.

But beyond that, for the larger cancer population, there is no specific recom-

mendation for prophylaxis just yet.”

Dr. Khorana, who was a member of the panel that developed the ASCO recommendations for VTE prophylaxis and treatment in patients with cancer, said the panel “did look at outpatient VTE, but at that time there were no data to support a recommendation.

We are in the process of updating our guidelines, and we hope to have an updated version out by the middle of 2012,” he said. The new studies about venous thromboembolism are among the triggers that prompted the ASCO panel to update the guidelines.

Meeting the Public Health Challenge The findings about the prevalence of VTE among cancer outpatients have important public health implicacontinued on page 78

The ASCO Post | JANUARY 15, 2012

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In the News

Venous Thromboembolism continued from page 77

the inpatient setting. So if nearly 80% of clots are occurring in the outpatient setting, even if you achieve 100% compliance with prophylaxis in the inpatient setting, you are not going to prevent up to 80% of the clots.”

To test the hypothesis that earlier hospital discharge might mean that pa-

FOCUS

tions, Dr. Khorana said, “because right now, the Joint Commission, regulatory authorities, and the Surgeon General, are stressing that we need to reduce the public health burden of VTE. But the only prophylaxis that occurs is in

FORTY UNDER

tients are being sent home with a blood clot that started in the hospital and was later diagnosed in the outpatient setting, the investigators looked at how many outpatients diagnosed with venous thromboembolism had been in the hospital in the preceding 30 days.

“It turned out about 20% were,” Dr.

Khorana said. “So there is some linkage to hospitalization. But again, 80% were not in a hospital within the past 30 days, so it is still primarily an outpatient diagnosis.”

The study also found that venous thromboembolism was an independent predictor of higher hospital costs.

Total mean annual hospital costs were more than twice as high for those with VTE ($22,917) than for those who did not have VTE ($11,250).

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Disclosure: Dr. Khorana is a consultant for and receives cancer-related research funding from several drug companies, including Roche/Genentech, Eisai, Johnson & Johnson, Boehringer Ingelheim, LEO Pharma, sanofiaventis, Bayer, Bristol-Myers Squibb, and Daiichi-Sankyo. Sanofi-aventis funded this study.

Each year, more than 70,000 adolescents and young adults are diagnosed with cancer.

YTRO FOCUS F

SUCO FORTY F

Get tips and tools on how to address the specific needs REDNUNDER U of this patient population, which often get overlooked.

Utilize this series of free, CME-accredited, eLearning aimed specifically at caring for patients between the ages of 15-39.

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

The Focus Under Forty™ Curriculum Includes Courses on:

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Clinical Trials Get information on how to find and access trials, and how to enroll adolescent and young adult patients in these trials. Learn more about the processes of consent, assent, and re-consent.

R IGHTS AND PER MISSIONS e-mail: Permissions@harborsidepress.com

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Melanoma Melanoma is one of the frequently diagnosed cancers in this population.

Learn about the new treatments that are now available as well as unique issues that are associated with caring for adolescent and young adult patients.

Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

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Cancer Care Clinical Trials Diagnosis & Treatment Role of the Primary Care Physician in Cancer Care Fertility Preservation Issues in Females Fertility Preservation Issues in Males Melanoma Supportive Care Survivorship

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The needs of adolescents and young adults with cancer ARE different.

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Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

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Awards

Conquer Cancer Foundation Awards Oncology Fellows for GI Cancer Research

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he Conquer Cancer Foundation of ASCO Merit Awards will be presented to 20 leading oncology trainees for their important contributions to gastrointestinal cancer research. This year’s recipients will be recognized at the 2012 Gastrointestinal Cancers Symposium, which takes place January 19-21 in San Francisco.

The Merit Awards are designed to promote clinical cancer research by young investigators and provide them with the opportunity to present their research at the 2012 Gastrointestinal Cancers Symposium. Recipients were selected based on the scientific merit of their abstracts and will receive funding to help with travel expenses to attend the meeting. The 2012 Gastrointestinal Cancers Symposium Merit Awards are supported through restricted educational grants from Amgen.

The recipients (and their research topics) are: ■■ Daniel Abbott, MD, The University of Texas MD Anderson Cancer Center Neoadjuvant chemoradiation versus surgery first for resectable pancreatic head adenocarcinoma: An economic and outcome analysis.

■■ Amanda Arrington, MD, City of Hope National Medical Center Laparoscopic gastrectomy for gastric adenocarcinoma: A single institution’s experience and oncologic outcomes of 65 consecutive patients.

■■ Genevieve Boland, MD, PhD,

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The University of Texas MD Anderson Cancer Center Association of NCCN guideline adherence with improved survival in high-risk stage II and stage III colon cancer.

Terence Chua, BSc Med, MB BS, University of New South Wales Early and long-term outcome data on 2,298 patients with pseudomyxoma peritonei of appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Sebastian De La Fuente, MD, H. Lee Moffitt Cancer Center and Research Institute Safety and oncologic outcomes of robotic-assisted esophagogastrectomy.

Mary Guye, MD, City of Hope National Medical Center The prognostic significance of extraintestinal tumor location for primary nonmetastatic gastrointestinal stromal tumors.

Danielle Hari, MD, John Wayne Cancer Institute at St. Johns Health Center A 21-year analysis of lymph node trends in colon cancer: Do quality measures really matter?

Alex Haynes, MD, MPH, The University of Texas MD Anderson Cancer Center Association between delays in adjuvant chemotherapy for stage III colon cancer and increased mortality.

Melissa Labonte, MD, Univer-

CONQUERING

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sity of Southern California Norris Comprehensive Cancer Center Use of EGF A61G polymorphism to predict overall survival in a phase III study of gemcitabine plus cetuximab versus gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma (SWOG 0205).

Anna Leung, MD, John Wayne Cancer Institute at St. Johns Health Center Changing national trends and survival in stage IV gastric cancer.

Lee McGhan, MB, BCh, Mayo Clinic Validation of a gastric cancer nomogram using a U.S. cancer registry.

Abigail Milby, MD, Hospital of the University of Pennsylvania Long-term cardiopulmonary mortality after radiation for locally advanced esophageal cancer.

Manali Patel, MD, Stanford University Medical Center Seventh edition (2010) of gastric adenocarcinoma AJCC staging system: Is there room for improvement?

Jose Pimiento, MD, H. Lee Moffitt Cancer Center and Research Institute Low 18F-fluorodeoxyglucose uptake on positron emission tomography as a prognostic factor for stage I and II pancreatic cancer.

Maria Russell, MD, The University of Texas MD Anderson Cancer Center Lymph node metastasis in patients

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with early pathologic T-stage rectal cancers: What does local excision leave behind?

Heath Skinner, MD, PhD, The University of Texas MD Anderson Cancer Center Phase I trial of radiotherapy with concurrent bevacizumab, erlotinib, and capecitabine for locally advanced pancreatic cancer (LAPC).

Akihiro Suzuki, MD, The University of Texas MD Anderson Cancer Center Nomograms for prognostication of patients with esophageal and gastroesophageal carcinoma undergoing definitive chemoradiotherapy.

Takashi Taketa, MD, The University of Texas MD Anderson Cancer Center Outcome of trimodality-eligible esophagogastric cancer (EC) patients who declined surgery after preoperative chemoradiation.

Ryan Thomas, MD, The University of Texas MD Anderson Cancer Center Selective reoperation for locally recurrent or metastatic pancreatic ductal adenocarcinoma following primary pancreatic resection.

George Van Buren, MD, University of Pittsburgh Phase II trial of fixed-dose rate gemcitabine, bevacizumab, and concurrent 30 gy radiotherapy as preoperative treatment for potentially resectable pancreatic adenocarcinoma.

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

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Participate in QOPI® This Spring Demonstrate Your Commitment to Deliver Quality Care

QOPI : THE QUALITY ONCOLOGY PRACTICE INITIATIVE ®

QOPI® is a practice-based quality assessment program, developed by practicing oncologists, to promote excellence in cancer care. Through QOPI, you compare the care your practice delivers to published, evidence-based guideline recommendations, established measures for quality oncology care, and to care delivered by other oncology practices throughout the U.S. You will gain key information to identify areas to target for your quality improvement efforts, and be able to demonstrate to your patients, payors, and colleagues your commitment to deliver the best care to every patient.

Additional benefits of data collection include: • Reports which are the only ABIM-approved oncology-specific data source for use towards MOC Part IV-Practice Improvement requirements • CME credit • Fellowship program quality assessment experience • Initial step towards earning QOPI® Certification, a designation that recognizes practices that consistently achieve the highest standards of care

The spring 2012 QOPI data collection starts March 22nd. Practices new to QOPI are encouraged to register to participate by February 22nd.

Visit qopi.asco.org for more information.

ASCOPost.com | JANUARY 15, 2012

PAGE 81

In the Literature

Emerging Clinical Data on Cancer Management LEUKEMIA Adding Alemtuzumab to Fludarabine in CLL In a randomized phase III trial among previously treated patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the combination of alemtuzumab (Campath) plus fludarabine resulted in significant improvements in progression-free survival, complete response rate, and overall survival compared to patients receiving fludarabine alone. “The fludarabine plus alemtuzumab combination provides clinical benefits with an acceptable safety profile,” trial investigators reported in The Lancet Oncology.

A total of 335 patients with relapsed or refractory CLL and evidence of progressive disease that required therapy after one previous treatment for CLL were enrolled in the trial at 5 North American and 43 European centers.

The patients were randomly assigned to open-label combination treatment (fludarabine at 30 mg/m2 per day and alemtuzumab at 30 mg per day on days 1–3) or to monotherapy (fludarabine at 25 mg/m2 on days 1–5). Both regimens were given intravenously for a maximum of six 28-day cycles.

Study Results Median progression-free survival for the 168 patients in the fludarabineplus-alemtuzumab group was 23.7 months vs 16.5 months for the 167 patients in the fludarabine-only group (P = .0003). Overall median survival was not reached in the combination group and was 52.9 months in the fludarabine-alone group. The complete response rate was 13% among patients receiving alemtuzumab and fludarabine vs 4% among patients receiving fludarabine alone.

All-cause adverse events occurred in 98% of patients receiving combination treatment and 90% of patients receiving fludarabine alone. Patients in the fludarabine-plus-alemtuzumab group had more cytomegalovirus events (14% vs < 1% in the monotherapy group).

Grade 3 or 4 toxicities occurring in the combination treatment and monotherapy groups were leukopenia (74% vs 34%), lymphopenia (94% vs 33%), neutropenia (59% vs 68%), thrombocytopenia (11% vs 17%), and anemia (9% vs 17%). Despite the difference in the incidence of grade 3/4 adverse events, the percentage of patients who discontinued treatment or died during treatment was similar in the two groups, the authors noted.

© Christopher Weyant/The New Yorker Collection/www.cartoonbank.com

“For second-line therapy, the fludarabine-plus-alemtuzumab regimen has several potential advantages,” the researchers stated. “First, unlike fludarabine plus cyclophosphamide and fludarabine plus cyclophosphamide plus rituximab [Rituxan], the fludarabineplus-alemtuzumab regimen spares patients from additional exposure to alkylating drugs, which theoretically might be associated with serious early and late toxicities.” Other potential advantages are reduced doses of each drug and a more convenient dosing schedule.

“This combination might become an important additional treatment option for patients with relapsed or refractory CLL,” the authors concluded.

Elter E, et al: Lancet Oncology 12:12041213, 2011.

NEUROENDOCRINE TUMORS Everolimus for Tumors Associated with Carcinoid Syndrome The combination of everolimus (Afinitor) plus octreotide (Sandostatin) long-acting repeatable (LAR) formulation improved progression-free survival by 23% over placebo plus octreotide LAR in a randomized phase III study of patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The combination treatment was associated with a “clinically meaningful” 5.1-month increase in median progression-free survival—16.4 vs 11.3 months in patients receiving placebo— investigators for the RADIANT-2 study stated in The Lancet. “Consistent with these findings, treatment with everolimus plus octreotide LAR was associated with tumour shrinkage and stabilisation and significant reduction in biochemical markers of neuroendocrine tumours,” the investigators added.

The study enrolled 429 patients from the United States, Canada, and several other countries. All patients were aged 18 years or older, had low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, disease progression, and a history of secretory symptoms (diarrhea or flushing) attributable to carcinoid syndrome. Researchers randomly assigned participants to receive treatment with 10 mg oral everolimus once daily or matching placebo, as well as intramuscular 30 mg octreotide LAR every 28 days.

Treatment continued until disease

progression (which occurred in 95 of the 215 patients receiving everolimus and 146 of the 211 patients receiving placebo), withdrawal from treatment because of adverse events, or withdrawal of consent.

The most commonly reported adverse events leading to disSEE PAGE 83 continuation of treatment with everolimus plus octreotide were fatigue, diarrhea, general physical health deterioration, interstitial lung disease, and pneumonia, each occurring in 2% of patients.

‘Worthwhile Advance’ “Our findings showing the efficacy of everolimus plus octreotide LAR in advanced neuroendocrine tumours are important because of the lack of effective anticancer treatment options,” the authors concluded. “Efficacy of everolimus in this population will need confirmation in a future study. Together with clear evidence of benefit from the recently completed RADIANT-3 trial of everolimus in patients with advanced pancreatic neuroendocrine tumours, our data support the efficacy of everolimus in a broad spectrum of advanced neuroendocrine tumours.

The addition of everolimus to octreotide LAR “does seem to be a worthwhile advance,” according to an accompanying commentary on the study report. “The benefit shown was somewhat compromised by an imbalance between groups, with the everolimus group containing more patients with worse performance status, more lung neuroendocrine tumours, and more patients who had received chemotherapy,” the commentators stated. They pointed out that “toxic effects related to everolimus are not insignificant,” and because of crossover, “we do not know the survival benefit.”

Pavel ME, et al: Lancet 378:2005-2012, 2011.

Rindi G, Caplin M: Lancet 378:19781980, 2011.

NASOPHARYNGEAL CANCER Chemoradiotherapy for Early-stage Nasopharyngeal Disease Adding chemotherapy to radiotherapy resulted in statistically significantly higher 5‑year overall, progression-free, and distant metastasis-free survival continued on page 82

The ASCO Post | JANUARY 15, 2012

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In the Literature

Emerging Clinical Data continued from page 81

among patients with stage II nasopharyngeal carcinoma in a phase III randomized trial. Adding cisplatin-based chemotherapy to radiotherapy resulted in 8.7%, 10.1%, and 10.9% increases in the 5-year overall, progression-free, and

distant metastasis–free survival rates, respectively, in the concurrent chemoradiotherapy arm, researchers from southern China—where nasopharyngeal carcinoma is endemic—reported in the Journal of the National Cancer Institute. There was, however, no statistically significant difference in the 5-year

locoregional relapse-free survival rate.

Several prospective randomized trials and meta-analyses have shown that concurrent chemoradiotherapy with or without adjuvant chemotherapy is superior to radiotherapy alone in the treatment of locoregionally advanced nasopharyngeal carcinoma, the researchers

The Role of Clinical Pathways in Supporting Community Oncology A discussion with Bruce Feinberg, M.D., Vice President & Chief Medical Officer, Cardinal Health Specialty Solutions Through its flagship service offering, P4 Pathways, Cardinal Health Specialty Solutions works with hundreds of community oncologists across the nation to establish clinically proven, evidence-based treatment protocols that promote the delivery of high quality, cost-efficient patient care. Since launching the nation’s first cancer care pathways program in 2008, more

Q: A:

Why should oncologists care about cancer care pathways?

Oncologists are increasingly being called upon to do more with less. They’re charged with caring for an increasing number of patients and improving the quality of the care they provide those patients. At the same time, they’re facing the continuing erosion of reimbursement. These challenges are creating uncertain times for community oncology, the backbone of our nation’s cancer care delivery system.

When implemented correctly, cancer care pathways can ultimately play an important role in protecting the longterm financial viability and autonomy of community oncologists. They can help physicians play a meaningful role in improving patient outcomes – and costs – through the consistent use of evidence-based best practices. When coupled with the right compliance measurement tools, pathways can also reduce administrative and other burdens to free up physician time for patient care. Cardinal Health Specialty Solutions is also leveraging pathways to develop new paradigms for compensating physicians for the quality of the care they provide.

Q:

In your view, what factors make pathways programs ‘work’ for physicians?

A:

Most importantly, pathways must improve outcomes. That has to be the number-one priority. Second, physicians need to lead the development of the pathways they’ll be expected to follow. Third, technology and other tools need to make it as efficient as possible for physicians to implement and track pathways compliance.

Cardinal Health Specialty Solutions also believes that pathways should be leveraged to remove administrative burdens – like prior authorization.

than 10 percent of U.S. oncologists have become engaged in P4 Pathways programs, which touch more than 20 million insured patients. Here, Dr. Bruce Feinberg shares his viewpoints on how physician-led pathways programs are creating new paradigms for improving patient care.

We advocate for payors to appropriately incentivize physicians to participate.

The most successful pathways programs provide fair reimbursement for generic medications, lock in reimbursement rates for branded drugs and allow physicians to share in cost savings that are created through reduced hospitalization and drug spend.

Cardinal Health Specialty Solutions understands that cancer care pathways represent a shift in the mindset of oncologists.

They’re helping us leverage pathways to improve the quality and consistency of care. And they’re developing new models that ensure doctors get fairly compensated for delivering that care to patients.

Ram Trehan, MD Greater Washington Oncology Assoc., Silver Spring, MD

Q:

Can pathways be used to help physicians deal with drug shortages?

A:

We are piloting an innovative new system that alerts regional Pathways Steering Committees – comprised of practicing oncologists – of current and potential shortages, and mobilizes them to review evidence to recommend next-best alternative therapies. This approach helps providers mitigate the impact shortages have on patient care, ensures consistency in approach and saves physicians a great deal of time.

Dr. Feinberg can be reached at bruce.feinberg@cardinalhealth.com.

Q:

Should physicians who do not comply with pathways be penalized?

A:

Cardinal Health Specialty Solutions always leads with a clear mandate that physicians have ultimate control of treatment decisions at the point of care. It’s impossible for 100% of patients to be cared for using a limited set of treatment protocols. That’s why our model allows room for individualized medicine and physician discretion.

We set compliance goals, but the physician has ultimate control of treatment decisions at the point of care. For example, we generally expect physicians to be pathways compliant 70+% of the time in year one and 80+% in year two.

To date, physician compliance in each of our pathways programs has exceeded these goals.

Q: A:

Is your approach to cancer care pathways working?

Yes. For example, physicians who participate in our more mature pathways programs spend an average of 40% less time than non-participating physicians on the management of the same disease, while their patients experience 15% fewer emergency room (ER) visits and hospitalizations. Reduced ER visits, alone, are a great example of how pathways programs can improve healthcare quality and costs. One of our more mature pathways programs reduced its ER-related expenses by $5 million in one year. These are great examples of physicians using pathways to free up their own time to focus on other areas of patient care while they’re removing unnecessary costs from the system.

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Cardinal Health Specialty Solutions

noted. However, patients with stage I–II nasopharyngeal carcinoma have generally favorable prognoses and have largely been excluded from clinical trials with concurrent chemoradiotherapy. “To the best of our knowledge, this study is the first randomized trial to compare concurrent chemoradiotherapy with radiotherapy alone in early-stage nasopharyngeal carcinoma,” the researchers stated.

Patients were evaluated using the Chinese 1992 staging system and were eligible for this study if they had biopsyproven World Health Organization type II/III nasopharyngeal carcinoma, stage II disease (T1-2, N1, M0 or T2, N0, M0 with parapharyngeal space involvement). Patients were excluded if they had previously been treated for nasopharyngeal carcinoma.

A total of 230 patients were randomly assigned to receive radiotherapy alone or with 30 mg/m2 concurrent cisplatin on day 1 weekly during radiotherapy. Cisplatin-based chemotherapy has been shown to result in higher response rates in previously untreated, recurrent, or metastatic nasopharyngeal carcinoma compared with noncisplatin regimens, the authors noted, adding that the optimal combination of cisplatin with radiotherapy has not yet been established.

Optimal Therapy At a median of 60 months, 22.8% of patients in the radiotherapy group developed tumor progression vs 11.2% in the concurrent chemoradiotherapy group.

Of the 25 reported deaths, 21 were disease-related, 16 in the radiotherapy group and 5 in the concurrent chemoradiotherapy group. Patients in the chemoradiotherapy group had statistically significant higher rates of overall survival (94.5% vs 85.8% in the radiotherapy group), progression-free survival (87.9% vs 77.8%), and distant metastasis–free survival (94.8% vs 83.9%).

“Although [concurrent chemoradiotherapy] patients experienced more severe hematologic, gastrointestinal, and mucositis acute toxic effects than the patients undergoing radiotherapy alone, they were all tolerant of this regimen,” the researchers wrote. “In summary, we think that the optimal choice for early-stage [nasopharyngeal carcinoma] is cisplatin, at a weekly dose of 30 mg/m2, for both an optimal chemotherapy effect to eradicate small distant tumors and to ensure [nasopharyngeal carcinoma] patient compliance.”

■

Chen QY, et al: J Natl Cancer Inst 103:1761-1770, 2011.

ASCOPost.com | JANUARY 15, 2012

PAGE 83

Patient’s Corner

Don’t Take Away Our Hope

When treatment after treatment failed to halt progression of my son’s neuroblastoma, I kept asking myself, “Is this really the best we can do?”

By Patrick Lacey, as told to Jo Cavallo

A

fter experiencing the loss of my wife Dina’s first pregnancy during her second trimester, we naturally worried that something would go wrong when she became pregnant again. But when our son Will was delivered at full term, we thought we could finally relax. Born at a whopping 10 lb, Will seemed by all measures a healthy, vibrant infant. A slightly drooping left eyelid and some swelling on the left side of his head were explained away as nothing more serious than baby fat.

But as the months wore on and these symptoms persisted, Dina insisted that testing be done to rule out anything serious.

After blood test results proved inconclusive, an x-ray picked up an enlarged left supraclavicular lymph node and a sizable posterior mediastinal mass along his spinal column. Further testing confirmed a diagnosis of stage IV intermediate-risk neuroblastoma. The news was stunning. Our son was just 7 months old.

From Denial to Despair Initially, Will’s prognosis seemed good. Our oncologist said that infants usually respond well to treatment and that Will’s survival odds were better than if he had been diagnosed when he was 18 months or older. The recommended front-line treatment was a brutal eight cycles of a combination of carboplatin, cyclophosphamide, doxorubicin, and etoposide. Although this regimen initially reduced his mediastinal tumor, by the end of the sixth cycle of treatment it was clear that he was no longer responding. Around this time, he underwent a resection of his pri-

mary tumor, which was interwoven on his brachial plexus. After finishing up the last two cycles of chemotherapy, we were told to come back in 3 months for a new set of CT scans. It turned out that those 3 months were the only time Will has been off therapy.

When Will was first diagnosed, I was in denial because I couldn’t conceive of the fact that my child has cancer, especially one as deadly as neuroblastoma. But I thought, he’s not like anyone else—we’ll do the treatment and get past this crisis, and the nonstop fog of pain and grief will be just a bad memory. But it didn’t turn out that way.

Over the next 2 years, Will underwent numerous cycles of chemothera-

fection would kill him. And even if by some miracle Will survived, we wondered what the long-term effects of his treatments might be: sterility, secondary cancers, heart disease, neurologic problems? He already has some hearing loss. As I watched him suffer from his therapies, all I could think was, “Is this really the best we can do?”

Patrick Lacey

us several therapies that stabilized Will’s cancer and improved his quality of life. Most recently, Will enrolled in a phase I study of one cycle of alphadifluoromethylornithine (DFMO), followed by four cycles of DFMO combined with etoposide. At the end of the study, Will’s disease remained stable, and he continues to take DFMO as a single agent.

Now age 7, Will is finally living a somewhat normal childhood. He has no side effects from his current therapy and was able to complete first grade without missing a day of school. But I’m not naive. I understand the realities of his disease. I’m just saying that while a cure for neuroblastoma may not be the reality today, it doesn’t mean it won’t be the reality tomorrow.

I don’t want physicians to fear giving parents hope. We just want to believe that with parents, clinicians, and researchers working together, a change in the course of neuroblastoma is possible. We just want a chance at a rational therapy to save our kids.

Working Together for a Cure After 18 months of unsuccessful treatment, our doctors told us we had exhausted all curative options and that we could take Will home and keep him comfortable with palliative care. But

While a cure for neuroblastoma may not be the reality today, it doesn’t mean it won’t be the reality tomorrow. peutic regimens, including different combinations of cyclophosphamide, topotecan, cisplatin, etoposide, doxorubicin, vincristine, dactinomycin, ifosfamide, prednisone, MIBG radiotherapy, and ABT-751. The therapies caused uncontrollable violent vomiting, mouth sores, diaper rash, and pain.

Because Will was so young when his treatments began, there was no way of explaining to him what was happening.

All we could do was comfort him, sleep by his crib, and change his sheets after each vomiting episode.

Since Will’s immune system was so compromised, we wouldn’t allow visitors to the house, terrified that an in-

Will Lacey

we weren’t ready to give up. I searched the Internet for online communities of parents of children with neuroblastoma to see what they were doing and phoned specialists and researchers in neuroblastoma to find new treatments being investigated. I also cofounded the Friends of Will Foundation to raise money for research.

All these efforts led me to Giselle Sholler, MD, Chair of the Neuroblastoma and Medulloblastoma Translational Research Consortium and Codirector of the Van Andel Research Institute’s Pediatric Cancer Translational Research Program in Grand Rapids, Michigan. Dr. Sholler offered

■

Patrick Lacey is a business manager for a leading information company in Boston and the cofounder and President of the Friends of Will Foundation (Beatnb.org).

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.

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When you see a code that you would like to scan, start your code-reading application.

2 Position your device in front of the code so that it fills about half your screen.

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3 The code will scan automatically.

If the scan is successful, you will be rerouted to the targeted link.

When testing for HER2

A second test may change her treatment Because of tumor heterogeneity and assay limitationsâ&#x20AC;&#x201D;

consider a second test

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