TAP Vol 3 Issue 18

Triple-negative Breast Cancer

3

| Liposomal Vincristine in ALL

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| Ziv-aflibercept Controversy

VOLUME 3, ISSUE 18

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DECEMBER 15, 2012

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

Hematology

Bone Marrow Transplants Reduce Risk of Graftvs-Host Disease Compared to Peripheral Blood

By Caroline McNeil

P

atients who receive bone marrow transplants are significantly less likely to develop chronic graft-vs-host disease than those who receive peripheral blood stem cell transplants, according to a new, large randomized trial, the first of its kind with unreFrederick R. Appelbaum, MD lated donors. Published recently in The New England Journal of Medicine,1 the study found higher rates of engraftment among the peripheral blood transplant recipients but no statistically significant difference in relapse or survival between the two groups.

The results should change current practice for some patients, said Frederick R. Appelbaum, MD, of the Fred Hutchinson Cancer Research Center, in

an accompanying editorial (see sidebar on page 16).

Currently, 76% of transplants in the United States use stem cells harvested from peripheral blood via apheresis. Bone marrow, which was the initial source of blood stem cells, is obtained while the donor is under anesthesia.

Evolving Practice The use of peripheral blood stem cells began to overtake bone See Page 119 marrow transplants after trials with matched sibling donors showed better rates of engraftment. Some studies with sibling donors have also shown better survival and lower relapse rates. However, the higher T-cell content of peripheral blood cells increases the risk of chronic graft-vs-host disease, a serious and sometimes fatal complication.

Recognizing and Managing Physician Burnout in Oncology

continued on page 16

Issues in Oncology

A new ASCO survey attempts to understand why physicians experience burnout more often than other professionals.

By Jo Cavallo

A

lthough job burnout occurs in all professions, it is more common among physicians, according to a study published recently in Archives of Internal Medicine.1 Physicians on the front line of care, such as those working in emergency rooms or in family medicine, experience the highest rates of burnout.

The research, led by Tait D. Shanafelt, MD, Di-

rector of the Mayo Clinic Department of Medicine Program on Physician Well-being, compared 6,179 practicing physicians ages 29 to 65 with a probabilitybased sample of 3,422 U.S. workers of the same age group in other fields. Of the nearly 7,300 physicians who answered questions about their work/life balance, 45.8% reported at least one symptom of serious burnout, such as emotional exhaustion (loss of enthusiasm for work) or depersonalization (high Caring for patients with cancer can degree of cynicism).

be extremely rewarding, but also one of the most demanding and stressful areas of medicine.

— Tait D. Shanafelt, MD, and Lotte Dyrbye, MD Tait D. Shanafelt, MD

Findings in Oncologists

ASCOPost.com

Screening for Ovarian Cancer: A Gynecologic Oncologist’s Perspective

By M. Steven Piver, MD

T

he recent U.S. Preventive Services Task Force (USPSTF) Reaffirmation Recommendation Statement concluded that in the population of asymptomatic women without known genetic mutations that increase risk for ovarian cancer, clinicians should not screen for ovarian cancer using transvaginal ultrasound and serum CA125 testing.

The USPSTF points out, correctly, that the recommendations only apply to asymptomatic women without known risk factors, including CA1 or BRCA2 deleterious mutations, Lynch syndrome, or family history of ovarian continued on page 122

Dr. Piver is Senior Gynecologic Oncologist, Sisters of Charity Hospital, and Founder of the Gilda Radner Familial Ovarian Cancer Registry, Roswell Park Cancer Institute, Buffalo, New York.

MORE IN THIS ISSUE Oncology Meetings Coverage 5th AACR Conference on Cancer Health Disparities �����������������7, 49 54th ASTRO Annual Meeting �����11, 12, 27, 48, 66, 68-70 11th International Kidney Cancer Symposium �������������������������������� 22 35th ESMO Congress ����������� 78, 82, 86 Statins and Cancer ������������������������������������� 17 Surgical Resection for Liver Metastases ���������������������������������������� 24 Sequestration and Cancer Research �������35 FDA Update ������������������������������������ 2, 37-41 Direct from ASCO ������������������������������������� 55 Letters to the Editor �������������������������� 94–97

An earlier article coauthored by Dr. Shanafelt and Lotte Dyrbye, MD, continued on page 19

A Harborside Press® Publication

The ASCO Post | DECEMBER 15, 2012

PAGE 2

FDA Update

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

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

Associate Editors Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Douglas W. Blayney, MD Stanford University Medical Center

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

Philip D. Bonomi, MD Rush University Medical Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Richard Boxer, MD University of Miami

George W. Sledge, MD Indiana University

Harold J. Burstein, MD Dana-Farber Cancer Institute

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology 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

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine

Cabozantinib Approved for Treatment of Progressive Metastatic Medullary Thyroid Cancer

T

he FDA recently approved cabozantinib (Cometriq), for the treatment of patients with progressive metastatic medullary thyroid cancer. Cabozantinib is a small molecule that inhibits the activity of multiple tyrosine kinases, including RET, MET, and VEGF receptor 2.

The approval was based on the demonstration of improved progression-free survival observed in an international, multicenter, randomized (2:1), placebo-controlled trial enrolling 330 patients with metastatic medullary thyroid cancer. Patients were required to have progressive disease within 14 months prior to entry.

Stanley H. Winokur, MD Singer Island, Florida

Study Design

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

Patients were randomly assigned to receive cabozantinib, 140 mg (n = 219) or placebo (n = 111) orally once daily. Randomization was stratified by age and prior tyrosine kinase inhibitor use. Patients were treated until disease progression or intolerable toxicity. At the time of disease progression, crossover to cabozantinib was not permitted in patients receiving placebo. An independent radiology review committee, using the modified RE-

International Editors Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Nagi El-Saghir, MD American University of Beirut, Lebanon 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

Michael P. Link, MD Stanford University Medical Center

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

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

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

Harborside Press® Publishing Staff

CIST criteria, determined radiographic progression and tumor response.

Of 330 patients, 67% were male, the median age was 55 years, 23% were 65 years or older, 54% had a baseline ECOG performance status of 0, and 92% had undergone thyroidectomy. Twentyfive percent received two or more prior systemic therapies and 21% had been previously treated with a tyrosine kinase inhibitor.

A statistically significant progressionfree survival prolongation was demonstrated in the cabozantinib arm compared to the placebo arm (HR = 0.28 [95% CI, 0.19–0.40]; P < .0001]. The estimated median progression-free survival was 11.2 and 4.0 months for the cabozantinib and placebo arms, respectively.

The overall response rate was significantly higher in the cabozantinib arm (27% vs 0%; P < .0001) and all were partial responses. The median response duration was 14.7 months (95% CI, 11.1– 19.3). No statistically significant difference in overall survival was observed between the treatment arms at the planned interim analysis and in an updated survival analysis requested by FDA.

■

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices.

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

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PAGE 3

Expert’s Corner Breast Cancer

Current Perspectives on Triple-negative Breast Cancers A Conversation with Lisa Carey, MD

By Caroline Helwick The remainder include the HER2enriched (9%), luminal A (5%), luminal B (6%), and normal-like (1%) subtypes.

Defining ‘Borderline’ Disease

Lisa Carey, MD

T

riple-negative breast cancer— which lacks expression of the estrogen receptor, progesterone receptor, and HER2 oncogene—is a challenge for oncologists. The emergence of data showing strong heterogeneity for this subtype of breast cancer creates even more confusion regarding prognosis and management. The ASCO Post asked Lisa Carey, MD, who has led much of the research in triple-negative breast cancer, to describe what is currently known, and remains unclear, about the disease.

Dr. Carey is the Preyer Distinguished Professor in Breast Cancer Research, Medical Director of the University of North Carolina Breast Center, Division Chief of Hematology-Oncology at UNC School of Medicine, and Physician-in-Chief of the North Carolina Cancer Hospital, Chapel Hill.

Molecular Subtypes Triple-negative breast cancer is now known to exist in the form of several subtypes. Can you describe these?

Molecular assays have shown that there is indeed discordance within breast cancers that we consider “triple-negative.” The main molecular subtype is basal-like (49%), which is high in proliferation genes and is genomically unstable. The second most common is the claudin-low subtype (30%), a more recently defined subset that is relatively low in proliferation genes and genetically more stable.

What constitutes “borderline” triplenegative breast cancer tumors, and how are these approached clinically?

Studies define triple-negative breast cancer variably. Some say there must be zero expression of estrogen and progesterone receptors, while others have allowed up to 10% expression of these receptors. These are called “borderline” triple-negative breast cancers, and research from cooperative groups has shown that there is much diversity within these tumors.

Often they are half luminal, half other types. Clinically, we should make no

come up with a 19% risk of relapse at 5 years, but you cannot rely on this.

The truth is, relapse in these models includes outcomes that from a prognostic standpoint are “noise,” such as in-breast and local recurrences, as well as new primaries and true relapse. Since these tumors relapse early, the better metric for decisionmaking in triple-negative breast cancer is the 10-year mortality risk, which is about 8%. It is a more useful number for you and your patient in decision-making.

tumors after third-generation neoadjuvant chemotherapy.1 There are no data suggesting you should use other than conventional agents in this setting.

The cautionary note is that while neoadjuvant studies are being used to give us a sense of how to use regimens in the future, the underlying population is key to the interpretation. If a study population has mostly luminal tumors, you can expect a lower pathologic complete response rate, regardless of the drug.

So, there actually are “good-prognosis” triple-negative tumors?

Untreated T1a and T1b node-negative tumors have a distant recurrencefree survival rate at 5 years of over 85%.

These patients can do quite well.

Association with BRCA Mutation

The cautionary note is that while neoadjuvant studies are being used to give us a sense of how to use regimens in the future, the underlying population is key to the interpretation.

—Lisa Carey, MD

assumptions about them. We should treat these patients with adjuvant endocrine therapy.

Determining Prognosis How do you determine prognosis for triple-negative breast cancer tumors?

Prognosis can be accurately estimated by the usual variables. Even stage III tumors are well represented in Adjuvant! Online and other models. At 10 years, these patients have an 85% risk of relapse and a 79% risk of death without systemic therapy.

With well-delivered third-generation chemotherapy regimens, however, risk can be reduced by 24%, so that their 10-year mortality risk becomes 55%.

We don’t do as well in estimating the outcome of very small tumors (T1a, N0 triple-negative breast cancer). The decision-making models

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

Optimizing Chemotherapy There is an assumption that standard chemotherapy regimens are not effective in triple-negative breast cancer. Is this accurate?

No. Third-generation chemotherapy regimens are, in fact, effective in the majority of subsets of triplenegative breast cancer. [Third-generation regimens are typically those including anthracyclines and taxanes given either for several cycles or in a dose-dense fashion. Examples include dose-dense doxorubicin plus cyclophosphamide followed by docetaxel (AC-T) and docetaxel, doxorubicin, and cyclophosphamide (TAC).] A study of 360 patients with the disease presented at the 2011 San Antonio Breast Cancer Symposium showed pathologic complete response rates of 73% in basallike tumors and 39% in claudin-low

What is the association between triple-negative breast cancer and the BRCA1 mutation?

Eighty percent of BRCA1-associated breast cancers are basal-like, so there is a tight association with triplenegative breast cancer. Also, there are clearly defined shared characteristics between BRCA1-associated tumors and sporadic triple-negative breast cancer, which has been labeled “BRCAness.” In addition to the propensity for the basal-like phenotype, there are other factors such as estrogen receptor and HER2 negativity, high grade, and sensitivity to DNA damage.

There are therapeutic implications of this BRCA loss, and one is that theoretically BRCA1 deficiency is targetable. This has implications for the choice of chemotherapy. If BRCA is key to repairing DNA damage, then with BRCA loss, the tumor should become hypersensitive to DNA-damaging drugs such as platinum agents. In the neoadjuvant setting, pathologic complete response rates to single-agent cisplatin in BRCA1 mutation carriers are extremely high—over 80%, according to small but biologically plausible studies.

We could exploit the DNA damage response as a mechanism of treatment itself, and this is where pocontinued on page 6

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.

Soft Tissue Sarcoma...

Most common primary sites of soft tissue sarcoma.1

HEAD AND NECK

[9%]

TRUNK

[19%] RETROPERITONEUM

[15%]

EXTREMITIES

[60%]

Raising Awareness of a Challenging Disease Soft tissue sarcomas are a heterogeneous group of more than 50 distinct histological subtypes with an estimated incidence of more than 10,000 cases per year in the United States.1 They can originate from connective tissue, including fat, muscle, nerve and nerve sheath, vasculature, and other connective tissues.1 They most commonly arise in the extremities, trunk and retroperitoneum. 1 The presentation of soft tissue sarcomas is variable, but patients often present with a painless mass that is increasing in size.2 Guidelines recommend a biopsy for diagnosis and histopathological classification of soft tissue sarcomas. The biopsy should be performed by an experienced surgeon or radiologist and assessed by a pathologist with sarcoma expertise.1 Guidelines also recommend that magnetic resonance imaging with or without computed tomography be performed for all masses with a chance of being malignant.1 1.

NCCN Guidelines速: Soft Tissue Sarcoma, V.1.2012. NCCN.org. http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed 05/01/2012. NCCN速 and NCCN GUIDELINES速 are trademarks owned by the National Comprehensive Cancer Network, Inc.

2.

Ilaslan H, Schils J, Nageotte W, Lietman SA, Sundaram M. Clinical presentation and imaging of bone and soft-tissue sarcomas. Cleveland Clinic Journal of Medicine. 2010;77:S2-7.

息2012 The GlaxoSmithKline Group of Companies ONO528R0 Printed in USA. May 2012

All rights reserved.

The ASCO Post | DECEMBER 15, 2012

PAGE 6

Expert’s Corner

Triple-negative Breast Cancer continued from page 3

ly-ADP-ribose polymerase (PARP) inhibition comes in. When BRCA1 or BRCA2 is already damaged, cells become dependent on other repair types. PARP inhibitors such as olaparib exploit this Achilles’ heel.

Olaparib as a single agent has been shown to produce high response rates in heavily pretreated BRCA mutation carriers.

In sporadic triple-negative breast cancer, we do not see incredible sensitivity to PARP inhibitors, but this is being further evaluated in randomized trials. At this point it appears that PARP inhibition is promising in BRCA-associated tumors, but its efficacy in sporadic triple-negative breast cancer is unclear.

Drugs Targeting Angiogenesis and EGFR How might antiangiogenic drugs and those targeting the epidermal growth factor receptor (EGFR) work in triple-negative breast cancer?

Preclinical data have suggested that triple-negative breast cancer may be particularly susceptible to antian-

giogenic approaches. The reality is that bevacizumab (Avastin) may improve progression-free survival but not overall survival. There is some reason to think, however, that the micro- and macrometastatic arenas may be different, and neoadjuvant and adjuvant trials are now addressing micrometastatic disease.

EGFR is frequently mentioned as a possible target in triple-negative breast cancer, and a randomized phase II trial that paired cetuximab (Erbitux) with cisplatin demonstrated a 20% response rate, vs 10.3% with cisplatin alone, and a doubling in progression-free survival from 1.5 to 3.1 months.2 So while there is some improvement, it is not enough.

We need a selection strategy for this approach.

Treating a Heterogeneous Disease If triple-negative breast cancer is so heterogeneous, will different approaches be needed for the various subtypes?

Acknowledging this heterogeneity in triple-negative breast cancer, we clearly will need more than one strategy. Biologically distinct groups will have multiple potential targets, such as

DNA damage response genes, growth factor pathways, and the PI3K/mTOR pathway.

Androgen receptor signaling may also be a target. In a study of patients with androgen receptor–positive triple-negative breast cancer presented at this year’s ASCO Annual Meeting,3 targeting of the receptor with bicalutamide (a nonsteroidal antiandrogen used in prostate cancer) yielded a clinical benefit rate of 21% and was well tolerated. The downside was that 450 patients were screened to find 52 who expressed the androgen receptor and 26 who were eligible for the trial.

Summing up How would you summarize the current state of knowledge and practice in the treatment of triple-negative breast cancer?

What we know for sure is that triple-negative breast cancer is a heterogeneous tumor and adjuvant chemotherapy works the same in these tumors as for other subtypes of breast cancer. You have the same treatment options as for other breast cancers, and you should make similar choices.

What we would like to learn is

how to identify BRCA-like tumors, or “BRCAness.” Outside of germline mutations, we don’t have much information. Triple-negative breast cancer is where we really need a “genomeforward” approach—ie, a means of identifying the molecular makeup of an individual tumor to guide therapy.

The alignment of tissue-based and clinical trials will be key to our success.

■

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

References 1. Prat A, Perou CM: Deconstructing the molecular portraits of breast cancer.

Mol Oncol 5:5-23, 2011.

2. Baselga J, Gomez P, Awada A, et al: The addition of cetuximab to cisplatin increases overall response rate and progression-free survival in metastatic triple-negative breast cancer: Results of a randomized phase II study (BALI-1). 2010 ESMO Congress. Abstract 2740. Presented October 11, 2010.

3. Gucalp A, Tolaney SM, Isakoff SJ, et al: Targeting the androgen receptor in women with AR+ ER-/PR- metastatic breast cancer. 2012 ASCO Annual Meeting. Abstract 1006. Presented June 5, 2012.

Send comments to editor@ASCOPost.com

Don’t Miss These Important Reports in this Issue of The ASCO Post

USPSTF Recommendations on Ovarian Cancer Screening,

by M. Steven Piver, MD, see page 1

Triple Negative Breast Cancer: A Conversation with Lisa Carey, MD, see page 3

Steven A. Curley, MD, on Surgical Resection for Colorectal Cancer Liver Metastases, see page 24

Barrie Cassileth, MS, PhD, on Acupuncture in Cancer Care see page 98

Leonard Saltz, MD, on MSKCC’s Decision Not to Offer Novel Drug, see page 110

A Conversation with Margaret Cuomo, MD, Author of A World Without Cancer, see page 115

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | DECEMBER 15, 2012

PAGE 7

Fifth AACR Conference on Cancer Health Disparities Breast Cancer

Gene-expression Profiles of Triple-negative Breast Cancers Differ between African American and Native African Women

By Susan London

T

riple-negative breast cancers in African-American women and native African women have differing gene-expression profiles that may have implications for treatment, according to the first study to directly compare tumor gene expression between these populations. Results were reported at the Fifth American Association for Cancer Research (AACR) Conference on The Science of Cancer Health Disparities, held recently in San Diego.

Lisa Baumbach-Reardon, PhD

Investigators led by Lisa Baumbach-Reardon, PhD, an Associate Professor in the Translational Genomics Research Institute (TGen) Integrated Cancer Genomics Division in Phoenix, and Director of the Institute’s DNA Diagnostic Laboratory in Cancer Genomics, performed transcriptome analysis of primary tumor tissue from 9 African American women living in south Florida and 7 African women living in Kenya. All of these women had triple-negative breast cancer without nodal involvement.

A heatmap with hierarchical clustering showed that 8,821 genes were differentially expressed between the two sets of tumors. Fully 60% of these genes were expressed at a lower level in the tumors from the Kenyan women

as compared with those from their U.S. counterparts.

Further Study Warranted “It’s very interesting to be able to directly compare the native Africans to immigrant Africans and see that there have been some influences,” she commented in a press briefing.

“We don’t know what they are yet— environment, diet, acculturation.…

So what our study suggests is that it just really merits further investigation of larger cohorts of these patients from Africa and U.S. Africans.

As we know, overall, African Americans are understudied in many, many trials, including breast cancer, and it’s very difficult to get these kinds of samples to work on from Africa. But we should work globally to collect these samples and to try to analyze them together.”

Additional analyses showed that several of the differentially expressed genes code for proteins lying on DNA repair pathways, according to Dr. Baumbach-Reardon. And one of the genes downregulated in the Kenyan tumors, STAT1, is especially noteworthy in that it has both tumor-suppressor and immune-regulating activities.

Levels of expression were six- to sevenfold lower in the Kenyan tumors as compared with the African-American ones.

“This is a very exciting observation,” she commented. “You can imagine a situation where you have a double whammy—where the tumor-suppression function is knocked down or significantly diminished in tumors in Kenyans, plus the immune system is knocked down, which inhibits your immune

Ethnic-specific Genetic Differences in Breast Cancer ■■ A direct comparison of gene-expression profiles from African-American

and native African women with triple-negative breast cancer revealed that 8,821 genes were differentially expressed between the two sets of tumors.

■■ Fully 60% of these genes were expressed at a lower level in the tumors from the Kenyan women vs those from the African-American women.

■■ Reasons for the differences remain to be explained, but the findings could lead to different treatment approaches for different ethnicities.

system to fight off tumor cells. These are preliminary findings and need to be validated in larger cohorts and samples, but we are very intrigued by these results.”

Tailored Therapy “The differences among women of color in Kenya and in North America are quite tantalizing and suggest that we may need to approach treatment very differently among the women in Kenya vs North America,” proposed William Nelson, MD, PhD, conference Co-Chair, press briefing moderator, and Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.

Research has now identified five to seven genetically distinct variants of triple-negative breast cancer, Dr. Baumbach-Reardon replied. “So I do think that tailored therapy is going to be one of the things that we are all going to be working on in the near future.”

Responsible Factors Dr. Nelson further wondered if the investigators had observed any phenotypic differences between the African American and Kenyan groups that may provide hints as to why their tumor genetic profiles differ. He noted that some apparent clinical differences may be related in part to the “unholy trinity of poverty, low health literacy, and poor access to health care.”

Teasing out the responsible factors is challenging, Dr. BaumbachReardon agreed. The tumors from Kenya tended to have higher grade, to occur at a younger age, and to be of later stage at diagnosis, “so it’s very possible that the metastatic invasiveness of these tumors is worse in Kenya,” she said. “Then we go back to all the sociocultural issues. … Is this late stage because they are delayed in presentation? That’s the same problem we have for African Americans in rural areas here [in the United States].”

Breast cancer mortality is 20% higher for African American women

than for their white counterparts, Dr. Baumbach-Reardon noted, giving some background to the study.

“From several parts of Africa (Nigeria, Ghana, Kenya), the reports are similar: African women present at a young age with more advanced, latestage disease.” In addition, “triplenegative breast cancer … is overrepresented in both African Americans and native Africans, as well as in U.S. Hispanic women.”

Noteworthy Merits The new research has several noteworthy merits, she pointed out. “First, all of the samples were formalin-fixed, paraffin-embedded tissues. We have clearly shown that we can achieve high-quality reproducible data from archived samples, even those from native Africa. Second, See Page 119 all studies were conducted on the same gene-expression platform in collaboration with Alma Diagnostics. Thus, we have direct comparison of data sets. This is the first such study of its kind.”

Taken together, the study’s findings add to accumulating evidence that breast cancer is a heterogeneous disease and underscore the importance of global collaboration in determining why, with the goal of applying that information clinically, Dr. Baumbach-Reardon maintained.

“We are just hitting the tip of this iceberg,” she concluded.

■

Disclosure: Drs. Baumbach-Reardon and Nelson reported no potential conflicts of interest.

The project described in this article has been supported by grants from the Department of Defense Synergistic Idea Award No. BC084468, the Susan G. Komen Breast Cancer Foundation, Grant No. POP0601150, BankheadColey Cancer Research Program Award No. 09BW-01-26814, and the Women’s Cancer Association of the University of Miami. This project has greatly benefited from a long-standing collaboration with Almac Diagnostics.

TREANDA (bendamustine HCI) for Injection is his chemo. 速

This is his therapy.

Single-agent TREANDA tripled median PFS* TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

Survival distribution function

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

P<.0001

HR†=0.27 (95% CI‡: 0.17, 0.43)

0

5

10

15

20

25

30

35

40

45

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). † HR=hazard ratio. ‡ CI=confidence interval.

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatmentnaïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301) • TREANDA is administered with a convenient dosing schedule – The recommended dose for TREANDA is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 cycles – In the phase 3 trial, patients received chlorambucil at a dose of 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles • In the pivotal phase 3 trial, the most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%) (n=150) Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur •Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment •TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA •The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia

Discover the elements of efficacy and safety LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

©2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2510a August 2012

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established.

CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely.

In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections.

Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death.

Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema.

Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert).

Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies.

There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial.

The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. 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: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.

Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period.

DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.

HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates.

TRE-2500 TRE-2511a (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation.

Information.

TRE-006 TREANDA

April 2012 August

ASCOPost.com | DECEMBER 15, 2012

PAGE 11

54th ASTRO Annual Meeting Supportive Care

Memantine Provides Modest Improvement in Cognition after Cranial Irradiation

By Alice Goodman

M

emantine, a drug used to treat Alzheimer’s disease, slowed cognitive decline in patients with brain cancer treated with whole-brain radiation therapy in a phase III trial reported at the 54th Annual Meeting of the American Society for Radiation Oncology (ASTRO), held recently in Boston.

Nadia N.I. Laack, MD

Cognitive decline commonly occurs after whole-brain radiotherapy; 4 months after radiation, about 60% of patients experience a decline in at least one cognitive domain, and the mechanism of cognitive impairment is similar to that of Alzheimer’s disease, explained lead author Nadia N.I. Laack, MD, the Mayo Clinic, Rochester, Minnesota. Dr. Laack and her colleagues evaluated memantine in the setting of radiation-induced cognitive decline.

“We are excited to see that adding memantine to the treatment plan for brain tumor patients helps preserve their cognitive function after wholebrain radiotherapy even 6 months after treatment. Our findings suggest that memantine may prevent the changes that occur in the brain following radiation therapy, impacting future treatment practices for these patients and suggesting a role for further study in patients receiving radiation to the brain,” she said.

EXPERT POINT OF VIEW

T

his memantine study is a critical first step in understanding and delaying cognitive deterioration in brain metastasis patients, noted formal discussant Vinai Gondi, MD, Associate Director of Research at the CDH Proton Center in Warrenville, Illinois, and Clinical Associate Professor at the University of Wisconsin.

“Cognitive decline can be prevented with memantine, but to a fairly modest extent,” he noted.

“Only some of the cognitive domains that benefited from memantine have shown sensitivity to cranial irradiation in prior studies; importantly, some cognitive domains highly impacted by cranial irradiation were not significantly affected by memantine,” Dr. Gondi explained. “Memantine may be preventing cognitive decline in brain metastasis patients, but it remains to be determined whether this benefit is specific to the effects of cranial irradiation.”

Dr. Gondi also emphasized that almost 50% of patients in the memantine arm of the study demonstrated cognitive decline at 4 months after treatment, a modest improvement over placebo. “Thus, our efforts to

Key Data The study enrolled 508 patients with brain metastases who received whole-brain radiotherapy between March 2008 and June 2010. Wholebrain radiotherapy was delivered as 37.5������������������������������ ����������������������������� Gy in 15 daily fractions. Patients were randomly assigned to memantine at 20 mg/d or placebo within 3 days of the start of radiation therapy.

Specific instruments were used to assess six domains of cogni-

Memantine to Counter Postradiotherapy Cognitive Decline ■■ Memantine slowed cognitive decline associated with whole-brain radiation therapy in patients with brain metastases, but the effect was modest.

■■ This study is a first step in understanding and treating the cognitive effects of brain irradiation.

■■ Compliance was poor with the cognitive testing protocol. Using the

office visit as an opportunity to perform cognitive testing may improve compliance.

prevent cognitive decline from cranial irradiation should not stop with memantine,” Dr. Gondi added. “We have much more to learn and many other neuroprotective strategies to test.”

The investigators of this trial have a large number of brain tissue specimens for translational research. They aim to identify biomarkers predictive of cognitive decline and/or memantine benefit, he said.

Other Strategies In addition, other cognitive protection strategies for patients receiving cranial irradiation are under investigation. Potential strategies include sparing the hippocampus (ie, the memory center) from high radiation doses and use of other investigational drugs.

“These are intriguing hypotheses and represent exciting opportunities to build upon the memantine study,” Dr. Gondi stated.

Dr. Gondi emphasized that this trial benefited from very rapid accrual, but suffered from poor compliance with follow-up cognitive testing. The poor compliance, while partly due to death and disease progression, may also have tive function (memory, processing speed, executive function, global function, self-reported cognitive function, and quality of life). Assessments were done at baseline and at 8, 16, 24, and 52 weeks. The primary endpoint was memory, as assessed by the Hopkins Verbal Learning Test–Revised, Delayed Recall (HVLT-R).

Compliance with the cognitive testing protocol was poorer than expected. Only 32% of patients completed the drug therapy and cognitive assessments for various reasons, and only 149 patients were analyzable at 24 weeks. For the primary endpoint, memantine reduced the decline in HVLT-R delayed recall by 0.9 at 24 weeks. The P value for this finding was .059, “teetering on the edge of significance,” according to Dr. Laack, due to small numbers of patients. At 24 weeks, me-

Vinai Gondi, MD

been due to the uniqueness of the study’s primary endpoint.

“The endpoint was not a CT scan, MRI, or survival. Rather, it was a 20-minute cognitive test that required time and effort of both patients and their health-care providers,” he continued.

“If we are to build upon the memantine study, our collective enthusiasm will need to extend beyond accrual and include an emphasis on follow-up cognitive testing,” Dr. Gondi stated. “With renewed focus on follow-up, we have the potential to identify additional neuroprotective strategies that may significantly benefit our patients.”

■

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

mantine reduced the relative risk of cognitive decline by 17% vs placebo (P = .01), and reduced the rate of decline in cognitive, executive, and global function as well as processing speed (P < .01).

Patients in both groups reported similar levels of grade 3 and 4 toxicities, including alopecia, fatigue, headache, and nausea. There was no difference between the groups in progressionfree and overall survival.

■

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

Reference 1. Brown PD, Shook S, Laack NN, et al: Memantine for the prevention of cognitive dysfunction in patients receiving wholebrain radiation therapy (WBRT): First report of RTOG 0614, a placebo-controlled, double-blind, randomized trial. 54th ASTRO Annual Meeting. Abstract 2. Presented October 29, 2012.

The ASCO Post | DECEMBER 15, 2012

PAGE 12

54th ASTRO Annual Meeting Breast Cancer

Radiation Therapy Extends Survival in Elderly Women with Early Breast Cancer

By Alice Goodman

C

hronologic age alone should not preclude use of radiation in elderly women with early breast cancer, suggest two studies presented at the 54th Annual Meeting of the American Society for Radiation Oncology (ASTRO). Both studies showed a survival improvement in elderly women with early breast cancer treated with adjuvant radiation.

SEER Database Analysis The first study showed that the addition of radiation therapy to lumpectomy improved overall survival as well as breast cancer–specific survival in women aged 70 or older.1 “These findings suggest that radiation should be considered as part of the treatment plan for appropriately selected elderly women. Age alone should not impact whether or not radiation treatment is presented as a vi-

(76%) received adjuvant radiation therapy.

Major Results Median survival was 13.1 years for women treated with surgery plus radiation and 11.1 years for those treated with surgery alone. Five-year cancerRandi Cohen, MD

able treatment option,” stated Randi Cohen, MD, University of Maryland School of Medicine, Baltimore.

The study population was drawn from a Survival, Epidemiology, and End Results (SEER) database of 29,949 women diagnosed with stage I, estrogen receptor–positive breast cancer who underwent lumpectomy with or without adjuvant radiation and survived at least 1 year after initial diagnosis. A total of 22,781 patients

Adjuvant Radiation for Older Women with Breast Cancer ■■ Two large population-based studies showed that adjuvant radiation

improved overall survival and breast cancer–specific survival in elderly patients with early breast cancer.

■■ Older age should not preclude use of adjuvant radiation; treatment selection should consider patient’s general health status, patient preference, and risk vs benefit.

specific survival was 98.3% for the adjuvant radiation group vs 97.6% for the surgery-alone group, a statistically

EXPERT POINT OF VIEW

Meena S. Moran, MD

“B

reast cancer in the geriatric population is a major health issue. Of the more than 230,000 new cases diagnosed annually, somewhere between 40% and 50% will occur in women 65 and over. Furthermore, the elderly population has been and will continue to increase exponentially over time,” stated Meena S. Moran, MD, Associate Professor at Yale University in New Haven, Connecticut, who was the invited discussant for these studies. “But because elderly patients are underrepresented in clinical trials, it remains unclear whether the benefits of radiation can be extrapolated to this elderly population.”

And while trials like CALGB 9394 provide data suggesting that overall survival may not be affected in el-

derly low-risk patients who only take tamoxifen after surgery (without radiation), it is important to recognize that clinically meaningful differences do exist between patients treated in routine practice and those who are treated on clinical trials such as these.

Population-based studies allow us insight into practice patterns and treatment trends that are more representative of the general U.S. population.

Three Lessons Dr. Moran pointed out the lessons we can learn from these studies: (1) Based on Dr. Cohen’s study, we know that patients who are not receiving radiation (often omitted because patients with comorbidities are perceived as having a shortened life expectancy) are still living more than 11 years.

(2) The omission of radiation therapy in the elderly population has continued to slowly increase since the publication of CALGB 9394 in 2004.

(3) It is highly unlikely that the benefits in survival that were reported in these studies at the ASTRO Annual Meeting can be attributed to radiation alone.

“It is more likely that selection bias-

significant difference (P < .0001).

Ten-year cancer-specific survival was 95.4% vs 93.3%, respectively <�������������������������������� ������������������������������� .0001), and 15-year cancer-spe(P ��������������������������������� cific survival was 91.4% vs 89.5%.

At all time points, the use of adjuvant radiation improved overall survival. At 5 years, overall survival

es, and possibly the inclusion of T2 tumors, are inflating these numbers,” Dr. Moran stated. “Relative to controlled trials, population-based data have inherent selection biases in the treatment delivered, where the patients perceived as likely to live longer are the ones living longer, and also are more likely to receive radiation. Remember, the Oxford Overview only showed a 3% benefit for all node-negative patients at 15 years, and this SEER subset includes lower-risk patients with shorter follow-up,” she noted.

“While we now have level I data supporting the omission of radiation in selected low-risk, elderly breast cancer patients” she continued, “that does not mean that we should be omitting radiation in all of these patients. The anxiety associated with recurrence varies from patient to patient, and we need to talk with patients individually to determine their goals for treatment.

Furthermore, the merits of radiotherapy should be considered on the basis of the data supporting their value, in conjunction with tumor characteristics, comorbities, life expectancy, and patient preferences.”

■

Disclosure: Dr. Moran is on the advisory board of Genomic Health.

was 88.6% for those who received radiation vs 73.1% for the surgeryalone arm (P < .0001); at 10 years, overall survival was 65% vs 41.7% <���������������������������������� ��������������������������������� .0001); at 15 years, overall sur(P ����������������������������������� vival was 39.6% vs 20%.

The use of radiation decreased with advancing age. Between the ages of 70 and 74 years, 80% of women were treated with radiation; between the ages of 75 and 79 years, 74% received radiation; and between the ages of 80 and 84 years, 61% were treated with radiation.

Dr. Cohen said the greater differences in overall survival between groups compared to between-group differences in cancer-specific survival probably can be explained by selection bias, resulting in the administration of adjuvant radiation to healthier women with a longer life expectancy.

She also said that the improvement in cancer-specific survival is likely to be related to improved locoregional control achieved by radiation.

Limitations of the study include its retrospective design and the lack of data on recurrence rates and use of hormonal therapy.

Similar Findings A related study, also based on SEER data, found that older women with early-stage, low-risk breast cancer treated with radiation after breast-conserving surgery had superior breast cancer–specific and overall survival rates compared to women who did not undergo radiation after

ASCOPost.com | DECEMBER 15, 2012

PAGE 13

54th ASTRO Annual Meeting breast-conserving surgery.2 The study, which also explored patterns of care, found a 6% decline in use of radiation after 2004, when results of the Cancer and Leukemia Group B (CALGB) 9394 trial suggested that radiation treatment could be omitted in elderly patients without compromising cancer-specific or overall survival.3

Overall, 69% received radiation therapy after breast-conserving surgery; from 2000 to 2004, 72.1% received radiation, but from 2005 to 2009, only 66.6% received radiation. Factors associated with a greater likelihood of receiving radiation were diagnosis at age younger than 80 years, being diagnosed before 2005, and

need for reexcision of the biopsy for residual disease.

Among those treated with radiation, 93% received external-beam radiation therapy. Use of brachytherapy increased over time, from less than 1% in 2000 to more than 10% by 2007, Dr. Korah said.

Breast cancer–specific survival fa-

vored radiotherapy. At 5 years, cancer-specific survival was 97% with radiotherapy vs 95% without it—an absolute difference of 2%. By 8 years, the absolute difference was doubled to 4%, favoring radiation: 95% vs 91%, respectively.

Overall survival also favored the continued on page 14

Mariam P. Korah, MD

The National Comprehensive Cancer Network (NCCN) revised its treatment guidelines in 2005 to state that omission of radiation therapy is reasonable for women over age 70 who have small estrogen receptor–positive tumors treated with adjuvant tamoxifen. Results of the present study suggest that the guidelines should be revisited.

“Our research shows that older patients with breast cancer who undergo radiation therapy after breastconserving surgery have a higher breast cancer–specific survival than those who do not. The large number of patients and breast cancer–specific events in this study highlight clinically meaningful survival advantages among patients who received radiation in conjunction with breastconserving surgery compared with those treated with surgery alone, which may not have been detected in earlier studies. In advancing the care of our patients, treatment recommendations should be guided by the best available evidence to date,” stated Mariam P. Korah, MD, lead author and a radiation oncologist at the University of Southern California Keck School of Medicine in Los Angeles.

INHIBIT ANDROGEN PRODUCTION

BLOCK THE ANDROGEN RECEPTOR

Learn more at inhibitandrogen.com/distinct

Key Data The study population included 32,885 patients with stage T1 or T2 node-negative, estrogen receptor– positive breast cancer who received breast-conserving surgery with a minimum follow-up of 3 months.

The majority of included women had tumors measuring 2 cm (85%).

*Other treatment options may also be considered.

References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. 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. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 08Z12191

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PAGE 14

54th ASTRO Annual Meeting Radiation in Older Women continued from page 13

addition of radiotherapy to surgery.

Five-year overall survival was 87% vs 68% respectively, with an absolute difference of 19% favoring radiation, and 8-year overall survival was 73% vs 50%, for an absolute difference of 23% favoring radiation.

In a multivariate analysis for survival, radiation therapy remained an independent and significant predictor for both overall and breast cancer– specific survival, she said.

Benefits in Context Putting the absolute benefits of ad-

juvant radiation in context, Dr. Korah said that chemotherapy is given to patients with early breast cancer for survival improvements of 2% to 3% at 5 to 10 years of follow-up.

The study’s limitations include lack of data on comorbidities, surgical margin status, hormonal therapy, and locoregional recurrence. Adjuvant hormonal therapy was already being recommended for patients with estrogen-receptor tumors during this study period. Dr. Korah estimated that about 70% to 80% of women in this study were prescribed hormonal therapy and that about 60% were compliant.

“Estimations of life expectancy, competing risk analysis, cost-effectiveness, convenience, and qualityof-life considerations become a factor in determining optimal cancer treatments for older women. Treating elderly patients is complex. We need to have a frank discussion about the benefits and side effects of our treatments, and we need to consider cost-effectiveness and quality of life. This is a moving target. We need to incorporate all the evidence to make treatment decisions,” she told listeners.

■

Disclosure: Drs. Cohen and Korah reported no potential conflicts of interest.

References 1. Cohen RJ, Li L, Citron W, et al: Improved survival with adjuvant radiation in elderly women with early stage breast cancer. 54th ASTRO Annual Meeting. Abstract 82. Presented October 29, 2012.

2. Korah MP, Sener SF, Tripathy D: Implications of omitting radiation after breast conserving surgery in elderly women with low risk invasive breast cancer.

54th ASTRO Annual Meeting. Abstract 84. Presented October 29, 2012.

3. Hughes KS, Schnaper LA, Berry D, et al: Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 351:971-977, 2004.

ASTRO Names Neurosurgeon Mark P. Carol, MD, 2012 Honorary Member

T

he American Society for Radiation Oncology (ASTRO) has named Mark P. Carol, MD, a distinguished leader in the fields of intensity-modulated radiation therapy (IMRT) and imageguided radiation therapy (IGRT), as its 2012 Honorary Member. The title of Honorary Member is the highest honor ASTRO bestows upon distinguished cancer researchers and leaders in disciplines other than radiation oncology, radiation physics or radiobiology. Dr. Carol was recognized with this honor during ASTRO’s 54th Annual Meeting.

Father of IMRT Dr. Carol has more than 30 years of experience in the medical device and health care services arenas, and he is often considered the father of IMRT. Since 1992, he has developed and created many novel and crucial devices and techniques that have influenced and shaped modern radiation oncology, such as CT/MRI image fu-

Pioneer in Radiation Oncology

Mark P. Carol, MD

sion with ultrasound treatment roombased localization, intensity modulated treatment delivery, DVH-based prescriptions, simulated annealing optimization and image guided therapy.

Most recently, Dr. Carol has been developing an innovative way to deliver radiation therapy that uses a multiplexed photon beam to treat patients in sitting and standing positions, thereby reducing overall costs while at the same time allowing advanced multimodality imaging to be introduced seamlessly into the treatment room.

“Throughout the years, Dr. Carol, who trained as a neurosurgeon, has been a pioneer and innovator in the field of radiation oncology,” said Michael L. Steinberg, MD, FASTRO, of UCLA Health System in Los Angeles and ASTRO President.

“His ground-breaking approach to the development of IMRT and IGRT has provided tremendous benefits for radiation oncology patients. He is most deserving of this year’s honor,” Dr. Steinberg said.

Dr. Carol graduated with distinction in research from the University of Rochester’s School of Medicine and Dentistry in Rochester, New York. At the University of Rochester, Dr. Carol worked on developing an artificial heart, for which he now holds a patent. From 1978-1984, he served as a neurosurgical resident and a fellow in neurotraumatology at the University of Maryland in Col-

lege Park, Maryland, and he later went on to practice at the Mary Imogene Bassett Hospital in Cooperstown, New York.

Dr. Carol has also taught as an Assistant Professor of Neurosurgery at Columbia University in New York, the University of South Florida in Tampa, Florida, and the Medical College of Ohio in Toledo, Ohio. Since 2009, Dr. Carol has been an Adjunct Assistant Professor of Radiation Oncology at Brown University in Providence, Rhode Island. He is currently the Chief Development Officer at US HIFU, a privately held health-care company focused on treating primary and recurrent prostate cancer using high-intensity focused ultrasound, headquartered in Charlotte, North Carolina.

■

Editor’s Note: Send your news and announcements to The ASCO Post at editor@ ASCOPost.com

News and Views from the World of Clinical Oncology and Hematology Visit The ASCO Post website at

www.ASCOPost.com

ASCOPost.com | DECEMBER 15, 2012

PAGE 15

Neuro-oncology

Bevacizumab Added to Radiation and Chemotherapy Improved Progression-free Survival in Newly Diagnosed Glioblastoma

R

ecently announced results of the phase III AVAglio study showed that bevacizumab (Avastin) in combination with radiation and temozolomide chemotherapy increased progression-free survival (a co-primary endpoint) by 36% compared to radiation and temozolomide chemotherapy plus placebo (hazard ratio [HR] = 0.64; P < .0001) in people with newly diagnosed glioblastoma.

The data were presented at the 17th Annual Meeting of the Society for Neuro-Oncology in Washington, DC.1

regions of the body excluding the brain (11.6% vs 8.1%), hypertension (37.5% vs 13%), proteinuria (14% vs 4%), and arterial thromboembolism (5.0% vs 1.6%).

AVAglio is a phase������������� ������������ III, randomized, double-blind, placebo controlled trial that assessed the efficacy and safety profile of bevacizumab in combination with radiation and

temozolomide chemotherapy following surgery or biopsy in patients with newly diagnosed glioblastoma.

Patients were randomly assigned to continued on page 16

Key Findings The interim results for overall survival, the other co-primary endpoint, did not reach statistical significance (HR = 0.89; P = .2135). Final

By meeting its coprimary endpoint of progression-free survival, AVAglio is the first positive phase III study in newly diagnosed glioblastoma since 2005. data on overall survival are expected in 2013.

A 4.4-month improvement in median progression-free survival was observed when people with newly diagnosed glioblastoma received bevacizumab in combination with radiation and chemotherapy, compared to those who received radiation and chemotherapy plus placebo (10.6 vs 6.2 months, respectively).

Safety Data No new safety findings were observed in the AVAglio study, and adverse events were consistent with those seen in previous trials of bevacizumab across tumor types for approved indications. Adverse events of all grades that occurred more often in the bevacizumab arm compared to the radiation/chemotherapy arm (> 2% increased incidence) included bleeding in mucous/skin linings (26.7% vs 8.9%) or other

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies.

Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed.

Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

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PAGE 16

Journal Spotlight

Bone Marrow Transplants continued from page 1

The multicenter trial, led by Claudio Anasetti, MD, at the H. Lee Moffitt Cancer Center and Research Institute, randomized 551 patients with unrelated donors to receive either bone marrow or peripheral blood stem cell transplants. All patients had undergone chemotherapy or chemotherapy plus whole-body irradiation before transplantation, as well as regimens to help prevent graftvs-host disease.

Claudio Anasetti, MD

Overall survival at 2 years, the primary endpoint of the trial, was 51% in the peripheral blood group vs 46% in the bone marrow group, a difference that was not statistically significant.

Among secondary endpoints, the incidence of chronic graft-vs-host disease at 2 years in the bone marrow group was a statistically significant 41% vs 53% in the peripheral blood group. Relapse rates and incidence of acute graft-vs-

host disease were similar in both groups.

Graft failure was statistically significantly higher in the bone marrow group—9% vs 3% in the peripheral blood group.

According to the authors, the choice of peripheral blood stem cells or bone marrow may depend on specific patient characteristics. For instance, those who have never undergone cytotoxic chemotherapy, and thus are not as immunosuppressed as those who have, may be more likely to reject a bone marrow graft. Such patients might benefit from peripheral blood stem cells with their higher rates of engraftment. The indication for one or the other source according to patient or donor characteristics will need validation in prospective trials.

The same reasoning could apply to patients who receive low-dose or nonmyeloablative treatment, which is common now in patients older than 50 years. But “bone marrow may be recommended for all other patients,” said the authors, “especially those who are immunosuppressed owing to prior chemotherapy since they have a lower risk of graft rejection.”

■

Disclosure: Drs. Anasetti and Appelbaum reported no potential conflicts of interest.

Reference 1. Anasetti C, Logan BR, Lee SJ, et al: Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 367:1487-1496, 2012.

Bone Marrow vs Peripheral Blood Stem Cell Transplants ■■ The first large randomized trial with unrelated donors showed that overall survival was not significantly different between the two sources of blood stem cells.

■■ The incidence of chronic graft-vs-host disease was significantly higher among patients who received peripheral blood transplants.

■■ The incidence of graft failure was significantly higher among patients who received bone marrow transplants.

■■ Choice of bone marrow or peripheral blood stem cell transplants may depend on specific patient characteristics.

Bevacizumab in Glioblastoma continued from page 15

receive either: ■■ Bevacizumab plus radiation and temozolomide chemotherapy for 6 weeks followed by a 4-week break. Patients then received bevacizumab and temozolomide for up to six cycles, followed by bevacizumab alone until disease progression.

■■ Radiation, temozolomide, and placebo for 6 weeks followed by a 4-week break. Patients then received temozolomide and placebo for up to six cycles, followed by placebo until disease progression.

By meeting its co-primary endpoint of progression-free survival, AVAglio is the first positive phase III study in newly diagnosed glioblastoma since 2005.

Among other indications, beva-

EXPERT POINT OF VIEW

C

ommenting on the trial of bone marrow vs peripheral blood stem cell transplants, Frederick R. Appelbaum, MD, at the Fred Hutchinson Cancer Research Center, wrote that the results should change practice. But he added in his editorial, “it will be interesting to see whether it really does.”1

Risk-Benefit Considerations The initial benefits of peripheral blood transplants—more rapid engraftment can cut hospital stays by 4 or 5 days or more—account for some of its current popularity, Dr. Appelbaum said in an interview. Its major risk, ie, the heightened chance of developing chronic graft-vs-host disease, doesn’t show up until later, after the patient has left the transplantation center.

Peripheral blood transplants also may be preferred by some donors because they do not involve general anesthesia. But both kinds of donation are a major commitment, noted Dr. Appelbaum. Donors who give peripheral blood must take large doses of colony-stimulating factor, which can cause pain for several days before the procedure, sometimes requiring strong medication.

Most important, the increased risk of chronic graft-vs-host disease in patients who receive peripheral blood stem cells is a serious one. Though usually manageable, the disease can make it necessary for some patients to be on immunosuppressive drugs for a number of years. Complications can range from mild to fatal.

Although practice should change for most patients as a result of this trial, there are some groups of patients who should have peripheral blood transplants, Dr. Appelbaum said. For instance, patients who have reduced-intensity chemotherapy have a greater risk of graft failure, and they should use peripheral blood transplants because of the higher engraftment rates.

Looking Ahead Eventually, new drugs could influence the choice of bone marrow or peripheral blood transplants. One area of study, he said, is better methods of preventing graftvs-host disease, which, if successful, could remove the main disadvantage of peripheral blood transplants. Also under study are methods to improve engraftment after bone marrow transplants, which would remove its principal disadvantage.

In the meantime, the need for unrelated donors for all patients who need stem cell transplants remains an important issue. Donors can be found for most whites, but because of greater HLA polymorphism and underrepresentation in the registries, most blacks, Hispanics, Asians, and Native Americans cannot be matched with a donor.

Researchers are investigating ways to identify allowable HLA mismatches as well as the use of haploidentical donors and mismatched cord-blood transplants, Dr. Appelbaum wrote in the editorial. “These efforts must be successful if we are to reach the long-sought goal of having an acceptable source of allogeneic hematopoietic stem cells for every patient in need.”

■

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

Reference 1. Appelbaum FR: Pursuing the goal of a donor for everyone in need. N Engl J Med 367:1555-1556, 2012.

cizumab is currently approved in the United States under the FDA’s accelerated approval program as a monotherapy for the treatment of adults with glioblastoma who have progressive disease following prior therapy. The drug’s effectiveness in this setting is based on improvement in objective response rate; no data are available from randomized controlled trials demonstrating improvement in disease-related symptoms or

increased survival with bevacizumab in glioblastoma.

■

Reference 1. Chinot O: Phase III trial of bevacizumab added to standard radiotherapy and temozolomide for newly-diagnosed glioblastoma: Mature progression-free survival and preliminary overall survival results in AVAglio. 17th Annual Meeting of the Society for NeuroOncology. Plenary Session 5. Abstract OT03. Presented November 17, 2012.

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PAGE 17

Journal Spotlight Risk Reduction

Statin Use Associated with Reduced Cancer-related Mortality in Danish Study

By Matthew Stenger

C

ancer-related mortality among patients in the Danish population receiving a diagnosis of cancer at age ≥ 40 years between 1995 and 2007 was significantly reduced in those who were receiving statin therapy at the time of diagnosis, according to an analysis reported by Nielsen and colleagues in The New England Journal of Medicine.1 All-cause mortality was also significantly reduced among regular statin users.

Regular statin use was defined as filling of statin prescriptions within 6 months and for 2 years prior to the date of cancer diagnosis. Follow-up continued through 2009, and median follow-up was 2.6 years (range, 0–15 years). Among patients aged ≥��������������������������������������� �������������������������������������� 40������������������������������������ ����������������������������������� years, 18,721 used statins regularly until cancer diagnosis and 277,204 never used statins. Statin users had a median age of 70 years and 57% were male; statin nonusers had a median age of 69 years and 46% were male.

Over a total of 1,072,503 personyears of follow-up, 195,594 patients died—162,067 from cancer, 14,489 from cardiovascular causes, and 19,038 from other causes. Almost all patents (97%) were white persons of Danish descent.

as total milligrams dispensed in the next-to-last prescription before cancer diagnosis divided by defined daily dose of the particular statin, with this value divided by the interval between the date of the last statin prescription

and the date of the next-to-last statin prescription before diagnosis. No statin dose response was observed for reducing risk of mortality.

Compared with patients not receiving statins, those with defined daily

doses per day of 0.1 to 0.75, 0.76 to 1.5, and > 1.5 had hazard ratios for death from cancer of 0.83, 0.87, and 0.87, respectively (all P < .001). Table 1 shows hazard ratios for various causes continued on page 18

Reduced Cancer-related and All-cause Mortality The cumulative incidences of death from any cause and death from cancer-related causes as a function of follow-up time from the date of cancer diagnosis were significantly reduced in statin users (both P < .001). For death from any cause, the cumulative incidence curves for statin users and nonusers crossed at 5 years, likely reflecting increased cardiovascular mortality among statin users.

On multivariate analyses, statin use was associated with a 15% reduction in risk for cancer-related death (hazard ratio [HR]������������������������������ = ��������������������������� 0.85, 95% confidence interval [CI]������������������������������ = ��������������������������� 0.82–0.87) and a 15% reduction in all-cause mortality (HR = 0.85, 95%������������������������������ ����������������������������� CI��������������������������� = ������������������������ 0.83–0.87). The NEJM article does not report whether statin use influenced incidence of cancer.

All Statin Doses Reduced Mortality Statin use was analyzed as “defined daily dose” per day (assumed average maintenance dose per day for a particular drug); the measure was calculated

Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer.

References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. 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. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline.

J Clin Oncol. 2007;25(12):1596-1605.

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PAGE 18

Journal Spotlight

Statins and Cancer

Table 1: Risk of Death (Hazard Ratios) by Daily Dose of Statin Compared to No Statin Use

continued from page 17

of death in each dosage group.

Daily Statin Dose

Cancer Death

Cardiovascular Death

Death from Other Causes

All-cause Mortality

Subgroup Analyses

0.1–0.75 mg

0.83 (P < .001)

1.08 (P = .08)

0.70 (P < .001)

0.82 (P < .001)

0.76–1.5 mg

0.87 (P < .001)

1.25 (P < .001)

0.76 (P < .001)

0.87 (P < .001)

> 1.5 mg

0.87 (P < .001)

1.24 (P = .01)

0.77 (P = .003)

0.87 (P < .001)

In subgroup analyses, cancer-related mortality was significantly reduced with regular statin use in both women and men, patients aged 40 to 69 years or > 69 years at diagnosis, those who did not receive chemotherapy, those who did and did not receive radiotherapy, those with small and large tumors, those with and without metastasis, those with and without cardiovascular disease before diagnosis, those with and without diabetes before diagnosis, and those diagnosed between 1995 and 2002 or between 2003 and 2007.

Cancer-related mortality was also significantly reduced in patients with any statin use (rather than regular statin use; HR = 0.87, P < .001).

In patients who received chemotherapy, regular statin use was not associated with a significant reduction in cancer-related mortality. The article does not discuss any potential explanations for this latter finding.

Data from Nielsen SF, et al.1

It is possible that statin use was a marker of increased health awareness, potentially biasing the results of the analyses. Statin users were more likely to be men and to have diagnosed cardiovascular disease or diabetes.

However, a nested 1:3 matched study (matching for sex, age at diagnosis, year of diagnosis, and cancer type) including equal numbers of men and women and excluding patients with cardiovascular disease and diabetes yielded results similar to the above analyses.

Further, in an attempt to avoid a “healthy-user” bias, the nested 1:3 matched study was repeated using propensity-score matching (matching for the probability that patients received

Statins and Cancer Deaths ■■ Regular statin use, irrespective of dose, reduced cancer-related and all-

cause mortality in patients receiving statin therapy at the time of diagnosis; reduced cancer-related mortality was also seen in patients with any statin use prior to diagnosis.

■■ Reduced cancer-related mortality was seen among all subgroups of statin users except those who received chemotherapy.

■■ Since the population was 97% white persons of Dutch descent, the findings may not apply to other ethnic groups.

statins on the basis of patterns in medical history). Results of this analysis were also similar to results of the primary analyses.

Among 27 types of cancer included in the analysis, regular statin use was associated with significantly reduced cancer-related mortality for 13. Among these 13, multivariable adjusted hazard ratios ranged from 0.64 for cervical cancer to 0.89 for pancreatic cancer.

Potential Mechanisms Recent large-scale studies of statins in patients without cancer have not shown a reduced incidence of cancer or related mortality. Their apparent effect in reducing cancer-related mortality in patients receiving statin therapy when cancer is diagnosed may thus have to do with effects on cancer cells.

Statins inhibit endogenous cholesterol by inhibiting the mevalonate pathway.

Endogenous cholesterol is essential for cell proliferation, and reductions in available cholesterol could lead to reduced proliferation and migration of cancer cells.

As noted by the authors, “[T]he mevalonate pathway is upregulated by mutated p53 (tumor suppressor

Medical and Behavioral Variables Have More Impact on Physical Functioning Than Finasteride Treatment

protein), which is common in cancer.

Accordingly, inhibition of this pathway with statins reverts the malignancy phenotype of p53-mutated cancer cells. The decrease in downstream products of the mevalonate pathway has been linked to apoptosis and to reduced matrix-metalloproteinase production and angiogenesis, as well as a reduction in the invasiveness of in situ cancers. Statins have been linked to the halting of cell-cycle progression in cancer cells with resulting antiproliferative effects, to inhibition of key cellular functions in cancer cells, and to increased radiosensitization.”

The authors concluded, “[A]mong patients with cancer, we observed an association between statin use at the time of diagnosis and a reduced risk of cancer-related mortality, with a reduction of up to 15%. Prospective evaluation of the hypothesis that statin use prolongs survival of patients with cancer is needed.”

■

Reference 1. Nielsen SF, Nordestgaard BG, Bojesen SE: Statin use and reduced cancerrelated mortality. N Engl J Med 367:17921802, 2012.

Genitourinary Oncology

By Charlotte Bath

T

aking finasteride over a 7-year period as part of the Prostate Cancer Prevention Trial (PCPT) “did not affect any of the three primary health-related quality-of-life domains—physical function, mental health, or vitality—either positively or negatively,” according to a study published in the Journal of the National Cancer Institute.1 Other medical and behavioral variables, particularly diabetes and smoking, had larger effects on physical function.

While finasteride was not associated with the physical functioning score at any of the study’s three time points—3 months prior to randomization, 6 months after randomization, and an-

nually for 7 years—having diabetes at enrollment was associated with an 8.06 point decrease and being a smoker at enrollment was associated with a 5.53 point decrease in the physical functioning score at 6.5 years after randomization.

The PCPT was a double-blind, placebo-controlled trial that randomly assigned 18,882 men aged 55 years or older to receive the 5α-reductase inhibitor finasteride or placebo. “There was a 24.8% reduction in the prevalence of prostate cancer over the 7-year trial duration associated with finasteride treatment,” the authors noted. “In that initial report, finasteride was associated with increased sexual dysfunction; however,

a subsequent publication demonstrated that the level of sexual dysfunction was minimal and decreased over time.”

Study Implications The authors noted that finasteride is approved for the treatment of benign prostatic hyperplasia and that PCPT participants randomly assigned to finasteride reported a 40% to 44% reduction in incident, symptomatic benign prostatic hyperplasia compared with men who received placebo.

“These lower urinary tract symptoms have been associated with more falls in men. Benign prostatic hyperplasia symptoms are also associated with

reduced health-related quality of life,” the authors stated. “These findings suggest that the use of finasteride to control benign prostatic hyperplasia symptoms may have health-related quality-of life benefits that were not measured in the PCPT. Taken together with the other findings discussed above, our results indicate that finasteride is a low-risk preventative agent with minimal impact on health-related quality of life.”

■

Reference 1. Moinpour CM, Darkea K, Donaldson GW, et al: Health-related quality-of-life findings for the Prostate Cancer Prevention Trial. J Natl Cancer Inst 104:1373-1385, 2012.

ASCOPost.com | DECEMBER 15, 2012

PAGE 19

Issues in Oncology

Burnout in Oncology continued from page 1

in the Journal of Clinical Oncology (JCO)2 reviewed the problem of burnout among all oncology specialties. According to the article, studies show the prevalence of burnout is between 25% and 35% among medical oncologists, between 28% and 36% among surgical oncologists, and 38% among radiation oncologists.

The authors acknowledged that caring for patients with cancer can be extremely rewarding. However, they wrote, “caring for patients with cancer can be one of the most demanding and stressful areas of medicine.”

They noted that the constant lifeand-death decisions oncologists must make, administration of therapies that have high levels of toxicity, limited ability to prolong life for many patients, a median of 63-hour work weeks, increasing productivity requirements, the constant bombardment of new information and new regulations, loss of autonomy, and a reduced work/life balance all take a physical and mental toll that can lead to depression, damaged relationships, alcohol abuse, and suicide.

The suicide rate among physicians is higher than other professionals— approximately 300 to 400 physicians commit suicide each year, according to the JCO article. That number “equates to the entire graduating class of three to four U.S. medical schools.”

In addition to the personal distress, feelings of burnout can also lead to more medical errors and is one of the leading reasons physicians decide to leave their current practice or retire early.

“Burnout is a manpower issue because if more people decide not to specialize in oncology or if you are losing oncologists from burnout, you end up with an aging population and fewer oncologists [to treat them

when they get cancer],” said Carolyn D. Runowicz, MD, Member, ASCO Board of Directors, and Executive Associate Dean for Academic Affairs and Professor of Obstetrics and Gynecology at Florida International University, Herbert Wertheim College of Medicine, Miami.

Physician Wellness Survey Whether symptoms of burnout among oncologists are more prevalent now than in the past is not known, but

activities, level of work satisfaction, and compensation. The survey of oncology fellows focuses on their career intention after completing training and quality-of-life issues. The surveys were mailed in October, and the results are expected to be published in spring 2013.

“We decided to initially focus on medical oncologists rather than radiation oncologists and surgical oncologists because medical oncologists are a more homogeneous group

How to Reduce Burnout

A

lthough definitive solutions to preventing or overcoming burnout are still being researched, Michael P. Kosty, MD, a member of ASCO’s Workforce Advisory Group and Director of the Scripps Green Cancer Center, said taking regularly scheduled time off and pursuing outside interests may help. “It appears that physicians with more outside interests, such as golf, running, or traveling, who are able to take time off from their Michael P. Kosty, MD work a little more frequently are probably less likely to have burnout than people with their nose to the grindstone all the time.”

One of the aspects of burnout the Workforce Advisory Group will be looking at in ASCO’s Physician Wellness survey is “what makes the difference in determining who becomes burned out and who does not among physicians who have been in practice for a similar amount of time,” said Dr. Kosty.

In addition to taking time off, ASCO’s Workforce Advisory Group suggests: ■■ Leaning on a mentor, supervisor, or colleague for support ■■ Recognizing the physical or mental signs of burnout—ie, unexplained headaches, backaches, or other physical ailments; fatigue; lack of job satisfaction; and using food, drugs, or alcohol to feel better—and seeking professional help

■

the problem is becoming an increasing concern for the medical profession. Thus, ASCO is collaborating with Dr. Shanafelt to conduct a Physician Wellness survey of 3,000 medical oncologists and 1,500 oncology fellows. The survey of medical oncologists is focused on their professional

of individuals,” said Michael P. Kosty, MD, Director of the Scripps Green Cancer Center in La Jolla, California, and a member of ASCO’s Workforce Advisory Group. He represents that group on the Society’s Physician Wellness Steering Committee. “We also wanted to survey

fellows in training to see how, as they transition to different points in their career, their perceptions of their career evolve and when burnout first starts to occur. We’re also looking at what work situations seem to lead to burnout with a higher degree of frequency and, conversely, whether there are work situations that reduce the likelihood of somebody developing physician burnout.”

The goals of the survey, said Dr. Kosty, are to get a clearer understanding of the causes of oncologist burnout and of why some oncologists are more susceptible to the problem than others. In addition, the group seeks to define strategies to mitigate or prevent burnout.

“We think we have an idea based on older surveys on burnout and from surveys looking at surgeons with burnout that the problem is not uncommon, but we are trying to quantify the phenomenon. Then I think we can present the data to our membership and say, ‘these are the risk factors’— whether it is the amount of time the oncologist has been in practice or, more likely, the amount of job satisfaction. And then we hope to say, ‘these are the medical practice situations that are less likely to result in burnout, and here are strategies that long-time practitioners without burnout have used to try to mitigate the problem,’” said Dr. Kosty.

■

Disclosure: Drs. Shanafelt, Runowicz, and Kosty reported no potential conflicts of interest.

References 1. Shanafelt TD, Boone S, Tan L, et al: Burnout and satisfaction with work-life balance among US physicians relative to the general US population. Arch Intern Med 172(18):1-9, 2012.

2. Shanafelt T, Dyrbye L: Oncologist burnout: Causes, consequences, and responses; J Clin Oncol 30:1235-1241, 2012.

Send comments to editor@ASCOPost.com

Physician Burnout in Oncology: Challenges and Solutions Studies show the prevalence of burnout is:

25% 35%

Between and among medical oncologists

2% 36%

Between and among surgical oncologists

38%

among radiation oncologists

Have you been affected by burnout? How do you avoid burnout? Write to editor@ASCOPost.com and we will publish selected letters in future issues of The ASCO Post.

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THORACIC ONCOLOGY UPDATE:

Molecular Biomarker Testing Is Essential for Non-Small Cell Lung Cancer Patients During the past decade the identification of molecular biomarkers for clinically relevant mutations or other genetic abnormalities in non-small cell lung cancer (NSCLC) has improved the understanding of lung cancer pathogenesis, and of the proliferation and survival of cancer cells.1 This significant development is setting the stage for a paradigm shift toward the adoption of treatments directed to the particular genetic makeup of the tumor.1,2

Over 50% of NSCLC Cases Are Linked to Known Molecular Biomarkers

At Least 10 Known Molecular Biomarkers in NSCLC3

with similar clinical stage and tumor histology can have dramatically different

50% of NSCLC cases are linked to one of

clinical outcomes.4

KRAS

at least 10 currently known biomarkers

Indeed, biomarkers may give clinicians

for NSCLC — and many of these patients genetic abnormalities that are “drivers” for their cancers and are treatable with approved biomarker-driven therapies or

Unknown EGFR

as well as the treatment sensitivity/

ALK

resistance of the tumor to specific agents.4,5

TP53

Moreover, as genomic and mutational PIK3CA

IDH1

CTTNB1

HER2 NRAS

BRAF

research continues, more biomarkers will inevitably be discovered, so that the proportion of NSCLC cases with unknown drivers will continue its decline. The

Now that more than half of NSCLC cases

ultimate goal of this approach to

can be linked to one or more of these

treatment is to identify every driver

biomarkers, it is possible to subdivide

mutation for non-small cell lung cancer,

the histological subtypes of NSCLC

and design a corresponding treatment

— adenocarcinoma, squamous cell

for each of these oncogenes.1,2,4

carcinoma, and large cell carcinoma — into clinically relevant molecular subsets.1

In partnership with:

an indication of the patient’s prognosis (outcome independent of treatment),

investigational agents in clinical trials.2,3

Sponsored by:

considerable heterogeneity of non-small cell tumors and suggest why patients

According to recent studies, more than

may test positive for mutations or other

These molecular subsets show the

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Curbside Consult New Diagnostic Paradigm: Histology + Molecular Profile

For patients whose tumors test positive

David R. Gandara, MD Director, Thoracic Oncology Program, UC Davis Comprehensive Cancer Center

for a biomarker that is treatable with approved or investigational agents, the

Recently it has been proposed that

benefits of testing are self-evident.1,5,6

lung cancer treatment be based on the histology of the tumor. But there is

But in the future, molecular profiling

a growing consensus that molecular

will help an increasing proportion

profiling — testing the tumor at biopsy

of patients with NSCLC because the

for all appropriate biomarkers — should

additional information it reveals about

be part of the clinician’s standard

their tumor has the potential to guide

approach to pathologic evaluation.1,2

clinical management.2,7

And this is supported by the National Comprehensive Cancer Network (NCCN®)

Molecular Profiling Is Key in NSCLC

Clinical Practice Guidelines in Oncology

The discovery of biomarkers has

(NCCN Guidelines®) for all non-squamous

demonstrated the molecular complexity

non-small cell lung cancer (NSCLC)

of NSCLC, and it highlights the need

histologies, which state :

to move toward molecularly based

5

classification and treatment of these tumors.1,4 But only if patients are tested is it possible for them to potentially benefit

of “ Determination the specific molecular

from these developments.

As additional mutations are discovered

abnormalities of the tumor is critical for predicting sensitivity or resistance to a growing number of targeted therapies.

through efforts such as the National Cancer Institute’s Lung Cancer Mutation Consortium (LCMC) and the Cancer Genome Atlas — and as new agents are

”

developed to address these abnormalities — the hope for the over 215,000 people

– NCCN Guidelines® Version 3.2012, for Non-Small Cell Lung Cancer 5

diagnosed with lung cancer each year is that these advances will lead to more treatment options.1,8-10 In the words of Dr. David Gandara, Director of Thoracic

The NCCN® recommends EGFR and ALK

Oncology at UC Davis Comprehensive

testing for all advanced non-squamous

Cancer Center, “Our goal is to learn the

NSCLC, in order to guide treatment

‘molecular fingerprint’ of each person’s

decisions. Multiplex molecular profiling

lung cancer, and to personalize their

assays may make the prospective

therapy based on this information. The

5

discoveries that could make this possible

genotyping of tumors possible, to aid clinical decision making and management.

1

What is the most significant development you’ve seen in the treatment of lung cancer today?

DG Knowing what is driving the cancer!

We have recently been using histology to treat cancer based on the appearance of the cells. But cells that look identical under the microscope can have dramatically different clinical outcomes because of what is driving them at the molecular level. And that is leading us to molecularly based treatment options.

Can many NSCLC patients benefit from this testing? Who should be tested?

DG When you consider both approved and investigational agents, yes, a considerable proportion of NSCLC patients can receive therapy based on molecular testing. But at present I believe that all patients with NSCLC of the adenocarcinoma subtype should be tested.

That seems like a lot of testing.

Wouldn’t that require a re-biopsy for many patients?

DG These tests do require adequate tumor tissue. Some patients will need to be re-biopsied — some for lack of sample tissue, but also to look for changes that have occurred over time and as a result of therapy.

Other patients may not have to be re-biopsied.

To do the testing that reveals the “molecular fingerprint” of each person’s lung cancer, we have to get sufficient tumor tissue at biopsy.

Visit www.lungcancerprofiles.com for the patient perspective on molecular profiling.

are being made at a rapid pace.”

References: 1. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175-180. 2. Gandara DR, Li T, Lara PN Jr, et al. Algorithm for codevelopment of new drug-predictive biomarker combinations: accounting for inter- and intrapatient tumor heterogeneity. Clin Lung Cancer. 2012;13(5):321-325. 3. Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22(12):2616-2624. 4. Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer: lung cancer. N Engl J Med. 2008;359(13):1367-1380. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Non-small Cell Lung Cancer V.3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed August 20, 2012. To view the most recent and complete version of the guideline, go online to http://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. 6. Carr LL, Finigan JH, Kern JH. Evaluation and treatment of patients with non-small cell lung cancer. Med Clin N Am. 2011;95:1041-1054. 7. Goetsch CM. Genetic tumor profiling and genetically targeted cancer therapy. Semin Oncol Nurs. 2011;27(1):34-44. 8. National Institutes of Health. Lung cancer mutation consortium protocol. http://clinicaltrials.gov/ct2/show/NCT01014286. Accessed January 19, 2012. 9. National Cancer Institute. The cancer genome atlas. http://cancergenome.nih.gov/abouttcga/overview. Accessed January 19, 2012. 10. Boland JM, Erdogan S, Vasmatzis G, et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol. 2009;40:1152-1158. © 2012 Pfizer Inc.

All rights reserved.

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The ASCO Post | DECEMBER 15, 2012

PAGE 22

11th International Kidney Cancer Symposium Genitourinary Oncology

Combination Therapy Not Better than Single-agent Bevacizumab for Advanced Renal Cell Carcinoma in BeST Trial

By Charlotte Bath

N

one of three combination therapies tested among patients with advanced renal cell carcinoma in the BeST trial came close to achieving the primary objective of a 67% improvement in median progression-free survival compared to single-agent bevacizumab (Avastin), Keith T. Flaherty, MD, reported at the 11th International Kidney Cancer Symposium in Chicago.

“We were looking to see a 67% improvement, a rather bold attempt admittedly. But we figured that based on the phase I data, to absorb the cost of toxicity and then potentially the cost of doublet therapy that might become chronic treatment in the future, one would really need to see a significant improvement in this screening study to warrant further investigation,” said Dr. Flaherty. He is lead investigator of the BeST trial (the Eastern Cooperative Oncology Group’s E2804), a randomized

Keith T. Flaherty, MD

phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy with bevacizumab, sorafenib (Nexavar), and temsirolimus (Torisel) in advanced renal cell carcinoma. He is also Director of The Henri and Belinda Termeer Center for Targeted Therapy, Cancer Center, Massachusetts General Hospital, and Associate Professor, Department of Medicine, Harvard Medical School, Boston.

Reporting data that matured sufficiently for presentation just 2 weeks

before the symposium, Dr. Flaherty added that all three combination arms met one of the secondary objectives of response rates greater than 20%. For the key secondary endpoint of safety, “the severe toxicity rate was substantially higher with each of the two-drug combinations compared to single-agent bevacizumab,” Dr. Flaherty said. “You see a near doubling in terms of the rate of grade 3 and a clear doubling if you combine grade 3 and 4 toxicities for each of the combination arms compared to single-agent bevacizumab.”

The symptomatic toxicities were hypertension, fatigue, hand-foot syndrome, and diarrhea. The laboratory toxicities were hypophosphatemia, proteinuria, and hyperglycemia. “For both symptomatic toxicities and laboratory toxicities, we are seeing an accentuation of expected toxicities in terms of greater severity, but not new unexpected toxicities,” Dr. Flaherty said.

Targeting Multiple Pathways “The design of the trial was not to be a definitive study, but rather a randomized phase II trial specifically to try to identify the most active twodrug combination,” Dr. Flaherty explained. That combination could then be tested against the best available single-agent therapy in a phase III trial. “At the time, sunitinib [Sutent] looked to be that agent,” Dr. Flaherty said, but “concurrent with the launch of this trial, the results were emerging from two sunitinib phase I trials suggesting that it could not be safely combined with either temsirolimus or bevacizumab.”

In the BeST trial, bevacizumab, with known single-agent efficacy, served as the control (arm A) and was compared to three combination regimens identified in previous phase I trials. Arm B consisted of bevacizumab/temsirolimus, arm C was bevacizumab/sorafenib, and arm���������������������������� ��������������������������� D was sorafenib/temsirolim-

What Combinations Should Be Tested?

If the therapy combinations tested in the BeST trial don’t deserve to move on to phase III trials, what other combinations do show enough promise against renal cell carcinoma to merit being tested in phase III trials?

“None at the present time,” maintained Bernard Escudier, MD, of the Institut Gustave Roussy, Villejuif, France, at the 11th International Kidney Cancer Symposium.

Before conducting a phase III trial of combination Bernard Escudier, MD therapy against renal cancer, “we need to have a good scientific rationale based on mechanism of action; we need good in vitro data; and moreover, we need convincing clinical data, both in terms of efficacy and in terms of toxicity,” Dr. Escudier said. These criteria have not been met, however, by combinations tested in phase I or II trials so far, he stated.

Toxic Combinations Phase I trials with various combinations of sunitinib (Sutent), temsirolimus (Torisel), everolimus (Afinitor), and sorafenib (Nexavar) have shown that the combined use of mTOR inhibitors and tyrosine kinase inhibitors is very toxic, Dr. Escudier said. Based on these results, it is not necessary to test every new tyrosine kinase inhibitor with an mTOR inhibitor, he added. Other trials have shown that combining bevacizumab (Avastin) and tyrosine kinase inhibitors is also toxic, in addition to not being particularly effective, he said.

A phase I trial with bevacizumab and an mTOR inhibitor found the combination was “feasible” at full dose, with promising efficacy, but that was based on just 8 of 12 patients achieving partial responses, Dr. Escudier noted. “Progression-free survival has never been reported [for this combination]. There were no complete responses in this group of patients. And based on that, it has been recommended for further testing,” he said.

That recommendation triggered two randomized phase II studies—the BeST study, with 360 patients, and the TORAVA trial, with 160 patients—as well as a phase��������������������������������������������������������������������������� �������������������������������������������������������������������������� III study, the INTORACT trial, with 822 patients, for a total of 1,342 patients. Dr. Escudier noted that patients receiving the bevacizumab/mTOR inhibitor combination in these trials did not show an increase in progression-free survival.

Ideal Combinations “Ideal combinations are combinations that could induce complete responses, and so far we have not seen any combinations that could induce complete responses,” Dr. Escudier continued. He proposed that before testing drugs in combination, they first be tested sequentially. Doing sequential testing “before embarking on a large phase III trial would avoid a lot of problems,” he said. “That might be an ideal way to test in a randomized phase II study, a combination that could lead to a positive phase III study.”

Dr. Escudier also pointed out that “drug company requests to speed up are dangerous” and not a good reason to go to phase�������������������������������� ������������������������������� III trials. “Analyzing preliminary data is critical,” he said.

While Dr. Escudier said that no combinations are currently suitable for phase III testing, “there is one just to think about,” he noted. That combination is bevacizumab plus low-dose interferon, which he called “quite attractive.” In a phase II trial involving 147 patients, he noted that progression-free survival was 15.6 months and overall survival, 30.7 months.1 “So maybe that would be a good combination to test,” he concluded.

■

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

Reference 1. Melichar B, Bracarda S, Matveev V, el al: BEVLiN: Prospective study of the safety and efficacy of first-line bevacizumab (BEV) plus low-dose interferon-α2a (IFN) in patients (pts) with metastatic renal cell carcinoma (mRCC). 2011 ASCO Annual Meeting.

Abstract 4546. Presented June 7, 2011.

ASCOPost.com | DECEMBER 15, 2012

PAGE 23

11th International Kidney Cancer Symposium us. Each arm included between 81 and 87 patients, mostly male.

At the time the BeST trial was conceived, the hypothesis was that targeting multiple growth and survival pathways in vascular endothelial cells would result in suppression of escape mechanisms arising with antiangiogenic therapy in renal cell carcinoma.

“Bevacizumab, sorafenib, and temsirolimus had all shown single-agent efficacy to a greater or lesser degree,” Dr. Flaherty stated. Combining bevacizumab with sorafenib or temsirolimus was envisioned as a way to block escape mechanisms upstream and downstream, and combining sorafenib and temsirolimus was considered a parallel pathway blockade.

Study Design Key eligibility criteria were > 75% clear cell histology, with prior nephrectomy required unless there was a high burden of disease elsewhere, and no prior therapy with VEGF, VEGFR, or mTOR inhibitors. Singleagent bevacizumab was given at the previously evaluated dose for renal cell carcinoma—10 mg/kg administered intravenously every 2 weeks (on days 1 and 15). This dose was also used in arm B, combined with temsirolimus at 25 mg IV weekly (days 1, 8, 15, and 22). Bevacizumab doses were attenuated in arm C to 5 mg/kg IV every 2 weeks (days 1 and 15), combined with sorafenib at 200 mg administered orally twice daily on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26. In arm D, sorafenib at 200 mg orally twice daily on days 1 to 28 was combined with temsirolimus at 25 mg IV weekly (days 1, 8, 15, and 22).

Among patients who were able to stay free of disease progression and on therapy, “bevacizumab as a single agent as well as in combination held its dose intensity reasonably well from cycle to cycle,” Dr. Flaherty reported.

Doses of temsirolimus and sorafenib were attenuated, and sorafenib, which was started at a substantial dose reduction compared to its single-agent

Visit

phase������������������������� ������������������������ II dose, was further attenuated due to toxicity.

Response and Survival Rates

Table 1: Median Progression-free Survival in the BeST Trial

Arm A

Regimen

Hazard ratio

Bevacizumab

Reference

P value

90% CI

Median PFS (months) 8.7

0.68–1.23 0.62 7.3 Disease progression, oc- Arm B Bevacizumab/temsirolimus 0.91 curring in 60% of patients Arm C Bevacizumab/sorafenib 0.84 0.62–1.13 0.32 11.3 “was the main reason that pa1.11 0.83–1.49 0.55 7.7 tients discontinued therapy, Arm D Sorafenib/temsirolimus although adverse events were PFS = progression-free survival notable at 21%,” Dr. Flaherty Courtesy of Kevin T. Flaherty, MD. said. The median progression-free survival was 8.7 Table 2: Response Rates in the BeST Trial months in the bevacizumabArm B Arm C Arm D alone arm, 7.3 months for Arm A Bevacizumab/ Bevacizumab/ Sorafenib/ the bevacizumab/temsiroliBevacizumab temsirolimus sorafenib temsirolimus mus arm, and 7.7 months for Assessed (n) 60 65 63 70 the sorafenib/temsirolimus Complete — — — 1 arm. response “Only the bevacizumab/ sorafenib arm had the sug- Partial 12% 28% 30% 26% gestion of a slightly im- response proved outcome”—11.3 Stable disease 50% 51% 41% 44% months—Dr. Flaherty con25% 2% 16% 16% tinued. But after doing the Progressive disease preplanned statistical analyses, the hazard ratio (0.84) Not evaluable 13% 15% 13% 13% only slightly favored this arm, a 16% improvement in Fisher’s Exact P progression-free survival, he Pairwise comparison added. “We were targeting a Arm A vs Arm B .03 67% improvement, meaning Arm A vs Arm C .02 the hazard ratio needed to .05 be a good deal lower to ap- Arm A vs Arm D proximate statistical signifiCourtesy of Kevin T. Flaherty, MD. cance. The P values did not come close to significance statistically significant (see Table 2). the other way around—say, a whis[see Table 1].”

For overall survival—another per of bevacizumab with full-dose In the absence of improved prosecondary endpoint—there was “no sorafenib or temsirolimus—could gression-free survival, response rates hint of difference in outcome, not have been potentially more advantawere “deemed to be the potential even a suggestion of improvement,” geous, but we did not have the freetie-breaker,” Dr. Flaherty noted, with Dr. Flaherty said. “It is fairly clear dom to explore that,” Dr. Flaherty regimens producing response rates that no combination arm was supesaid. greater than 20% considered to be rior to single-agent bevacizumab for He also noted that survival data worthy of further study. “Although the progression-free survival primary continue to be gathered and will rethe progression-free survival data did endpoint.” flect not only the impact of the study not suggest superiority, … response In response to a question from a therapies but of subsequent treatment rate was superior with each of the symposium participant about whethreceived by trial participants. Those doublets, compared to single-agent er dialing up and down the doses of data are currently immature, he said, bevacizumab,” Dr. Flaherty said. “Just the drugs could have changed the but they could eventually prove usefocusing on objective responses, it outcome, Dr. Flaherty noted that this ful in understanding the course of the does appear that the combinations was not allowed in the E2804 trial. He disease after treatment with these trial have an impact on tumor regression,” acknowledge the possibility that “fullregimens.

Disclosure: Dr. Flaherty reported no he added, noting that the pairwise dose bevacizumab with just a small potential conflicts of interest. comparisons between arms were all fraction of a dose of another agent, or

■

website at ASCOPost.com

The ASCO Post | DECEMBER 15, 2012

PAGE 24

Expert’s Corner Gastrointestinal Oncology

Surgical Resection for Colorectal Cancer Liver Metastases: Who, When, How? A Conversation with Steven A. Curley, MD

By Caroline Helwick

Steven A. Curley, MD

M

any patients with colorectal liver metastases can undergo surgical resection with curative intent. Who are these patients and how are they best managed? In an interview with The ASCO Post, Steven A. Curley, MD, Professor of Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston, offered some answers.

Evolving Approach How has the thinking about colorectal cancer–related liver metastasis changed in the past decade or so?

The surgical management of colorectal cancer liver metastases has greatly evolved over the course of my career. In 1988, a seminal paper,1 based on the Registry of Hepatic Metastases from 24 institutions, suggested that we not consider resection for any patient with extrahepatic disease (even if deemed resectable), when resection margins would be < 1 cm, with short disease-free intervals, with stage IV disease at the time of diagnosis of the primary tumor, and with more than three metastatic liver lesions.

This created dogma for the time, but we later realized we needed to push the envelope, because many patients have potentially resectable metastases but do not otherwise fit these criteria. For example, I have a patient with eight liver metastases. On imaging, we found that all were in the right lobe of the liver, so technically, these could be resected with a right hepatectomy. If we followed the Registry recommendations, we would not have considered surgery. He is now a 10-year survivor.

So, in 2012, how do you handle the patient with asymptomatic primary colorectal cancer who presents with liver metastasis?

Resection of liver metastasis, usually after neoadjuvant chemotherapy, is the optimal treatment for this patient, and that is always our chief goal. As a surgeon, my first question is whether I can do this operation safely. Can I leave the patient with an adequate volume of functional liver that is well perfused and has good biliary drainage? Today, we do CT volumetry to help answer this question.

This test helps us estimate the volume of the future liver remnant. There is a clear correlation between the volume of liver resection and survival and complication rates. Patients with normal livers can tolerate resections of up to 80% of the organ, but this drops to about 60% to 70% in patients with steatotic livers, and becomes very small for patients with cirrhotic livers, which, thankfully, is not common in patients with colorectal cancer liver metastases.

Impact of Liver Disease How does underlying liver disease influence outcomes?

Patients with underlying liver disease don’t tolerate resection as well as

duced our transfusion rate from over 60% to under 5%.

Radiofrequency Ablation When do you incorporate radiofrequency ablation into treatment?

Radiofrequency ablation came onto the scene in the 1990s, and it allows us to treat more patients. The MD Anderson database is very informative about the technique, though I emphasize that these are not randomized trial data.

We evaluated 418 patients with liver-only metastases; of these, 348 had a potentially curative procedure, which was resection in 190 patients.

For the other 158 patients, a complete resection was not possible, and of this group, 101 had resection plus radiofrequency ablation, whereas 57 had radiofrequency ablation alone.

There were also 70 patients deemed unresectable due to extrahepatic disease, and they received no resection or radiofrequency ablation but could receive chemotherapy.

Overall survival at 5 years for the 348 patients treated with curative intent was 44%. When we broke this down, we found that overall survival was best

The old dogma that we need negative margins to be ≥ 1 cm is not true. We (and others) have shown that a negative margin of only 1 to 2 mm is adequate, and is associated with a very low risk of local recurrence.

— Steven A. Curley, MD

those without. Clearly, patients with an abnormal liver from, say, steatosis or nonalcoholic steatohepatitis cannot tolerate resection of a large volume.

For patients wth a healthy liver, if the future liver remnant is < 20%, the risk for liver-specific complications rises to 50%. If you leave ≥ 20% behind, the complication rate drops to about 20%.

Clearly, this is a key factor in surgical planning.

We also are concerned about the blood vessels lying beneath the surface of the organ. With imaging, we want to determine the association of the tumor with these important blood vessels so that we can control for problems during surgery. We now have surgical instruments that can help produce a bloodless surgical field, which has re-

in the patients who received resection only. Overall survival at 3 years was 73% with resection, 43% with resection plus radiofrequency ablation, and 37% with radiofrequency ablation alone. At 5 years, overall survival was 58% with resection but only about 20% in the other arms (P < .0001).2 Recurrence-free survival was also best with resection only.

In the unresectable (for curative intent) group, there also appeared to be some benefit for radiofrequency ablation, alone or with resection, compared to chemotherapy, which resulted in a 3-year overall survival of only 12% and a 5-year overall survival of 7%.

These results have been mirrored in multiple other modern series, all showing about a 58% overall survival rate at 5 years after resection alone for colorectal

cancer liver metastases. The data have led surgeons to be much more aggressive about attempting resection. While there may be a role for newer ablation techniques, an advantage over resection has not been show in any randomized trial.

For patients with unresectable disease, radiofrequency ablation may have a role in improving overall survival when combined with chemotherapy, but this needs to be confirmed in randomized trials.

Ongoing Challenges What continues to frustrate you in attempting resection in these patients?

I am frustrated by patients with bilobar tumors that I cannot resect and leave an adequate volume of liver, and patients with one or two tumors that are in locations not amenable to resection with negative margins. We can operate near major blood vessels, but there are patients whose pattern of metastasis is such that we cannot resect them.

Incidentally, the old dogma that we need negative margins to be ≥ 1 cm is not true. We (and others) have shown that a negative margin of only 1 to 2 mm is adequate, and is associated with a very low risk of local recurrence.

Then, does number of metastases no longer matter? Are patients no longer excluded based on number of lesions?

An MD Anderson study of 159 patients with at least four metastatic lesions, who underwent resection or resection plus radiofrequency ablation, found overall survival at 5 years to be 51%,3 suggesting that we should question the dogma that patients with at least five lesions are not surgical candidates. We encourage all patients to be assessed by a surgeon to determine if they are candidates for resection.

Neoadjuvant Chemotherapy What is the role of neoadjuvant chemotherapy?

Response to neoadjuvant chemotherapy increases the odds of longterm survival 2.5-fold. This can be a response in the form of reduction in tumor volume, increased calcification of lesions on CT scan, or reduction in serum carcinoembryonic antigen levels. Several studies have shown the survival advantage of achieving a pathologic complete response, but 85% of patients with radiographic dis-

ASCOPost.com | DECEMBER 15, 2012

PAGE 25

Expert’s Corner

appearance of lesions still have viable tumor cells at those metastatic sites.

In our own series, major pathologic response (≤ 10% viable cells in the tumor specimen) was an independent predictor of improved disease-free and overall survival, but it is hard to select out this group.

Timing of Resection What is the time course for treating these patients—that is, how do you time the resection?

The timing of liver resection should be considered by a multidisciplinary team. When a patient has a lesion in a critical location, disease progression while on chemotherapy can render them less resectable. These patients should probably undergo surgery promptly, followed by adjuvant chemotherapy. Other patients may benefit from a neoadjuvant approach, which allows us to evaluate their response and determine whether they are good

candidates for resection.

You also have to be cognizant of the effects of systemic chemotherapy on liver quality. Hepatotoxicity has been reported with fluorouracil, irinotecan, and oxaliplatin, which speaks to the need for multidisciplinary management early in the disease course. I often see patients who have had 12 to 18 months of chemotherapy. On imaging, I can see that they once had resectable disease, but now they have irinotecanrelated steatohepatitis and the metastases cannot be resected because of treatment-induced liver damage. The chemotherapy-related liver injury has taken them out of the realm of potentially curative surgical therapy.

Role of Biomarkers Can molecular markers be incorporated into decision-making regarding resection?

Data on tumor biology as it relates to resection outcomes are being col-

lected, but there are no answers yet.

We are most interested in identifying the subset of patients who respond to neoadjuvant chemotherapy and undergo resection, yet 6 months later develop new disease. Clearly, in these patients, local therapy did not help. We conduct an ongoing prospective analysis of tissue samples to try to differentiate these patients.

Unanswered Questions What are the remaining uncertainties about resection of liver metastases?

Unresolved issues include the role of preoperative portal vein embolization to increase the size of the future liver remnant in borderline resectable patients; the benefit of staged resections, which are associated with high morbidity and mortality and should be carefully considered; and timing of the resection in patients with stage IV disease—ie, should we resect the primary or metastasis first? In addition, we need to clarify

the assessment of liver damage related to neoadjuvant chemotherapy, the number of cycles and dose of neoadjuvant chemotherapy, the correlation of molecular markers with resectability, and the assessment of liver damage related to comorbid conditions.

■

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

References 1. Resection of the liver for colorectal carcinoma metastases: A multi-institutional study of indications for resection.

Registry of Hepatic Metastases. Surgery 103:278-288, 1988.

2. Abdalla EK, Vauthey JN, Ellis LM, et al: Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 239:818-825, 2004.

3. Pawlik TM, Abdalla EK, Ellis LM, et al: Debunking dogma: Surgery for four or more colorectal liver metastases is justified. J Gastrointest Surg 10:240-248, 2006.

Richard R. Barakat, MD, Elected 2014 President of Two Gynecologic Oncology Medical Societies International Society Announces New Officers at Biennial Meeting

R

ichard R. Barakat, MD, was results of the recent election for recently named President-elect new Officers, Council Members, of the Society of Gynecologic Onand Committee Members, and these cology (SGO) and the International positions became effective followGynecologic Cancer Society (IGCS). He will serve as President of both societies beginning in 2014. Dr. Barakat is Vice Chair, Clinical Activities, Department of Surgery; Chief, Gynecology Service; Ronald O. Perelman Chair in Gynecologic Surgery, Memorial Sloan-Kettering Cancer Center, New Robert L. Coleman, MD Richard R. Barakat, MD York. Dr. Barakat is also an ing the 14th Biennial Meeting of the editorial advisory board member of Society held recently in Vancouver, The ASCO Post.

Canada.

The International Gynecologic In addition to Dr. Barakat as PresCancer Society also announced the

Council, Africa/Europe/Middle East, Roberto Angioli, MD, of University of Rome, Italy Council, America, Nadeem AbuRustum, MD, of Memorial Sloan-Kettering Cancer Center, New York Council, Pathology. Elvio Silva, MD, of CedarsSinai Medical Center, Los Angeles Finance committee member, Paolo Zola, MD, PhD, University of Turin, Elvio Silva, MD Italy.

ident-elect, new officers for the IGCS include: Vice President, Soon-Beom Kang, MD, Seoul National Universi-

Nadeem Abu-Rustum, MD

ty College of Medicine, Seoul, Korea Secretary-Treasurer-elect, Robert L. Coleman, MD, of the UT-MD Anderson Cancer Center, Houston

■

Visit SGO.org and IGCS.org for more information about these gynecologic oncology societies.

More on Gynecologic Oncology M. Steven Piver, MD, of Sisters of Charity Hospital and Roswell Park Cancer Institute, Buffalo, New York, discusses the recent U.S. Preventive Services Task Force Reaffirmation Recommendation Statement in this issue of The ASCO Post.

See pages 1 and 122 where Dr. Piver provides his perspective on the subject and recommendations for advising primary care physicians and general obstetrician-gynecologists about screening for ovarian cancer.

NOW

APPROVED in five indications!

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54th ASTRO Annual Meeting Breast Cancer

Plenary Session Included Findings on Partial- vs Whole-breast Techniques and Patient Beliefs about Radiotherapy

By Alice Goodman

W

hen the dates were picked for the 54th Annual Meeting of the American Society for Radiation Oncology (ASTRO), no one could have anticipated that the meeting would coincide with Hurricane Sandy’s devastation of parts of the northeast. As the storm approached on Monday and Boston shut down its transit system, ASTRO attendees had to evacuate the convention center by 2:00 PM. Thus, the Plenary Session scheduled for Monday afternoon was delivered to video cameras and tape recorders instead of to a live audience. Happily, Boston was largely spared and the ASTRO Annual Meeting reopened on Tuesday.

In addition to our more in-depth coverage of ASTRO presentations, we have compiled brief reports of a few further meeting highlights here, including two presentations from the Plenary Session.

Mistaken Beliefs about Radiotherapy Many patients with terminal lung cancer reported mistaken beliefs about their expectations for palliative radiation therapy in a study reported by the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) at the Plenary Session.1 Only 36% of patients correctly stated that radiation therapy was not at all likely to cure their disease.

Aileen B. Chen, MD

CanCORS was a population-based and health system–based prospective cohort study that enrolled 5,013 patients with newly diagnosed lung cancer in 5 geographic regions, at 10 Veterans Administration sites and 5 large health maintenance organizations from 2003 to 2005. Patients older than age 21 with stage “wet” IIIB or IV lung cancer who received or were scheduled

to have radiation therapy were interviewed about 4 months after diagnosis.

The investigators analyzed responses to various questions that began: “After talking with your doctors about radiation therapy, how likely did you think it was that radiation would …?”

Responses to surveys from 384 patients were analyzed. Median survival was 11.5 months. Most patients were optimistic that radiation therapy could help them. More than three-quarters (78%) of patients believed that radiation was very likely or somewhat likely to help them live longer, and about two-thirds (67%) believed that radiation was very likely or somewhat likely to help them with problems from lung cancer. Also, 66% believed that radiation therapy was very likely or somewhat likely to have side effects or complications. The authors were concerned, however, that 64% did not understand that radiation therapy was not at all likely to cure their cancer.

These results suggest that physicians need to be more proactive in having conversations about expectations of radiation therapy with patients who have incurable lung cancer. Several studies have shown that it is difficult for physicians to have end-of-life discussions with patients, but other studies show that being honest with patients about the risks and benefits of therapy actually empowers them to make decisions that are right for them, explained lead author of this study, Aileen B. Chen, MD, a radiation oncologist at Dana-Farber Cancer Institute in Boston.

“To help patients make informed decisions about radiation treatments near the end of life, health-care providers need to improve communication with patients and understanding about the goals and limitations of palliative radiotherapy. While palliative radiotherapy can be very effective at relieving symptoms from cancer, overly intensive care can reduce patients’ quality of life and lead to significant time and financial burdens for patients and their families.”

Long-term Cardiac Safety of Breast Irradiation Patients with breast cancer who were treated with radiation did not have a

Cosmetic Outcomes for Partial- vs Whole-breast Irradiation

Charles B. Simone, II, MD

higher risk of cardiovascular mortality compared to those treated with modified radical mastectomy, according to the first study to document comprehensive cardiac outcomes 25 years after treatment.2 The study was reported

by Charles B. Simone, II, MD, a radiation oncologist at the Hospital of the University of Pennsylvania in Philadelphia.

The investigation focused on longterm outcomes in 247 patients with stage I and II breast cancer who were enrolled in an NCI breast-conservation trial from 1979 to 1987. Twentyfive years following treatment, 102 patients were alive. Fifty of these patients participated in this study; 26 underwent breast-conserving therapy plus radiotherapy, and 24 had modified radical mastectomy.

Evaluations included a detailed cardiac history, exam, cardiac laboratory tests, and 3T cardiac MRI to assess anatomic and functional abnormalities, as well as a CT angiogram to evaluate coronary stenosis and determine whether patients had a high coronary arterial calcium score for atherosclerosis. For all parameters assessed, no higher risk of adverse cardiovascular outcomes was found in patients who underwent breast irradiation.

This is good news, since these findings were in women treated with older radiation techniques. “Over the past 2 decades, radiation has become more precise and safer with modern techniques. We are pleased to find that patients with early-stage breast cancer treated with modern radiation therapy treatment planning techniques do not have an increased risk of long-term cardiac toxicity and that breast-conservation therapy with radiation therapy should remain a standard treatment option,” Dr. Simone commented.

Accelerated partial-breast irradiation with three-dimensional (3D) external-beam radiation therapy for patients with breast cancer who have had breast-conserving surgery can result in a worse cosmetic outcome compared with whole-breast irradiation, according to interim safety results of the phase III RAPID trial presented at the Plenary Session.3 Accelerated partial-breast irradiation may be offered to women following breast-conserving surgery as part of their treatment, explained lead author Timothy Whelan, MD, Juravinski Cancer Centre, Hamilton, Ontario, Canada. “Our study supports earlier

Timothy Whelan, MD

phase������������������������������������ ����������������������������������� II trial research, finding that accelerated partial-breast irradiation using 3D conformal radiation therapy can increase the risk of moderate radiation side effects, which may affect cosmetic outcome for some patients.

Additional research on [3D conformal radiotherapy–based accelerated partial-breast irradiation] is needed before offering it to women as a standard option,” he stated.

At a median follow-up of 2.5 years, nurses found that 32% of 850 patients had adverse cosmesis compared with 19% of patients treated with wholebreast irradiation. Oncologists and patients had similar assessments in the rate of observed adverse cosmesis with accelerated partial-breast irradiation vs whole-breast irradiation.

The rates of late grade��������������� �������������� 1 and 2 radiation toxicities were higher in women treated with accelerated partial-breast irradiation vs whole-breast irradiation.

Grade 3 and 4 toxicities were rare in both treatment groups. continued on page 28

The ASCO Post | DECEMBER 15, 2012

PAGE 28

54th ASTRO Annual Meeting Partial- vs Whole-breast Irradiation continued from page 27

Stereotactic Body Radiation Therapy for Inoperable Stage I NSCLC A preliminary study found that the safety and efficacy of stereotactic body radiation therapy compared favorably to historical results with conventional radiation therapy in patients with inoperable stage I non–small cell lung cancer (NSCLC).4 In 100 patients treated from June 2004 to November 2008 at 15 institutions in Japan, 3-year overall survival was 59.9%, and toxicity was mild.

Three-year progression-free survival was 49.8%, local progression–

free survival was 52.8%, and eventfree survival was 46.8%. The rates of grade������������������������������� ������������������������������ 3 adverse events included dyspnea in 10% of patients, hypoxia in 8%, pneumonitis in 7%, chest pain in 2%, and cough in 1%. Only 2% of patients reported grade 4 adverse events (dyspnea and hypoxia), and no grade 5 adverse events were seen. “[Stereotactic body radiation therapy] can be delivered in a shorter window of time with lower rates of toxicity than conventional radiation therapy.

In this study, [stereotactic body radiation therapy] for patients with inoperable stage I lung cancer was highly effective and showed mild toxicity. This treatment should replace conventional radiotherapy as standard treatment for

this population of patients,” stated lead author Yasushi Nagata, MD, Department of Radiation Oncology at Hiroshima University in Hiroshima, Japan, as study coordinator of the Japan Clinical Oncology Group ( JCOG) 0403 trial.

■

Disclosure: Drs. Chen, Whelan, Simone, and Nagata reported no potential conflicts of interest.

References 1. Chen AB, Cronin A, Weeks J, et al: Patient beliefs about palliative radiation therapy (RT) in incurable lung cancer.

54th ASTRO Annual Meeting. Abstract 1.

Presented October 29, 2012.

2. Simone CB, Sibley C, Dan TD, et al: Cardiac toxicity is not increased 25 years after treatment of early-stage breast carci-

Fox Chase Researchers Find Most Medicare Patients Wait Weeks before Breast Cancer Surgery

A

lthough patients may feel anxious waiting weeks from the time of their first doctor visit to evaluate their breast until they have breast cancer surgery, new findings from Fox Chase Cancer Center in Philadelphia show that these waits are typical in the United States. Results were published recently online in the Journal of Clinical Oncology.1 Looking at data collected from more than 72,000 Medicare patients diagnosed with nonmetastatic breast cancer, researchers—led by Richard J. Bleicher, MD, FACS, attending surgeon and Director of the Breast Fellowship Program at Fox Chase— found that, in 2005, half of the breast cancer patients underwent breast cancer surgery at least 32 days after first consulting their doctor about their breast problem. This is an increase from 1992, when half of the patients waited no more than 21 days.

Typical Wait Time “For many Medicare patients, it can take a month or more from the time they first see their doctor to evaluate their breast concern, make a diagnosis, and get them to the operating room,” said Dr. Bleicher. “So if a woman learns that her surgery date is weeks after her evaluation, where she was found to have a breast cancer, she should know this length of time is typical, and should not be concerned.”

He added, “Although this interval may sound alarming at first, it does

Richard J. Bleicher, MD, FACS

not appear to have a detrimental effect on outcomes. We don’t have the outcomes data for this group of patients yet, but we have seen improvements in survival over the past few decades in breast cancer overall.”

Before this study, Dr. Bleicher explained, it was unclear how long people were actually waiting for surgery and how the surgery type and workup affected that wait. Experts had data from individual institutions, but nothing that captured waiting times nationwide. So when patients got anxious hearing their surgery was weeks away, doctors were unable to tell them whether such wait times were longer than the norm, and thus potentially dangerous.

Reasons for Longer Delays “It’s not clear why people are waiting longer for surgery,” said Dr. Bleicher. Now that patients have access to more information about cancer, they may take longer to make decisions about surgery; alternatively, a larger patient population could be filling operating rooms, making it harder

to schedule surgeries. Indeed, patients undergoing more complicated procedures—such as mastectomy with breast reconstruction—waited longer than average.

Longer delays were also seen in patients who received certain types of biopsies and imaging. This suggests that part of the increase in wait time may stem from greater use of a wider variety of current tools to detect and image the tumors before surgery, said Dr. Bleicher. This may also explain why patients may be living longer, even though the time from presentation to their doctor until surgery steadily increased from 1992 to 2005.

“Patients should be aware that even though breast cancer feels like an emergency needing to be addressed tomorrow, it doesn’t have to be dealt with in a matter of days,” said Dr. Bleicher. “These results should reassure women that, if they are not in the operating room tomorrow, that’s typical.”

He added that the findings apply only to patients receiving Medicare, and wait times may differ for those with private insurance or no insurance at all.

■

Disclosure: The authors reported no potential conflicts of interest.

Reference 1. Bleicher RJ, Ruth K, Sigurdson ER, et al: Preoperative delays in the US Medicare population with breast cancer. J Clin Oncol. November 19, 2012 (early release online).

noma with mastectomy or breast conservation therapy from the National Cancer Institute randomized trial. 54th ASTRO Annual Meeting. Abstract 87. Presented October 29, 2012.

3. Whelan T, Olivotta I, Parpia S, et al: Interim toxicity results from RAPID: A randomized trial of accelerated partial breast irradiation (APBI) using 3-D conformal external beam radiation therapy (3-D CRT). 54th ASTRO Annual Meeting. Abstract LBA2. Presented October 29, 2012.

4. Nagata Y, Hiraoka M, Shibata T, et al: Stereotactic body radiation for T1N0M0 non-small cell lung cancer. First report for inoperable population of a phase II trial by Japan Clinical Oncology Group. 54th ASTRO Annual Meeting. Abstract 115. Presented October 29, 2012.

Contact

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

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

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

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2012 Novartis

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ZOM-1052241

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

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

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

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

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

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

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

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

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

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

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

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

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

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

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

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

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

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

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

© 2012 Novartis

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ZOM-1052241

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

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

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

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

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

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

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

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

T:13”

B:14.25”

S:12.75”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Grade 4

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

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

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

86 (100) 81 (94)

103 (100) 95 (92)

38 14

(44) (16)

34 21

(33) (20)

9

(11)

2

(2)

25 23 15 14 12 8

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

28 13 17 13 17 14

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

19

(22)

18

(18)

10

(12)

4

(4)

11 10 9

(13) (12) (11)

2 16 5

(2) (16) (5)

10

(12)

10

(10)

13 12 11 11

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

10 8 13 8

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

19 10

(22) (12)

20 12

(19) (12)

12

(14)

15

(15)

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

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

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

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

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

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

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

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

(2%) (1%) (51%) —

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

(3%) (2%) (33%) —

Laboratory Parameter

Creatinine1

Serum Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

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

— — (1%) —

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

(1%) — (5%) (1%)

1Grade

3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) 2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L) Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.

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

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

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

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

Table 7: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%) Patients Studied Total No. of Patients 1031 (100) Total No. of Patients with any AE 1015 (98) Blood and Lymphatic Anemia 344 (33) Neutropenia 124 (12) Thrombocytopenia 102 (10) Gastrointestinal Nausea 476 (46) Vomiting 333 (32) Constipation 320 (31) Diarrhea 249 (24) Abdominal Pain 143 (14) Dyspepsia 105 (10) Stomatitis 86 (8) Sore Throat 82 (8) General Disorders and Administration Site Fatigue 398 (39) Pyrexia 328 (32) Weakness 252 (24) Edema Lower Limb 215 (21) Rigors 112 (11) Infections Urinary Tract Infection 124 (12) Upper Respiratory Tract Infection 101 (10) Metabolism Anorexia 231 (22) Weight Decreased 164 (16) Dehydration 145 (14) Appetite Decreased 130 (13)

Pamidronate 90 mg n (%)

Placebo

556 (100) 548 (99)

455 (100) 445 (98)

175 83 53

(32) (15) (10)

128 35 20

(28) (8) (4)

266 183 162 162 81 74 65 61

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

171 122 174 83 48 31 14 17

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

240 172 108 126 62

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

130 89 114 84 28

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

50 82

(9) (15)

41 30

(9) (7)

81 50 60 48

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

n (%)

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

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

Pamidronate 90 mg n (%)

Placebo n (%)

569 239 216 156 143

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

316 143 131 106 84

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

284 74 73 40 52

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

205

(20)

97

(17)

89

(20)

191 180 166 149 127

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

149 91 111 85 65

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

50 58 73 35 43

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

146 112 74

(14) (11) (7)

95 73 39

(17) (13) (7)

49 37 47

(11) (8) (10)

282 224

(27) (22)

155 129

(28) (23)

107 65

(24) (14)

125 114

(12) (11)

80 74

(14) (13)

36 38

(8) (8)

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

Table 8: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 3 Laboratory Parameter T:13”

B:14.25”

S:12.75”

Zometa 4 mg n/N

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

(%)

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

Pamidronate 90 mg n/N

(%)

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

Placebo n/N

(%)

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

1Grade

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

Creatinine1*

Serum Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5 1Grade

Zometa 4 mg

Pamidronate 90 mg

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

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

(<1%) (<1%) (<1%) — (<1%)

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

(<1%) (<1%) — — (<1%)

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

— (<1%) (<1%) (<1%) —

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

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

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

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

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

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

27/246 2/26 29/272

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

23/246 2/22 25/268

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

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

17/154 1/11 18/165

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

10/143 1/20 11/163

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

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

12/82 4/10 16/92

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

8/68 2/10 10/78

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

ASCOPost.com | DECEMBER 15, 2012

PAGE 35

Expert’s Corner Health-care Policy

How Sequestration May Affect Cancer Research A Conversation with Senator Sherrod Brown

By Jo Cavallo in the federal deficit—is scheduled to take effect. Unless a bipartisan resolution can be reached before the end of the year, funding for every federal program, including the NCI and the NIH, will be cut by 8%, threatening the continuation of progress made in biomedical and cancer research.

The ASCO Post asked Senator Brown about these issues.

Senator Sherrod Brown

S

T:13”

B:14.25”

S:12.75”

enator Sherrod Brown (DOhio) began his political career in 1974 as a state representative in Ohio.

He served as Ohio’s Secretary of State between 1983 and 1991, went on to serve in the U.S. Congress from 1993 to 2006, and was elected to the Senate in 2006. A supporter of biomedical and cancer research, Senator Brown sponsored the Access to Cancer Clinical Trials Act, which was folded into the Patient Protection and Affordable Care Act as an amendment.

He also successfully led a bipartisan effort to add another amendment to the Affordable Care Act that prohibits insurers from dropping health-care coverage to policyholders who participate in cancer clinical trials and from denying coverage for routine care during the clinical trial.

In 2011, ASCO recognized Senator Brown with its Public Service Award for his efforts in supporting patient protections in the Affordable Care Act, his commitment to ensuring exceptional cancer care, education, and research in Ohio’s cancer hospitals and medical schools, and his support in increasing funding for the National Cancer Institute (NCI) and the National Institutes of Health (NIH). In October, the American Association for Cancer Research also recognized Senator Brown’s advocacy for biomedical and cancer research and his contributions to public health policy with its 2012 Distinguished Public Service Award.

On January 2, 2013, a deficitbudget mechanism known as sequestration—crafted by Congress in the Budget Control Act of 2011 to force across-the-board cuts to defense and domestic spending to rein

Budget Crisis Can Congress resolve the budget crisis before the end of the year?

We can address our nation’s fiscal problems in a manner that does not undercut important investments like

for increased funding of cancer and biomedical research and improving cancer care for patients?

Virtually all of us know someone who has been diagnosed with cancer, and cancer affects not just the patient but also family, friends, and loved ones. With more than 1.6 million Americans expected to be diagnosed with cancer this year, we must continue to support advancements in the prevention, detection, and treatment of cancer.

Coverage for Patients in Clinical Trials Participation in clinical trials by people with cancer is notoriously low—less

We must recognize that funding medical research is a win-win for the health of our citizens and for driving economic growth.

—Senator Sherrod Brown

cancer research. That is why I support a measured, balanced approach to spending and revenue. It is only by undertaking such an approach that we can get our fiscal house in order.

I believe that Republicans and Democrats must work together on a balanced approach that avoids sequestration, which could impose severe across-the-board cuts on every federal program. Sequestration could seriously injure our economy and have a devastating impact on a variety of federal agencies, including the NIH.

Fighting for Funding Is it inevitable that the NIH and NCI budgets will be reduced regardless of how sequestration is resolved?

At a time when the government must tighten its belt, most federal agencies, including the NIH and the NCI, are being asked to do more with less. I will keep fighting for funding for the NIH and NCI because the work that these agencies do furthers American innovation and helps save lives. Investments like those made by the NIH and the NCI save money in the long term.

Why are you such a strong advocate

than 5%. Do you think your amendments in the Affordable Care Act will help increase enrollment?

Clinical trials constitute one of the most effective weapons in our nation’s ongoing fight against cancer, but nearly 20% of patients with cancer who try to enroll in a clinical trial face delays in approval from their insurance companies—or worse yet, denials of coverage. Thanks to health-care reform, beginning in 2014, it will be illegal for insurers to establish illogical or unethical coverage exclusions for routine care costs when a patient enrolls in a clinical trial.

In fiscal year 2011, Ohio scientists and physicians attracted more than $710 million in grant funding, including $104 million dedicated to cancer research. We must recognize that funding medical research is a win-win for the health of our citizens and for driving economic growth.

Editor’s note: As this issue of The ASCO Post went to press, Congress was working on proposals to address the automatic budget cuts.

For the most current developments on this and other policy issues, visit ascoaction.asco.org. See page 59 in this issue of The ASCO Post for more on this topic.

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Disclosure: Senator Brown reported no potential conflicts of interest.

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.

Points of Persuasion How do you encourage Congress to recognize the importance of annual increases in NIH and NCI budgets that are at least comparable to the biomedical rate of inflation?

Thanks to the discoveries made by cancer researchers, many people with cancer are living longer.. But being a strong supporter of cancer research isn’t just about ensuring our loved ones have the best treatment and therapies available; cancer research funding also supports jobs.

Write to The ASCO Post at editor@ASCOPost.com.

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

The ASCO Post | DECEMBER 15, 2012

PAGE 36

News Thoracic Oncology

Effects of LKB1 Mutation and mTOR Inhibition on IGFR1 Pathway in Non-small Cell Lung Cancer

By Matthew Stenger

L

KB1 is a serine/threonine kinase that has been found to be mutated in approximately 20% to 30% of patients with non–small cell lung cancer (NSCLC). LKB1 acts as a tumor suppressor by activating AMPK, and loss of LKB1 by point mutation or deletion suppresses AMPK, leading to increased mTOR signaling.

LKB1 Mutation Increases IGFR1 Pathway Proteins Emrullah Yilmaz, MD, in collaboration with John V. Heymach, MD, PhD, at The University of Texas MD Anderson Cancer Center, investigated the effects of LKB1

mutation and mTOR inhibition on cell signaling pathways, measuring protein expression in NSCLC cell lines by reverse phase protein array.1 They found that LKB1 mutant cell lines had significantly lower expression of phosphorylated AMPK and tuberous sclerosis complex compared with LKB1 wild-type cell < .01), consistent with prilines (P ���������������������������� or observations. In addition, mutant cell lines expressed higher levels of proteins in the insulin-like growth factor 1 receptor (IGFR1) pathway, < .0001), amincluding IGFR1b (P ������������� plified in breast cancer-1 (AIB1)— which is known to upregulate IGF1 < .0001), and IGF binding pro(P ������������������������������ tein 2 (IGFBP2) (P = .016).

AMPK Activation and mTOR Inhibition

Emrullah Yilmaz, MD

LKB1 mutant cell lines were 1.5fold more sensitive to the AMPK activator metformin than wild-type LKB1 cell lines, although the difference was not significant (P = .10).

Expression levels of IGFR1 pathway

John V. Heymach, MD, PhD

proteins increased significantly after 48 hours of treatment with metformin, the mTOR inhibitor temsirolimus (Torisel), and the dual PI3K/ mTOR inhibitor PI103, with the modulation of the IGFR1 pathway by these drugs being independent of LKB1 mutation status.

IGFBP2 and AIB1 were elevated after metformin treatment (P = .02 and P = .005, respectively), and insulin receptor substrate-1 and IGFR1 were elevated after temsirolimus or PI-103 ����������������������� .05 for both). Treattreatment (P < ment with metformin and temsirolim< .01 for both) also increased exus (P ���������������������������������� pression of phosphorylated Akt, which

is a downstream target of IGFR1 and an mTOR activator.

As stated by the investigators, “LKB1 mutant cell lines have increased IGFR activity with higher baseline IGFR1, IGFBP2, and AIB1, suggesting that IGFR may be a potential therapeutic target in LKB1 mutant tumors. In addition, inhibition of the mTOR pathway upregulates the IGFR pathway, possibly as a feedback mechanism. These results support the investigation of IGFR inhibitors in combination with drugs targeting the mTOR pathway, particularly for tumors bearing LKB1 mutations.”

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Disclosure: The investigators reported no potential conflicts of interest.

Reference 1. Yilmaz E, Byers LA, Diao L, et al: Use of proteomic analysis of LKB1/ AMPK/mTOR pathways to identify IGF1R pathway upregulation with LKB1 loss or mTOR inhibition in NSCLC: Implications for targeted combinations. 2012 ASCO Annual Meeting. Abstract 10612.

Presented June 4, 2012.

Molecular Breast Imaging an Option for Early Detection in High-risk Women

M

olecular breast imaging, also known as breast-specific gamma imaging, was a key topic of discussion at the Radiological Society of North America (RSNA) Annual Meeting, held recently in Chicago.

Molecular breast imaging can detect breast cancer missed by mammography, according to clinical data presented by Rachel Brem, MD, Director of Breast Imaging and Vice Chair of Radiology at George Washington University Medical Center.

In a study presented by Dr. Brem, 364 high-risk patients who had a recent, negative mammogram underwent molecular breast imaging. In this group, molecular breast imaging detected breast cancer in nine patients.

All cancers were in women with dense

breasts.

“We have long recognized that patients at high-risk for breast ma-

imaging/breast-specific gamma imaging could be a good option for this population.”

These results indicate that molecular breast imaging/breastspecific gamma imaging could be a good option for this [high-risk] population.

—Rachel Brem, MD

lignancy would likely benefit from additional imaging beyond the mammogram,” Dr. Brem said. “These results indicate that molecular breast

Breast cancer was found in 2.5% of these patients with a recent, negative mammogram. “That’s pretty impressive,” Dr. Brem said. She added,

“Although breast magnetic resonance imaging (MRI) is another option, in our practice we find that many patients are unable to have an MRI, such as those with pacemakers or claustrophobia. For others, the cost of an MRI study is simply out of reach.”

The researchers concluded that the molecular breast imaging/ breast-specific gamma imaging procedure provides a low-cost, well tolerated exam that is capable of filling the need for the high-risk group, especially for women who have dense breasts.

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Disclosure: Dr. Brem is on the Board of Directors, iCAD and Dilon Technologies LLC; Stock options, iCAD, Inc. Stockholder, Dilon Technologies LLC; Consultant, U-Systems, inc. Consultant, Dilon Technologies and Dune Medical Devices.

ASCOPost.com | DECEMBER 15, 2012

PAGE 37

FDA Update

FDA Grants Fast Track Designation to Etirinotecan Pegol for the Treatment of Metastatic Breast Cancer

N

ektar Therapeutics announced that the FDA has designated etirinotecan pegol (NKTR-102) as a Fast Track development program for the treatment of patients with locally recurrent or metastatic breast cancer progressing after treatment with an anthracycline, a taxane, and capecitabine (ATC). Etirinotecan pegol is a unique, targeted topoisomerase I inhibitor designed using Nektar’s proprietary polymer conjugate technology. The drug candidate is currently being evaluated in a phase III study in women with metastatic breast cancer.

“Patients with advanced breast cancer who have progressed following ATC therapies have limited treatment options to manage their disease,” said Robert Medve, MD, Chief Medical Officer of Nektar Therapeutics. “As a novel targeted topoisomerase I inhibitor, etirinotecan pegol is a different mechanism of action than currently approved therapies and has the potential to deliver improved efficacy while offering a more tolerable therapy for women with this aggressive disease.”

Nektar requested Fast Track designation from the FDA for etirinotecan pegol based upon its safety and efficacy profile to date from the nonclinical and clinical phase I and phase II studies, as well as its potential to deliver better efficacy and a more tolerable therapy for patients with locally recurrent or metastatic breast cancer progressing after treatment with ATC. The agent was designed to improve the efficacy of irinotecan by modifying the distribution of the drug candidate within the body. Etirinotecan pegol has a nonoverlapping mechanism of action with other agents used to treat breast cancer which may mitigate potential cancer cross-resistance and reduce overlapping toxicities.

Phase III Study Now Enrolling The phase III BEACON study will enroll approximately 840 patients with metastatic breast cancer who have had prior treatment with ATC in either the adjuvant or metastatic setting. The primary endpoint of the BEACON

study is overall survival. Secondary endpoints include progression-free survival, objective tumor response rates, clinical benefit rate, duration of response, pharmacokinetic data, safe-

ty, quality-of-life measurements, and measurement of healthcare resource Bleed:7.875” utilization for the two study arms.

Trim:7.625” Exploratory objectives of the study Live:7” include collecting specific biomarker

data which will be correlated with efficacy outcome measures. Enrollment in the BEACON study began in December 2011 and is expected to be completed by the end of 2013.

■

NOW AVAILABLE ZALTRAP®, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatincontaining regimen.

IMPORTANT SAFETY INFORMATION FOR ZALTRAP WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage.

GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation.

Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed.

WARNINGS AND PRECAUTIONS • Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events — Monitor patients for signs and symptoms of bleeding — Do not initiate ZALTRAP in patients with severe hemorrhage — Discontinue ZALTRAP in patients who develop severe hemorrhage Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

Visit www.ZALTRAP.com to learn more.

For more information about ZALTRAP, call 1-855-ZALTRAP (1-855-925-8727).

FPO

The ASCO Post | DECEMBER 15, 2012

PAGE 38

FDA Update

Surefire Medical Receives FDA Clearance for Angiographic Catheters

S

urefire Medical, Inc, announced that the company has received 510(k) FDA clearance to market its line of Surefire Angiographic Catheters.

Surefire Medical will launch these products in the United States later this year.

Surefire’s Angiographic Catheter line is designed to provide interventional radiologists with greater flexibility and the highest level of trackability when performing infusion procedures. The catheters have a large inner lumen of 0.054

inches and will be available in a variety of different curve styles for accessing a wide range of patient anatomies.

Bleed:7.875” This is the third FDA 510(k) clearTrim:7.625” ance received by Surefire Medical since Live:7” July 2011.

■

NOW AVAILABLE

IMPORTANT SAFETY INFORMATION FOR ZALTRAP® (cont’d) • GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP — Monitor patients for signs and symptoms of GI perforation — Discontinue ZALTRAP in patients who experience GI perforation • Discontinue ZALTRAP in patients with compromised wound healing — Suspend ZALTRAP for at least 4 weeks prior to elective surgery — Do not initiate/resume ZALTRAP until at least 4 weeks after surgery and surgical wound is fully healed • Fistula formation involving GI and non-GI sites occurs at a higher incidence in patients treated with ZALTRAP. Discontinue ZALTRAP therapy in patients who develop fistula • An increased risk of Grade 3-4 hypertension has been observed in patients receiving ZALTRAP — Monitor blood pressure every two weeks or more frequently and treat with appropriate anti-hypertensive therapy during treatment with ZALTRAP — Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles — Discontinue ZALTRAP in patients with hypertensive crisis • Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. Discontinue ZALTRAP in patients who experience an ATE • Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP — Suspend ZALTRAP when proteinuria ×2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours — If recurrent, suspend until proteinuria <2 grams/24 hours and then reduce ZALTRAP dose to 2 mg/kg — Discontinue ZALTRAP if nephrotic syndrome or TMA develops • A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP — Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ×1.5 x 109/L • Incidence of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI — The incidence of diarrhea is increased in patients ×65 years of age. Monitor closely • Discontinue ZALTRAP in patients who develop reversible posterior leukoencephalopathy syndrome

ADVERSE REACTIONS • The most common adverse reactions (all grades, ×20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache • The most common Grade 3-4 adverse reactions (×5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia • Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection • In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI Please see accompanying Brief Summary of full Prescribing Information, including Boxed WARNING. In the U.S., ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2012 sanofi-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

US.AFL.12.07.046

8/12

Printed in U.S.A.

ASCOPost.com | DECEMBER 15, 2012

PAGE 39

FDA Update

Supplemental New Drug Application Submitted for Erlotinib as a First-line Therapy in Genetically Distinct NSCLC

A

stellas Pharma US, Inc, announced it has submitted a supplemental New Drug Application (sNDA) to the FDA seeking approval for erlotinib (Tarceva) tablets for first-

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion

line treatment of patients with locally advanced or metastatic non–small cell Bleed:7.875” lung cancer (NSCLC) whose tumors Trim:7.625” have epidermal growth factor receptor Live:7” (EGFR)–activating mutations as de-

Rx Only

Brief Summary of Prescribing Information WARNING:

HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Hemorrhage: Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

Gastrointestinal Perforation: Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Compromised Wound Healing: Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

continued on page 40

Bleed:10.75”

Live:10”

Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line.

Administer ZALTRAP using an infusion set made of one of the following materials: • PVC containing DEHP • DEHP free PVC containing trioctyl-trimellitate (TOTM) • polypropylene • polyethylene lined PVC • polyurethane 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/ hemorrhage (all grades) were reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP. Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2)].

5.2 Gastrointestinal Perforation Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three Phase 3 placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation events occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo.

Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2)].

5.3 Compromised Wound Healing ZALTRAP impairs wound healing in animal models [see Nonclinical Toxicology (13.2) in the full prescribing information].

Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI regimen and in none of the patients treated with placebo/ FOLFIRI regimen.

Suspend ZALTRAP for at least 4 weeks prior to elective surgery. Do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with compromised wound healing [see Dosage and Administration (2.2)].

5.4 Fistula Formation Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with ZALTRAP. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 placebo-treated patient (0.2%).

Discontinue ZALTRAP therapy in patients who develop fistula [see Dosage and Administration (2.2)].

5.5 Hypertension ZALTRAP increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% of patients treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Among those patients treated with ZALTRAP/FOLFIRI developing Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment.

Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with ZALTRAP. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled, and permanently reduce ZALTRAP dose to 2 mg per kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.2)].

5.6 Arterial Thromboembolic Events Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. In patients with mCRC, ATE was reported in 2.6% of patients treated with ZALTRAP/FOLFIRI and 1.7% of patients treated with placebo/ FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE [see Dosage and Administration (2.2)].

5.7 Proteinuria Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. In patients with mCRC,

first-line use of erlotinib versus platinum-based chemotherapy in patients with EGFR-activating mutation-positive advanced NSCLC.

Trim:10.5”

Trim:10.5”

Bleed:10.75”

Live:10”

1 INDICATIONS AND USAGE ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen [see Clinical Studies (14) in the full prescribing information].

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule Administer ZALTRAP 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment [see Clinical Studies (14) in the full prescribing information].

Continue ZALTRAP until disease progression or unacceptable toxicity.

2.2 Dose Modification / Treatment Delay Recommendations Discontinue ZALTRAP for: • Severe hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised wound healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula formation [see Warnings and Precautions (5.4)] • Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5)] • Arterial thromboembolic events [see Warnings and Precautions (5.6)] • Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7)] • Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10)] Temporarily suspend ZALTRAP: • At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3)] • For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5)].

• For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7)].

For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information.

2.3 Preparation for Administration Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles.

Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial.

Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6–8 mg/mL. Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags.

Store diluted ZALTRAP at 2–8°C (36–46°F) for up to 4 hours. Discard any unused portion left in the infusion bag.

2.4 Administration Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon.

Do not administer as an intravenous (IV) push or bolus.

tected by an approved test.

The sNDA submission is based on results of the international EURTAC trial, a prospective, randomized, controlled phase III trial evaluating the

The ASCO Post | DECEMBER 15, 2012

PAGE 40

FDA Update

sNDA for Erlotinib continued from page 39

The cobas EGFR Mutation Test, a companion diagnostic,to identify patients with NSCLC whose tumors have EGFR-activating mutations, is currently under review by the Center for Devices and Radiological Health to support the EURTAC sNDA. It is esti-

mated that as many as 10% of people in Western populations with lung cancer and 30% of Asian people with lung cancer have EGFR-activating mutations.

Study Design The EURTAC trial was designed and sponsored by the Spanish Lung Cancer Group and conducted in Spain,

France and Italy in cooperation with Roche. From February 2007 to Janu-

Bleed:7.875” Trim:7.625”

ary 2011, 174 predominantly CaucaLive:7” sian patients were randomly assigned

proteinuria was reported in 62% patients treated with ZALTRAP/FOLFIRI compared to 41% patients treated with placebo/FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with ZALTRAP/FOLFIRI to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies.

Monitor proteinuria by urine dipstick analysis and urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during ZALTRAP therapy.

Obtain a 24-hour urine collection in patients with a UPCR greater than 1.

Suspend ZALTRAP administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg. Discontinue ZALTRAP in patients who develop nephrotic syndrome or TMA [see Dosage and Administration (2.2)].

5.8 Neutropenia and Neutropenic Complications A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with ZALTRAP/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Grade 3–4 febrile neutropenia occurred in 4% of patients treated with ZALTRAP/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with ZALTRAP/FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI. Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay ZALTRAP/FOLFIRI until neutrophil count is at or above 1.5 × 109/L. 5.9 Diarrhea and Dehydration The incidence of severe diarrhea is increased in patients treated with ZALTRAP/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with ZALTRAP/FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/ FOLFIRI [see Adverse Reactions (6.1)]. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age [see Geriatric Use (8.5)]. Monitor elderly patients closely for diarrhea.

5.10 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy.

Confirm the diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death [see Dosage and Administration (2.2)].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal Perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised Wound Healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula Formation [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] • Arterial Thromboembolic Events [see Warnings and Precautions (5.6)] • Proteinuria [see Warnings and Precautions (5.7)] • Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8)] • Diarrhea and Dehydration [see Warnings and Precautions (5.9)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.10)] 6.1 Clinical Trial Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with ZALTRAP 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI or 8 cycles of placebo/FOLFIRI. The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm , in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache (see Table 1).

The most common Grade 3–4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1).

The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.

to receive erlotinib or platinum-based chemotherapy. The primary endpoint was investigator-assessed progressionfree survival.

An analysis of the EURTAC data, reflecting a total of 133 progressionfree survival events, is included in the submission to the FDA. In the 133 progression-free survival event analy-

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion The ZALTRAP dose was reduced and/or omitted in 17% of patients compared to placebo-dose modification in 5% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI. The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥5% (all grades) in patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients treated with ZALTRAP/FOLFIRI compared to placebo/FOLFIRI are shown in Table 1.

Table 1 – Selected Adverse Reactions and Laboratory Findings in Study 1: Placebo/FOLFIRI ZALTRAP/FOLFIRI (N=605) (N=611) Primary System Organ Class All grades Grades All grades Grades Preferred Term (%) 3–4 3–4 Infections and infestations Urinary Tract Infection 6% 0.8% 9% 0.8% Blood and lymphatic system disorders Leukopenia 72% 12% 78% 16% Neutropenia 57% 30% 67% 37% Thrombocytopenia 35% 2% 48% 3% Metabolism and nutrition disorders Decreased Appetite 24% 2% 32% 3% Dehydration 3% 1% 9% 4% Nervous system disorders Headache 9% 0.3% 22% 2% Vascular disorders Hypertension 11% 1.5% 41% 19% Respiratory, thoracic and mediastinal disorders Epistaxis 7% 0 28% 0.2% Dysphonia 3% 0 25% 0.5% Dyspnea 9% 0.8% 12% 0.8% Oropharyngeal Pain 3% 0 8% 0.2% Rhinorrhea 2% 0 6% 0 Gastrointestinal disorders Diarrhea 57% 8% 69% 19% Stomatitis 33% 5% 50% 13% Abdominal Pain 24% 2% 27% 4% Abdominal Pain Upper 8% 1% 11% 1% Hemorrhoids 2% 0 6% 0 Rectal Hemorrhage 2% 0.5% 5% 0.7% Proctalgia 2% 0.3% 5% 0.3% Skin and subcutaneous tissue disorders Palmar-Plantar 4% 0.5% 11% 3% Erythrodysesthesia Syndrome Skin Hyperpigmentation 3% 0 8% 0 Renal and urinary disorders Proteinuria* 41% 1% 62% 8% Serum creatinine increased 19% 0.5% 23% 0 General disorders and administration site conditions Fatigue 39% 8% 48% 13% Asthenia 13% 3% 18% 5% Investigations AST increased 54% 2% 62% 3% ALT increased 39% 2% 50% 3% Weight decreased 14% 0.8% 32% 3% Note: Adverse Reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 *Compilation of clinical and laboratory data Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.

In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%).

In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients

ASCOPost.com | DECEMBER 15, 2012

PAGE 41

FDA Update

sis, the median progression-free survival was 10.4 months in the erlotinib group and 5.1 months in the platinumbased chemotherapy group. Erlotinib reduced the risk of lung cancer getting worse by 66% (HR = 0.34, P < .0001).

The safety profile for erlotinib in the EURTAC study was consistent with previous studies of erlotinib in

NSCLC. The most frequent (> 10%) adverse events were diarrhea, asthenia, rash, cough, and dyspnea in the erlotinib group and asthenia, anemia, nausea, neutropenia, and cough in the chemotherapy group. Two patient deaths Bleed:7.875” in the chemotherapy arm and two paTrim:7.625” tient deaths in the erlotinib arm were Live:7” reported as related to treatment.

i

mmatics biotechnologies GmbH announced that the cancer vaccine IMA901 has been granted orphan drug designation from the FDA for

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion 8.8 Females and Males of Reproductive Potential Male and female reproductive function and fertility may be compromised during treatment with ZALTRAP, as suggested by findings in monkeys [see Nonclinical Toxicology (13.1) in the full prescribing information]. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment.

10 OVERDOSAGE There have been no cases of overdose reported with ZALTRAP. There is no information on the safety of ZALTRAP given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks.

Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807, A SANOFI COMPANY U.S. License # 1752 ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2012 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC ZIV-BPLR-SA-AUG12

Revised: August 2012

the treatment of renal cell carcinoma (RCC) in HLA-A*02 positive patients. The FDA grants orphan drug designation to novel drugs aimed at treating rare diseases or conditions.

In addition, it has completed patient recruitment into the pivotal phase III IMPRINT trial evaluating IMA901 for RCC. IMA901 is a rationally designed cancer vaccine comprising 10 different tumor-associated peptides that are found to be highly overexpressed in the majority of patients suffering from RCC.

Patient Recruitment Completed

Bleed:10.75”

Live:10”

The phase III IMPRINT trial is designed to show an overall survival benefit with IMA901 in combination with sunitinib (Sutent), standard first-line therapy, in comparison to sunitinib alone in patients with metastatic and/or locally advanced RCC. The secondary endpoints include immune response to the peptides contained in IMA901, progression-free survival, safety, and tolerability.

The trial has completed patient inclusion, and it is expected that around 345 patients will be randomly assigned across 10 countries in the United States and Europe. The first (interim) overall survival results are expected during the first half of 2014.

The study aims to build on the promising survival and immune response data observed in the phase II study with IMA901 in patients with advanced RCC. These data show that patients who produced an immune response to two or more of the tumor-associated peptides contained in IMA901 had a significantly longer survival. Key data from the scientific and clinical development of IMA901 were recently published in Nature Medicine.

Chief investigator of the trial is Brian Rini, MD, of Lerner College of Medicine, Department of Solid Tumor Oncology at the Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio. The European lead investigator is Tim Eisen, MD, Clinical Director of Medical Oncology at Addenbrooke’s Hospital, University of Cambridge, UK. Trim:10.5”

Bleed:10.75”

Live:10”

Trim:10.5”

treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo.

The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data.

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 ZALTRAP with the incidence of antibodies to other products may be misleading.

7 DRUG INTERACTIONS No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic drug-drug interactions were found between ziv-aflibercept and irinotecan/SN-38 or 5-FU, based on cross-study comparisons and population pharmacokinetic analyses.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with ZALTRAP in pregnant women. ZALTRAP was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data Ziv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose.

8.3 Nursing Mothers It is not known whether ZALTRAP 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 ZALTRAP, 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 in pediatric patients have not been established.

8.5 Geriatric Use Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9)].

The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI. No dose adjustment of ZALTRAP is recommended for patients greater than or equal to 65 years of age.

8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept.

Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function [see Clinical Pharmacology (12.3) in the full prescribing information]. There are no data available for patients with severe hepatic impairment.

8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept.

Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function [see Clinical Pharmacology (12.3) in the full prescribing information].

■

IMA901 Granted Orphan Drug Designation by FDA

■

The ASCO Post | DECEMBER 15, 2012

PAGE 42

In the Clinic Hematology

Liposomal Vincristine for Adult Patients with Relapsed/ Refractory Acute Lymphoblastic Leukemia

By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication

I

n August 2012, vinCRIStine sulfate LIPOSOME injection (Marqibo) was granted accelerated approval for the treatment of adult patients with Philadelphia chromosome–negative (Ph–) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more antileukemia therapies.1,2 Approval was based on the rate of complete remission plus the rate of complete remission with incomplete blood count recovery in a single-arm, single-agent trial of liposomal vincristine in adults in second or greater relapse of ALL. As a condition of the accelerated approval, the manufacturer (Talon Therapeutics, Inc), must evaluate the effect of liposomal vincristine on overall survival in a randomized controlled trial in adult patients with ALL. In the single-arm trial (HBS407 trial),2 65 patients aged ≥ 18 years with Ph– ALL in second or greater relapse or whose disease had progressed after at least two antileukemia treatments received liposomal vincristine via IV infusion at 2.25 mg/m2 over 60 minutes every 7 days. Patients had to have achieved complete remission from one of the prior antileukemia chemotherapies, defined as a leukemia-free interval of at least 90 days. Patients were not eligible for immediate hematopoietic stem cell transplantation at the start of the study. All patients had received prior vincristine sulfate; 22

OF NOTE Unlike conventional vincristine, liposomal encapsulation of vincristine prolongs circulation of active drug and passively targets it to tissues with fenestrated vasculature, for increased penetration and accumulation in tumor tissue.

(34%) had not received asparaginase products. Fifty-one percent of patients were male, 45% were aged > 30 years, and 11% were aged ≥ 65 years; 85% had precursor B-cell ALL, and 15% had precursor T-cell ALL. Concomitant corticosteroid treatment was not permitted beyond day 5 of the study.

The complete remission rate was 4.6% (3/65 patients), and the rate of complete remission with incomplete blood count recovery was 10.8% (7/65 patients). Among the 10 patients achieving complete remission or complete remission with incomplete blood count recovery, the median remission duration was 28 days (95% CI = 7–36 days), and the median duration to first event (relapse, death, or subsequent chemotherapy) was 56 days (95% CI = 9–65 days).

How It Works The newly approved vincristine product is a sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine sulfate.2,3 Vincristine induces cell cycle–specific cytotoxicity by binding to tubulin during mitosis, resulting in microtubule depolymerization and metaphase arrest and thus apoptosis. The degree of killing increases with higher drug concentration and longer duration of exposure.

Since free vincristine undergoes rapid cellular uptake and extensive tissue binding, it has a half-life of minutes and low levels of free drug are present in plasma. Dosing of conventional vincristine is limited by significant neurotoxicity due to binding to neuronal tubulin, with such toxicity occurring at doses higher than 1.4 mg/m2 and leading to capping of the total dose of vincrsitine.

Liposomal encapsulation of vincristine prolongs circulation of active drug and passively targets it to tissues with fenestrated vasculature (eg, bone marrow, lymph nodes, spleen, liver, and solid tumors), resulting in increased penetration and accumulation in tumor tissue and potentially reducing levels in neural tissue compared with free vincristine.

Liposomal vincristine has shown greater antitumor activity in vitro and in animal models compared with conventional vincristine at equivalent

Liposomal Vincristine in Acute Lymphoblastic Leukemia ■■ VinCRIStine sulfate LIPOSOME injection (Marqibo) was approved to

treat adult patients with Philadelphia chromosome–negative acute lymphoblastic leukemia in second or greater relapse or whose disease has progressed following at least two antileukemia therapies.

■■ Liposomal vincristine is given at 2.25 mg/m2 by IV infusion over 1 hour once every 7 days. Administration by any route other than IV is fatal.

(mg/kg) doses, and was more likely to be curative in mouse models using leukemia cell lines.

How It Is Given Liposomal vincristine is given at 2.25 mg/m2 via IV infusion over 1 hour once every 7 days. It is for IV use only; administration by any other

OF NOTE A boxed warning for liposomal vincristine sulfate emphasizes that it is for IV use only and is fatal if given by other routes, that death has occurred with intrathecal use, and that it has different dose recommendations than conventional vincristine sulfate injection. route is fatal. The liposomal formulation of this drug has different dosage recommendations than vincristine sulfate injection. The final drug product is prepared on site from components in the supplied Marqibo Kit; extensive careful preparation is required.

Contraindications to liposomal vincristine use include demyelinating conditions (including Charcot-MarieTooth syndrome) and intrathecal use; intrathecal use is fatal.

Dose interruption and reduction are required for peripheral neuropathy. Treatment should be interrupted for grade 3 or persistent grade 2 neuropathy, discontinued if neuropathy remains at or worsens to grade 3 or 4, and restarted at 2.00 mg/m2 if it recovers to grade 1 or 2. For persistent grade 2 neuropathy after the initial dose reduction, treatment should be interrupted and then resumed at 1.825 mg/m2 and subsequently 1.5 mg/m2 if neuropathy recovers to grade 1 and should be discontinued for neuropathy of grade 3 or 4.

Safety Profile The safety of liposomal vincristine at 2.25 mg/m2 weekly was evaluated in two single-arm trials (HBS407 and VSLI-06 trials) including a total of 83 patients with ALL in second or greater relapse.2 Adverse events occurred in 100% of patients, with the most common (>���������������������������� 30% ��������������������������� of patients) being constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia See Page 119 (34%), decreased appetite (33%), and insomnia (32%).

Adverse events of grade 3 or higher occurred in 96% of patients, with the most common (>������������������ ����������������� 10%) being infections (40%, including pneumonia, septic shock, and staphylococcal bacteremia), neuropathy (32.5%, including peripheral motor and sensory neuropathy in 17%), febrile neutropenia (31%), neutropenia (18%), anemia (17%), thrombocytopenia (17%), pyrexia (14.5%), and fatigue (12%).

Dose reduction or delay occurred in 53% of patients during treatment. Treatment was discontinued due to adverse events in 28% of patients, with the most common non–leukemia-related causes continued on page 43

REPORT ADVERSE EVENTS Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at 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 (1-800-FDA-1088).

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

now indicated in combination with carboplatin for the first-line treatment of advanced Non–Small Cell lung Cancer

Scan with your mobile device to learn more at www.abraxane.com

Please see Important Safety Information for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on adjacent pages, and Brief Summary on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Important Safety Information WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1,500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 for metastatic breast cancer (MBC) and Days 1, 8, and 15 for non-small cell lung cancer (NSCLC) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1,500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • The starting dose should be reduced for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood

Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with single-agent use of ABRAXANE in the MBC study were alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), abnormal ECG (all patients 60%; patients with normal baseline 35%), fatigue/ asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), AST elevation (any 39%), alkaline phosphatase elevation (any 36%), anemia (all cases 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe <1%) and infections (24%) • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note included vomiting (any 18%; severe 4%), renal dysfunction (any 11%; severe 1%), fluid retention (any 10%; severe 0%); mucositis (any 7%; severe <1%), hepatic dysfunction (elevations in bilirubin 7%), hypersensitivity reactions (any 4%; severe 0%), thrombocytopenia (any 2%; severe <1%), and injection site reactions (<1%). In all ABRAXANE treated patients (n=366) ocular/visual disturbances were reported (any 13%; severe 1%). Dehydration and pyrexia were also reported • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Non-Small Cell Lung (NSCLC) Cancer Study • Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin in NSCLC were anemia (28%); neutropenia (47%); thrombocytopenia (18%), and peripheral neuropathy (3%) • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin for NSCLC were anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC were anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

Please see Brief Summary for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on following pages.

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group) Post-marketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or to human albumin has not been studied • There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • Dose adjustment is recommended for patients with moderate and severe hepatic impairment and patients who experience severe neutropenia or severe sensory neuropathy during treatment with ABRAXANE • Withhold ABRAXANE if AST >10 x ULN or bilirubin >5 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicities • Monitor patients closely

ABRAXANE® is a registered trademark of Celgene Corporation. ©2012 Celgene Corporation 11/12 US-ABR120070

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a brief summary; refer to full prescribing information for complete product information.

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC = 6 mg•min/mL on Day 1 only of each 21-day cycle, beginning immediately after the completion of ABRAXANE administration.

2.3 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.

For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.

For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated.

Monitor patients closely [see Warnings and Precautions (5.4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin Levels ABRAXANE Dosea Levels MBC NSCLC Mild < 10 x ULN > ULN to ≤ 1.25 x ULN 260 mg/m2 100 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN 200 mg/m2 75 mg/m2 Severe < 10 x ULN 2.01 to 5 x ULN 130 mg/m2 b 50 mg/m2 c > 10 x ULN OR > 5 x ULN not eligible not eligible MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Increase dose to 75 mg/m2 in subsequent courses, as tolerated.

2.4 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2.

For Grade 3 sensory neuropathy hold treatment until resolution to

Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].

Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle.

Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.

• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose 2 (mg/m ) (AUC mg•min/mL) Neutropenic Fever (ANC less than 500/mm3 First 75 4.5 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC Second 50 3 less than 1500/mm3 OR Third Discontinue Treatment ANC less than 500/mm3 for more than 7 days First 75 4.5 Platelet count less than 50,000/mm3 Second Discontinue Treatment First 75 4.5 Severe sensory Neuropathy – Second 50 3 Grade 3 or 4 Third Discontinue Treatment 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.

• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC) and 47% of patients with non-small cell lung cancer (NSCLC).

Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3.

In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.

In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.4)].

5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.4)].

5.3 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience

a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug.

5.4 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.5 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

5.6 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman.

Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.

There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)].

5.7 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)].

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

The most common adverse reactions (â&#x2030;Ľ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)].

The most common adverse reactions (â&#x2030;Ľ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)] The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%).

6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 3 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 (continued)

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Febrile Neutropenia 2 1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity.

Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose

of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials.

Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients.

Bradycardia, during the 30-minute infusion, occurred in <1% of patients.

These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.

Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.

Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.

No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial.

Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible.

Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days.

Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.

Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported.

6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion.

The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose- and schedule-dependent adverse reactions.

Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma,

43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment.

The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group).

Table 4 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 4: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) plus carboplatin plus carboplatin Grades Grade Grades Grade 1-4 (%) 3-4 (%) 1-4 (%) 3-4 (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 5 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 5: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups Paclitaxel Injection ABRAXANE (200 mg/m2 2 (100 mg/m weekly) every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) MedDRA Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 System Organ v 12.1 Toxicity Toxicity Toxicity Toxicity Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General Edema 10 0 4 <1 disorders and peripheral administration site conditions 7 0 2 0 Respiratory Epistaxis thoracic and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective 10 <1 19 2 tissue disorders Myalgia a Peripheral

neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).

For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord par esis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.

Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage.

These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes.

After cessation of treatment, CME improves and visual acuity may return to baseline.

Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.

Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration.

Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.

Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.

6.4 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received.

However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

There are no clinically important pharmacokinetic drug-drug interactions between carboplatin and ABRAXANE [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.6)].

There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman.

If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles.

A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.

8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older.

Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old.

8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment.

10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.

16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light.

16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information).

• ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.7)].

• Patients must be informed of the risk of low blood cell counts and instructed to contact their physician immediately for fever or evidence of infection.

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties, or signs of an allergic reaction.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE. • Patients must be informed that hypersensitivity reactions may occur, which could be severe and sometimes fatal.

Manufactured for: Celgene Corporation Summit, NJ 07901 ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2012 Abraxis BioScience, LLC. All Rights Reserved.

Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006; 7,820,788; 7,923,536; 8,034,375; 8,268,348; and RE41,884.

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In the Clinic Neuro-oncology

Revised Everolimus Dosing and New Safety/Efficacy Data for Approval in Subependymal Giant Cell Astrocytoma

By Matthew Stenger

O

n August 29, 2012, everolimus in a tablet for oral suspension form (Afinitor Disperz) was given accelerated approval for the treatment of pediatric and adult patients with tuberous sclerosis complex who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.1,2 Everolimus in a tablet for oral administration form (Afinitor) was granted accelerated approval for treatment of tuberous sclerosis complex with SEGA in October 2010 on the basis of a single-arm trial in 28 patients. The new approval, based on a randomized, double-blind trial, expands the indication to treatment of children aged less than 3 years and includes an increased starting dose, revised dose modification guidelines, and new safety and efficacy data from the randomized trial.

Everolimus also has indications in advanced hormone receptor–positive breast cancer, progressive neuroendocrine tumors of pancreatic origin, advanced renal cell carcinoma, and renal angiomyolipoma with tuberous sclerosis complex.

Single-arm Trial In the randomized trial, 117 patients with subependymal giant cell astrocytoma received Afinitor Disperz at 4.5 mg/m2 per day (n = 78) or placebo

OF NOTE Everolimus in a tablet for oral suspension is the first pediatric formulation to be approved to treat a tumor occurring primarily during childhood.

Liposomal Vincristine continued from page 42

being peripheral neuropathy (10%) and tumor lysis syndrome (2%). Neuropathy-related adverse events leading to discontinuation included decreased vibratory sense, facial palsy, hyporeflexia, constipation, asthenia, fatigue, and musculoskeletal pain.

Death occurred in 23% of patients (n = 15) in the HBS407 trial. Causes of deaths were respiratory failure in 4 patients, pneumonia and septic shock in

(n = 39). Patients had a median age of 9.5 years (range, 0.8–26 years), 93% were Caucasian, and 57% were male.

The primary outcome measure was SEGA response rate as determined by an independent central radiology review panel, with response defined as a ≥ 50% reduction in the sum of the volumes of SEGA target lesions relative to baseline in the

plex 1 and 2 (TSC1, TSC2) are regulators of mTORC1 signaling, and loss or inactivation of either suppressor leads to activation of downstream signaling.

In tuberous sclerosis complex, inactivating mutations in either the TSC1 or TSC2 gene lead to hamartoma formation throughout the body.

Everolimus in a tablet for oral suspension is the first pediatric formula-

New Dosage Form and Dosing for Everolimus ■■ Everolimus in a tablet for oral suspension form (Afinitor Disperz) was

granted accelerated approval in pediatric and adult patients with tuberous sclerosis complex who have subependymal giant cell astrocytoma (SEGA) that cannot be curatively resected.

■■ The recommended starting dose of everolimus for adult and pediatric patients with SEGA is now 4.5 mg/m per day, with maintenance of everolimus trough levels at 5 to 15 ng/mL. 2

absence of worsening of nontarget SEGA lesions, a new SEGA lesion ≥��������������������������������� �������������������������������� 1 cm, or new or worsening hydrocephalus. SEGA responses were observed in 27 (35%) of 78 patients in the everolimus group and none of the placebo patients (P < .0001).

With a median follow-up of 8.4 months for the total study population, all responses were ongoing and the median response duration was 5.3 months (range, 2.1–8.4 months) in everolimus-treated patients.

tion to be approved for the treatment of a tumor occurring primarily during childhood. The new dosage form (tablets for oral suspension) is more rapidly dissolved using smaller volumes of water than the tablet dosage form used in prior clinical trials and provides for smaller dose increments, allowing greater dosing flexibility.

This formulation also provides another option for adult patients with SEGA.

How It Works

The recommended starting dose of both Afinitor Tablets and Afinitor Disperz for adult and pediatric patients with SEGA is now 4.5 mg/m2 per day, with subsequent dosing based on therapeutic drug monitoring to achieve and maintain everolimus trough levels of 5 to 15������������������������� ������������������������ ng/mL. Trough concentra-

Everolimus inhibits mTOR kinase downstream of the PI3K/AKT pathway by forming an inhibitory complex with mTOR complex 1 (mTORC1).

The mTOR pathway is dysregulated in several human cancers. The oncogene suppressors tuberous sclerosis com3, intracerebral hemorrhage and multisystem organ failure in 2 each, and brain infarct, liver failure, pulmonary hemorrhage, and sudden cardiac death in 1 each.

Liposomal vincristine carries a boxed warning regarding appropriate use, emphasizing that the formulation is for IV use only and is fatal if given by other routes, that death has occurred with intrathecal use, and that it has different dose recommendations than vincristine sulfate injection. It also carries warnings/

How It Is Given

precautions for intrathecal administration; extravasation; neurologic toxicity; myelosuppression; tumor lysis syndrome; constipation, bowel obstruction, and paralytic ileus; fatigue; hepatic toxicity; and embryofetal toxicity.

■

References 1. U.S. Food and Drug Administration: VinCRIStine sulfate LIPOSOMAL injection. Available at http://www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm315111.htm. Accessed August

tions should be assessed approximately 2 weeks after initiation of treatment, a change in dose, a change in coadministration of CYP3A4 or Pglycoprotein inducers or inhibitors, a change in hepatic function, or a change in dosage form between Afinitor Tablets and Afinitor Disperz.

The starting dose of both forms should be reduced by approximately 50% in patients with severe hepatic impairment and in patients taking moderate inhibitors of CYP3A4 or Pglycoprotein and should be doubled when coadministered with strong inducers of CYP3A4.

Safety Profile In the randomized trial, the most common adverse events of any grade in everolimus-treated patients (≥ 20%) were stomatitis (62% vs 26% with placebo), respiratory tract infection (31% vs 23%), pyrexia (23% vs 18%), vomiting (22% vs 13%), rash (21% vs 8%), and anxiety, aggression, or other behavioral disturbance (21% vs 3%). The most common (≥ 5%) grade 3 or 4 adverse events were stomatitis (9% vs 3%), pyrexia (6% vs 3%), See Page 119 pneumonia, gastroenteritis (5% vs 0%), anxiety, aggression, or other behavioral disturbance (5% vs 0%), and amenorrhea. Grade 4 adverse events were very uncommon.

Amenorrhea occurred in 17% of everolimus-treated patients aged 10 to 55 years (3/18) and in none of the females in the placebo group. Abnorcontinued on page 44

20, 2012.

2. MARQIBO® (vinCRIStine sulfate LIPOSOME injection) for intravenous use prescribing information. Talon Therapeutics, Inc, August 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202497s000lbl.pdf.

Accessed August 20, 2012.

3. Thomas DA, Kantarjian HM, Stock W, et al: Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia.

Cancer 115:5490-5498, 2009.

The ASCO Post | DECEMBER 15, 2012

PAGE 44

In the Clinic

New Everolimus Dosing continued from page 43

malities included dysmenorrhea (6%), menorrhagia (6%), and metrorrhagia (6%).

The most common laboratory abnormalities (≥�������������������� ������������������� 40%) were hypercholesterolemia (81% vs 39%), elevated partial thromboplastin time (72% vs 44%), neutropenia (46% vs 41%), and anemia (41% vs 21%). The most common grade 3 lab abnormalities (no grade 4 abnormalities) were neutropenia (9% vs 3%) and elevated partial thromboplastin time (3% vs 5%).

Serious adverse events were reported in 24% of everolimus-treated patients and 13% of placebo recipients, with pyrexia being the most

common event occurring more frequently in the everolimus group.

Serious adverse events due to infection were more common in patients aged less than 3 years, occurring in 46% (6/13) of everolimus-treated patients and 28.5% (2/7) of placebo patients. No adverse events resulted in permanent discontinuation of study treatment. Dose interruptions or reductions due to adverse events occurred in 55% of patients given everolimus, with stomatitis being the most common cause. No deaths occurred in either treatment group.

Additional Risk Considerations Everolimus carries warnings/ precautions for noninfectious pneu-

are underway to further evaluate the long-term safety and effectiveness of everolimus in adult and pediatric patients with SEGA.

OF NOTE Everolimus inhibits mTOR kinase downstream of the PI3K/AKT pathway by forming an inhibitory complex with mTOR complex 1.

■

References 1. U.S. Food and Drug Administration: Approved drugs. Everolimus for tuberous sclerosis complex. Available at http:// www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm317490. htm. Accessed September 12, 2012.

2. AFINITOR® (everolimus) tablets for oral administration, AFINITOR DISPERZ® (everolimus tablets for oral suspension) prescribing information.

Novartis Pharmaceuticals Corporation, August 2012. Available at http://www. accessdata.fda.gov/drugsatfda_docs/ label/2012/203985s000lbl.pdf.

Accessed September 12, 2012.

monitis, infections, oral ulcers, renal failure, laboratory test abnormalities, use of live vaccine and contact with others who have received live vaccine, and embryo-fetal toxicity. Renal function, blood glucose, lipids, and hematologic parameters should be measured prior to treatment and periodically during treatment.

The long-term effects of everolimus on growth and pubertal development are unknown. Confirmatory studies

2012 In Review: Oncology Drugs/Indications Newly Approved by FDA

A

t press time, the FDA had granted approval for the following new agents and indications for cancer treatment in 2012.

■■ Cabozantinib (Cometriq) for the treatment of progressive metastatic medullary thyroid cancer.

Cabozantinib is a small molecule that inhibits the activity of multiple tyrosine kinases, including RET, MET, and VEGF receptor 2.

November 29, 2012 ■■ Omacetaxine mepesuccinate (Synribo) for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors. October 26, 2012 ■■ Rituximab (Rituxan) 90-minute infusion starting at cycle 2 for patients with non-Hodgkin lymphoma who did not experience a grade 3 or 4 infusion-related adverse reaction during cycle 1. October 19, 2012 ■■ Pemetrexed (Alimta) labeling was expanded to include the results of an additional trial evaluating the drug’s safety and efficacy for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer followed by pemetrexed maintenance in patients whose disease has not progressed after four cycles of platinum and

■■

■■

■■

■■

■■

pemetrexed as first-line chemotherapy. October 17, 2012 Paclitaxel, albumin-bound (Abraxane) for use in combination with carboplatin for the initial treatment of patients with locally advanced or metastatic non-small cell lung cancer who are not candidates for curative surgery or radiation therapy. October 11, 2012 Regorafenib (Stivarga) for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. September 27, 2012 Bosutinib (Bosulif) for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome positive chronic myelogenous leukemia in adult patients with resistance or intolerance to prior therapy. September 4, 2012 Enzalutamide (Xtandi) for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. August 31, 2012 Everolimus (Afinitor) received accelerated approval for the treatment of pediatric and adult patients with tuberous sclerosis

■■

■■

■■

■■

complex who have subependymal giant cell astrocytoma that requires therapeutic intervention but cannot be curatively resected.

August 30, 2012 Vincristine sulfate liposome injection (Marqibo) received accelerated approval for the treatment of adult patients with Philadelphia chromosomenegative acute lymphoblastic leukemia in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. August 9, 2012 Ziv-aflibercept (Zaltrap) for use in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin (Eloxatin) containing regimen.

August 3, 2012 Everolimus (Afinitor) for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole (Femara) or anastrozole (Arimidex). July 20, 2012 Carfilzomib (Kyprolis) received accelerated approval for the treatment of patients with multiple

■■

■■

■■

■■

myeloma who have received at least two prior therapies, including bortezomib (Velcade) and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. July 20, 2012 Cetuximab (Erbitux) for use in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment of patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer as determined by FDA-approved tests for this use. FDA also approved the Therascreen KRAS RGQ PCR Kit (Qiagen) concurrent with this cetuximab approval. July 9, 2012 Pertuzumab (Perjeta) for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. June 8, 2012 Pazopanib (Votrient) for the treatment of patients with advanced soft tissue sarcoma who have received prior chemotherapy. April 26, 2012 Everolimus (Afinitor) received accelerated approval for the treatment of adults with renal angiomyolipoma, associated with tuber-

ASCOPost.com | DECEMBER 15, 2012

PAGE 45

FDA Update

ous sclerosis complex, who do not require immediate surgery. April 26, 2012 ■■ Imatinib mesylate (Gleevec) received regular approval for the adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive gastrointestinal stromal tumors.

Accelerated approval for this indication was granted in December 2008. Labeling is also revised to include the results of a randomized trial demonstrating that recurrence-free survival and overall survival

were improved by continuing adjuvant imatinib therapy to 36 months. January 31, 2012 ■■ Vismodegib (Erivedge) for the treatment of adults with metastatic basal cell carcinoma or with locally advanced basal cell carcinoma that

has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. January 30, 2012 ■■ Axitinib (Inlyta) for the treatment of advanced renal cell carcinoma after failure of one prior

systemic therapy. January 27, 2012 ■■ Glucarpidase (Voraxaze) for the treatment of toxic plasma methotrexate concentrations (> 1 μmol/L) in patients with delayed methotrexate clearance due to impaired renal function. January 17, 2012

■

Watch future issues of

The ASCO Post

for comprehensive coverage of these important meetings: ■■ 2012 Quality Care

Symposium November 30–December 1, 2012 San Diego, California

■■ San Antonio Breast

Cancer Symposium December 4–8, 2012 San Antonio, Texas

■■ American Society of

Hematology Annual Meeting December 8–11, 2012 Atlanta, Georgia

■■ 2013 Gastrointestinal

Cancers Symposium January 24–26, 2013 San Francisco, California.

■■ 2013 Genitourinary

Cancers Symposium February 14–16, 2013 Orlando, Florida

Our world centers around theirs ACTION PURPOSE IMPACT

As cancer researchers, we dare to advocate uncharted paths in science and research.

We engage and execute with a vision, collaborating with the oncology community to deliver personalized and measurable outcomes that improve and extend lives.

We strive to advance the fight against cancer, continuously applying research to clinical practice and targeting the individual needs of people living with cancer.

This is our pledge. This is GSK Oncology.

Visit The ASCO Post online at ASCOPost.com

Learn more at the new GSKoncology.com

© 2012 GlaxoSmithKline. All Rights Reserved.

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The ASCO Post | DECEMBER 15, 2012

PAGE 46

Journal Spotlight Risk Reduction

Significant Reduction in Cancer Risk Seen with Daily Multivitamin Use in Middle-aged and Older Men

By Matthew Stenger

L

arge-scale trials over the past several years have shown a general lack of effect of single vitamins or small numbers of vitamins given at high doses in preventing cancer. However, as recently reported in JAMA by Gaziano and colleagues, the Physicians’ Health Study������������������������������� II ������������������������������ has found a modest but significant reduction in risk for “total cancer”—ie, all new cancers—in men taking a daily multivitamin compared with those taking placebo.1 A small reduction in cancer mortality was not statistically significant.

Physicians’ Health Study The Physicians’ Health Study II was a randomized, double-blind, placebocontrolled 2�������������������������� ×������������������������� 2������������������������ ×����������������������� 2���������������������� ×��������������������� 2 factorial trial assessing multivitamins, vitamin E, vitamin C, and beta-carotene use. The components of the trial other than the multivitamin component were terminated several years ago.

In the multivitamin component of the study, 14,641 male physicians aged ≥��������������������������� 50 �������������������������� years were randomly assigned to receive a daily multivitamin (n������������������������������������� ������������������������������������ =����������������������������������� ���������������������������������� 7,317) or placebo (n�������������� ������������� =������������ ����������� 7,324). Patients had a mean age of 64.3 years. At entry, 1,312 men had a history of cancer (8.9% of multivitamin group, 9.1% of placebo group), excluding melanoma skin cancer. The two groups were well balanced with respect to age, body mass index, smoking status, frequency of exercise, alcohol consumption, aspirin use, parental history of cancer, self-reported history of cancer, and general dietary habits. Enrollment began in 1997, and follow-up continued through June 1, 2011.

Reduced Risk of Total Cancer Over a median follow-up of 11.2 years, 2,669 men (18.2%) had confirmed cancer, including 1,373 (9.4%) with prostate cancer and 210 (1.4%) with colorectal cancer. The incidence of total cancer was 17.0 events/1,000 person-years in the multivitamin group vs 18.3 events/1,000 personyears in the placebo group, representing a significant 8% reduction in risk with multivitamin use (hazard ratio [HR] = 0.92, 95% confidence interval [CI] = 0.86–0.988, P = .04).

No significant effect of multivitamin use was found for prostate cancer

(9.1 vs 9.2 events/1,000 person-years (HR = 0.98, P = .76), colorectal cancer (1.2 vs 1.4 events/1,000 person-years (HR = 0.88, P = .39), or other sitespecific cancers, including lung cancer = .26) and bladder can(HR = 0.84, P ����������������������� cer (HR = 0.72, P = .10). As noted by the authors, the power to detect differences was limited in site-specific cancers with low event rates.

Multivitamin use was associated with a significant 12% reduction in risk for all cancers when prostate cancer was excluded from analysis (HR = = .02) and a significant 8% re0.88, P ������������������������������� duction in risk for all epithelial cancers (carcinomas including all cancers except lymphomas and leukemias; HR = 0.92, P = .04).

Among men with a history of cancer at baseline, multivitamin use was associated with a significant 23% reduction in risk for total cancer (HR = 0.73, 95% CI = 0.56–0.96, P = .02).

However, this reduction did not dif������������������ .07 ���������������� for interacfer significantly (P =����������������� tion) from the nonsignificant reduction in risk among subjects without

Multivitamins and Cancer Risk ■■ Daily multivitamin use modestly reduced risk for total cancer, total cancer other than prostate cancer, and epithelial cancers in middle-aged and older men.

■■ No reductions in risk for prostate cancer, colorectal cancer, or other sitespecific cancers were observed.

■■ The total cancer rates in the study were likely influenced by increased

PSA screening and subsequent diagnoses; prostate cancer accounted for approximately half of confirmed cancers, and most were earlier-stage, lower-grade disease associated with high survival rates.

those with parental history (HR = 1.05, 95% CI = 0.94–1.17, P = .37), and the P value for the interaction ��������������� .02). No sigwas significant (P = nificant heterogeneity was found according to other clinical, lifestyle, or select dietary factors or according to the previously terminated beta-carotene, vitamin C, or vitamin E interventions in the study.

In men with history of cancer at baseline, subgroup analyses showed no significant differential effect of multivitamin use according to diagnosis < 5 years before baseline (HR = 0.80,

Multivitamin use was associated with a significant 12% reduction in risk for all cancers when prostate cancer was excluded from analysis. baseline history of cancer (HR = 0.94, = .15). The ef95% CI = 0.87–1.02, P ��������������� fect of multivitamin use was stronger for total epithelial cancer in men with history of cancer (HR = 0.66, P = .004) than among those without history of cancer (HR = 0.95, P = .21), and the P value for interaction was significant (P = .02).

P = .33) vs diagnosis ≥ 5 years before baseline (HR = 0.70, P = .04; P = .70 for the interaction). Likewise, there was no differential effect according to whether the most recent type of cancer was prostate cancer (HR = 0.66, P = .21) vs other/unknown cancer (HR = 0.78, P = .10; P = .62 for interaction).

Few Subgroup Differences

No Significant Effect on Mortality

Subgroup analyses showed that multivitamin use significantly reduced risk of cancer in men aged ≥ 70 years (HR = 0.82, 95% CI = 0.72–0.93). However, the test for heterogeneity across age groups (HR = 0.96 for ages 50–59 and 1.01 for ages 60–69) did not reach significance (P = .06 for interaction). Risk was reduced by multivitamin use among subjects with no parental history of cancer (HR = 0.86, 95% CI = 0.76–0.98, P = .02) but not among

A total of 2,757 men (18.8%) died during follow-up, including 859 (5.9%) due to cancer. A reduction in risk of cancer mortality with multivitamin use fell short of significance (4.9 vs 5.6 events/1,000 person-years, HR = 0.88, 95% CI = 0.77–1.01, P = .07), and no significant reductions in risk for death from site-specific cancers were observed. Multivitamin use was not associated with reduction in risk for overall mortality (HR = 0.94, 95% CI 0.88–1.02, P = .13).

There were no significant differences in rates of reported adherence between the multivitamin and placebo groups at 4 years (76.8% vs 77.1%), 8 years (72.3% vs 70.7%), or end of follow-up (67.5% vs 67.1%). At the end of follow-up, there was no difference between groups with regard to proportions of subjects reporting avoidance of nonstudy multivitamin use (< 30 days per year; 81.0% vs 80.3%).

With regard to safety, no differences between groups were found in for gastrointestinal symptoms, fatigue, drowsiness, skin discoloration, or migraine. Multivitamin use was associated with a higher frequency of rash (HR = 1.07, P = .03).

Inconsistent effects on minor bleeding See Page 119 were observed, with multivitamin use being associated with reduced hematuria (HR = 0.91, P = .02), increased epistaxis (HR = 1.10, P = .01), and no effect on easy bruising or other bleeding (HR = 0.99, P = .77).

The authors note that total cancer rates in the trial were likely influenced by increased prostate-specific antigen surveillance and subsequent diagnoses of prostate cancer starting in the late 1990s. Approximately half of all confirmed cancers in the study were prostate cancers, and the majority of these were earlier-stage, lower-grade disease with high survival rates. Thus, the significant reduction in risk for total cancer other than prostate cancer may indicate that multivitamin use has a greater benefit in more clinically relevant cancer diagnoses.

The authors also acknowledge that adherence is of concern, as it is in any continued on page 48

MULTIPLE MYELOMA NEVER GIVES UP.

BUT NEITHER DO WE.

For 15 years, Celgene has been working to develop innovative therapies and has partnered with the multiple myeloma community to advance patient care. We’re relentless. We’re persistent. We’re progressive. And we’re not done yet.

© 2012 Celgene Corporation

06/12

US-CELG120121a

www.celgene.com

The ASCO Post | DECEMBER 15, 2012

PAGE 48

54th ASTRO Annual Meeting Oral Rinse Doxepin Relieves Painful Mucositis in Head and Neck Cancer

By Alice Goodman

D

oxepin oral rinse significantly improved oral mucositis in patients treated with radiation therapy for head and neck cancer according to results of a phase III trial presented at the 54th Annual Meeting of the American Society for Radiation Oncology (ASTRO) in Boston. However, the improvement was modest.

reasons: The first is that oral mucositis pain is often poorly controlled, and this medication can help us do a better job of reducing patient discomfort. The second is that patients can become dehydrated and undernourished during the weeks of head and neck radiation due to their mucositis keeping them from eating, and this can interrupt their cancer therapy. By treating their pain more effectively, we reduce the risk of an interruption in their cancer treatment that might reduce its effectiveness.”

Study Details

Robert C. Miller, MD

Lead author of the study, Robert C. Miller, MD, of the Mayo Clinic in Rochester, Minnesota, explained that radiation-induced oral mucositis pain is a significant problem that does not always resolve with narcotics and traditional mouth rinses. Doxepin is a tricyclic antidepressant approved in the United States for depression, anxiety, and moderate pruritus. Smaller studies suggested that doxepin reduces mucositis pain in patients with cancer when used as a mouth rinse. The study presented at the ASTRO meeting establishes the drug’s effectiveness in alleviating oral mucositis pain.

“Our study validates doxepin rinse as an effective way to alleviate oral pain and sets a new standard of care,” Dr. Miller said. “This is important for two

N09C6 was a double-blind, randomized, placebo-controlled trial of 140 patients with head and neck cancer who had oral mucositis pain scores above 4 (out of 10). Patients with head and neck cancer were enrolled between December 2010 and May 2012 and treated with radiation at doses above 50 Gy involving more than one-third of the oral cavity. Patients assigned to doxepin used an oral rinse at a dosage of 25 mg in 5 mL of water for 1 minute on day 1; patients then crossed over to the other treatment arm on day 2. Continued treatment with doxepin was allowed on an as-needed basis.

Pain was measured by the area under the curve (AUC) on a pain scale over time. On day 1, doxepin-treated patients reported a pain reduction to –9.1 vs –4.7 for placebo recipients (P = .0003). Crossover data from day 2 showed similar findings, with an AUC pain score of –7.9 in the doxepin group vs –5.6 in the placebo group (P = .009).

Doxepin in Radiation-induced Mucositis ■■ Doxepin oral rinse achieved a reduction in oral mucositis pain score

compared with placebo in patients with head and neck cancer undergoing radiation therapy.

■■ The improvement in oral mucositis pain with doxepin was modest.

■■ Ideally, another study should compare the doxepin rinse with slight adjustment in pain medication regimen or with commonly used anesthetic mouth rinses to determine whether doxepin provides an additional benefit.

Multivitamins and Cancer Risk continued from page 46

long-term trial. Drop-in rates of nonstudy vitamin use increased over time, mirroring increased use of vitamin supplements in the general U.S. population.

However, analyses accounting for adherence did not greatly affect the hazard ratios for total or site-specific cancers.

The authors conclude, “[A] daily multivitamin supplement significantly but modestly reduced risk of total cancer during a mean of 11 years of

EXPERT POINT OF VIEW

F

ormal discussant of this trial, Paul Harari, MD, University of Wisconsin School of Medicine and Public Health, Madison, commended the N09C6 investigators for conducting a randomized controlled phase III trial on symptom relief.

“Most phase III trials are conducted to evaluate a new cancer treatment regimen. We need more phase III trials like this that address challenging cancer treatment toxicities,” he noted. Another strength of this trial is that it was a multicenter efPaul Harari, MD fort, which adds to its strength and balance, he said.

Most cancer clinics currently use some form of anesthetic mouth rinse consisting of agents such as lidocaine, diphenhydramine hydrochloride, or aluminum hydroxide/magnesium hydroxide to assist with oral mucositis pain, Dr. Harari explained. These rinses provide only temporary relief, however. Patients with head and neck cancer typically receive narcotic analgesics as well to get through their radiation therapy course.

Transient Reduction The current study showed a modest, 1-point reduction in pain score over placebo [although a 2-point reduction from baseline] during a 4-hour test period following doxepin rinse. Baseline median pain score was 5.5; score decreased to 4.5, after placebo rinse, “a beautiful example of the placebo effect,” Dr. Harari said. Doxepin treatment reduced the median pain score to 3.5.

“It is important to consider whether a transient 1-point reduction in pain score over placebo [on a 10-point scale] warrants introduction of a whole new class of agent in patients already receiving multiple medications. It may be possible to achieve the same or better relief with slight adjustment in narcotic pain medication or additional use of anesthetic mouth rinses,” Dr. Harari commented.

Dr. Harari suggested it would be valuable to compare the doxepin rinse with anesthetic mouth rinses used at many institutions, and to compare doxepin rinse against a slight adjustment in pain medication to gain a better appreciation of the ultimate value of introducing this new agent. “This would be a logical question to consider,” he said.

■

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

Doxepin was well tolerated, but was associated with more stinging and burning (mean pain score of 3.7 for doxepin vs 1.1 for placebo) as well as an unpleasant taste (mean unpleasant taste score at 5 minutes of 2.9 for doxepin vs 1.6 for placebo), and caused greater drowsiness (mean drowsiness score of 3.9 for doxepin vs 2.8 for placebo). During the optional continuation phase, the majority of patients (64%) elected to continue doxepin.

Disclosure: Dr. Miller is on the scientific advisory board of Tekcapital.

treatment and follow-up. Although the main reason to take multivitamins is to prevent nutritional deficiency, these data provide support for the potential use of multivitamin supplements in the prevention of cancer in middleaged and older men.”

Reference 1. Gaziano JM, Sesso HD, Christen WG, et al: Multivitamins in the prevention of cancer in men: The Physicians’ Health Study II randomized controlled trial.

JAMA. October 17, 2012 (early release online).

■

■

Reference 1. Miller RC, Leenstra J, Qun R, et al: N09C6 (Alliance): A phase III, randomized double-blind study of doxepin rinse versus placebo in the treatment of oral mucositis pain in patients receiving head and neck radiotherapy with or without chemotherapy. 54th ASTRO Annual Meeting. Abstract LBA1. Presented October 29, 2012.

ASCOPost.com | DECEMBER 15, 2012

PAGE 49

Fifth AACR Conference on Cancer Health Disparities Gastrointestinal Oncology

Genetic Variation in Vitamin D Pathway Is Tied to Colorectal Cancer Risk among African Americans

By Susan London

A

frican Americans’ risk of colorectal cancer varies according to whether they have certain genetic variants that affect vitamin D metabolism, according to a study presented at the Fifth American Association for Cancer Research (AACR) Conference on The Science of Cancer Health Disparities, held recently in San Diego.1

Left-sided Colon Cancer Risk In a research project led by Fabio Pibiri, PhD, postdoctoral associate at the University of Illinois at Chicago, genotyping of approximately 1,800 African-American subjects, half of whom had colorectal cancer, identified single nucleotide polymorphisms in two genes—the GC gene (which codes for a vitamin D–binding protein) and the CYP24A1 gene (which codes for an enzyme involved in degrading active vitamin D)—as significantly associated with the risk of left-sided colorectal cancer. However, no such associations were found for right-sided disease.

“We think that people who have polymorphism in the CYP24A1 gene express less of the enzyme this gene encodes, so that maybe they have higher levels of vitamin D, particularly in the left colon,” Dr. Pibiri commented in a press briefing. “So there is a difference in the protective effect of vitamin D between the right and left colon.” He added, “This is a nice hypothesis, and we are starting to test it right now in our laboratory.

We have RNAs for all these samples.

So we are pretty excited about these results, and we hope to clarify why there is this big difference in colorectal cancer risk.”

Clinical Application William Nelson, MD, PhD, conference Co-Chair, press briefing moderator, and Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, wondered if this new information can be applied clinically.

“One of the challenges in this country—as people are really starting to think about vitamin D and health— is whether this is a rationale for targeted supplementation,” Dr. Nelson commented. “You found African

this country should take 2,000 IU per day, or something like that.”

Study Rationale

William Nelson, MD, PhD

Americans with these particular [single nucleotide polymorphisms] who might be especially prone to developing colorectal cancer. Is this the kind of person in whom we should measure the vitamin D levels and, if they are low, then supplement them? Does that make sense?” he asked.

“Yes, it totally makes sense, talking about tailoring the different approaches to preventing cancer, depending on which race you belong

Giving some background to the research, Dr. Pibiri noted that there is a substantial racial disparity in colorectal cancer, with African Americans having a higher incidence and mortality than whites.

“It is starting to be accepted that vitamin D is a protective factor against several types of cancer, especially colorectal cancer,” he continued. “Vitamin D is usually low in the serum of African-American people. We also think that genetic variants are present in vitamin D–related genes that may be associated with the higher risk that African Americans have for colorectal cancer.”

In the study, the investigators obtained samples from 292 patients with

Vitamin D, Colorectal Cancer, and Race ■■ Recent research revealed that single nucleotide polymorphisms of two

vitamin D–related genes—GC and CYP24A1—significantly increased the risk of left-sided colorectal cancer in African Americans.

■■ Vitamin D may be protective against various types of cancer, but people

with darker skin make lower amounts of vitamin D with the same exposure to sun as whites. Thus, there may be a rationale for targeted vitamin D supplementation based on race, particularly among African Americans with specific genetic variations.

to” and vitamin D status, Dr. Pibiri replied. He stressed that over 80% of circulating vitamin D depends on activation in the skin through exposure to ultraviolet light in sunshine. Thus, people with more darkly pigmented skin, as well as those living in northern latitudes, may have difficulty achieving adequate vitamin D levels. Moreover, it would be daunting to try to obtain sufficient amounts through typical dietary sources, such as milk, because very few dietary sources contain high levels of vitamin D. “So we should consider this,” Dr. Pibiri maintained. “For example, taking 1,000 IU per day of vitamin D can be good for people in some southern parts of the United States and for whites. But maybe the black population, people with darker skin, and those who live in the northern part of

right-sided colorectal cancer, 443 patients with left-sided colorectal cancer, and 838 healthy individuals who served as controls. They opted to look at cancer sidedness because tumors arising in the right and left colon have differing characteristics, Dr. Pibiri explained. Additionally, the proportion of cancers that are left-sided is lower among African Americans than among whites.

Key Findings The investigators tested for 39 putatively functional single nucleotide polymorphisms in a set of important genes involved in vitamin D synthesis and catabolism: CYP27A1, GC, CY� P3A4, CYP2R1, DHCR7/NADSYN1, VDR, CYP27B1, and CYP24A1. The results showed that after adjustment for age and sex, none of the single nucleotide polymorphisms studied were

associated with the risk of right-sided colorectal cancer. However, four were associated with the risk of left-sided colorectal cancer.

Specifically, the T base pair of the rs16847024 variant in the GC gene

Fabio Pibiri, PhD

was associated with increased risk of left-sided disease (odds ratio = 1.56; P = .003), as was the G base of the rs6022990 variant in the CYP24A1 gene (odds ratio = 1.48; P = .006).

The C base pair of the rs1155563 variant of the GC gene was associated with deceased risk of left-sided disease (odds ratio = 0.77; P = .039), as was the A base pair of rs73913755 variant of the CYP24A1 gene (odds ratio = 0.67; P = 1.9 × 10–4).

After additional adjustment for multivariate testing, only the last association remained statistically significant (P = .009), Dr. Pibiri reported. “Most of these single nucleotide polymorphisms are African American–specific, so they don’t exist in whites,” he pointed out.

The investigators plan a variety of related studies, according to Dr. Pibiri, including analysis of serum vitamin D levels in African American colorectal cancer, analysis of interactions between single nucleotide polymorphisms and vitamin D levels in African-American colorectal cancer, and determination of vitamin D gene-expression levels relative to genotype.

■

Disclosure: Drs. Nelson and Pibiri reported no potential conflicts of interest.

Reference 1. Pibiri F, Kittles RA, Sandler RS, et al: Genetic variation in the vitamin D pathway and risk for colorectal cancer in African Americans. Fifth AACR Conference on Cancer Health Disparities. Plenary Session 2. Presented October 28, 2012.

The ASCO Post | DECEMBER 15, 2012

PAGE 50

Journal Spotlight Gastrointestinal Oncology

Finding Lynch Syndrome among Patients with Colorectal Cancer: Routine Tumor Testing Looks Best

By Caroline McNeil

O

ncologists generally agree that screening patients with colorectal cancer for Lynch syndrome is a good thing. Patients who turn out to have the hereditary syndrome can inform their first-degree relatives, who in turn can undergo genetic testing.

Those who have the characteristic mutations can take preventive measures—frequent colonoscopies, for instance—that are known to be effective. The question is who to screen and how.

Now, a large study suggests that testing tumor samples of all patients with newly diagnosed colorectal cancer—a strategy known as universal tumor testing—is more sensitive and efficient than other strategies that rely on family history and clinical criteria.

The study, a pooled analysis involving more than 10,000 patients, was led by Leticia Moreira, MD, of the University of Barcelona, Spain, and published in the Journal of the American Medical Association.1 People with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer, or HNPCC) have germline See Page 119 mutations in one

or more mismatch repair (MMR) genes. The mutations cause microsatellite instability (MSI) and put carriers at high risk of colorectal cancer as well as endometrial and other cancers.

Design and Data To determine which patients with

which identified patients for testing who were age 70 and younger or fulfilled at least one of the criteria in the revised Bethesda guidelines.

Of the 10,206 patients in the analysis, 3.1% were mismatch repair gene mutation carriers. As expected, universal tumor testing was 100% sensitive at identifying patients with Lynch syndrome.

Screening for Lynch Syndrome ■■ Identifying patients with colorectal cancer who have Lynch syndrome

might reduce the incidence of this and other cancers in first-degree relatives who test positive for the syndrome and take preventive measures.

■■ The most sensitive method of identifying patients with Lynch syndrome is routine testing of all tumors, compared to methods that use family history and clinical criteria.

■■ More research is needed on the cost-effectiveness of different strategies. colorectal cancer should undergo germline genetic testing for Lynch syndrome, the researchers compared universal tumor testing with three other approaches: (1) the Bethesda guidelines, which combine family history with clinical and pathologic criteria; (2) the Jerusalem recommendations, which call for testing of all patients with colorectal cancer under age 70; and (3) a “selective strategy,”

The specificity of this approach was 93%.

Next most efficient was the selective strategy, with 95.1% sensitivity and 95.5% specificity, indicating fewer falsepositives. The Bethesda guidelines had 87.8% sensitivity and 97.5% specificity, the Jerusalem recommendations, 85.4% sensitivity and 96.7% specificity.

Study Conclusions These data indicate that “unless a

universal screening approach, consisting of tumor [mismatch repair] testing in all patients with colorectal cancer, is performed, a clinically meaningful proportion of [mismatch repair] gene mutation carriers will remain undiagnosed,” the authors wrote.

They also noted that the selective strategy had almost the same diagnostic yield as universal tumor testing. It missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer patients requiring tumor mismatch repair testing and 28.6% fewer patients undergoing germline mutational analysis.

Where resources are limited, the selective strategy could be an alternative to universal tumor testing, the authors said, though “it remains to be demonstrated whether this strategy can be implemented consistently in a clinical setting.”

They added that more cost-effectiveness research is needed on all the strategies evaluated in their study.

■

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

Reference 1. Moreira L, Balaguer F, Lindor N, et al: Identification of Lynch syndrome among patients with colorectal cancer.

JAMA 308:1555-1565, 2012.

Don’t Miss These Important Announcements in this Issue of The ASCO Post

ASTRO Honors Mark P. Carol, MD see page 14

Richard R. Barakat, MD, Named 2014 President of Two Gynecologic Oncology Medical Societies, see page 25

Karen E. Knudsen, PhD, Named Editor-in-Chief of Molecular Cancer Research, see page 84

Armand Keating, MD, Announces Launch of ASH Foundation, see page 90

American Cancer Society Honors Waun Ki Hong, MD, see page 93

Lewis C. Cantley, PhD, Assumes Leading Role at Weill Cornell/NY Presbyterian, see page 109

Visit The ASCO Post online at ASCOPost.com

XGEVA速 (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

XGEVA速 is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

Please see the following pages for Important Safety Information.

XGEVA®, THE FIRST AND ONLY RANK LIGAND INHIBITOR TO PREVENT SREs

INDICATION XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

IMPORTANT SAFETY INFORMATION Hypocalcemia

Osteonecrosis of the Jaw (ONJ)

• XGEVA® can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to XGEVA® treatment.

Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ.

• Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

• Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®.

• Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

©2012 Amgen Inc. All rights reserved. 7/12 64000-R6-V1 G69095-R1-V1

www.XGEVA.com

SUPERIORITY XGEVA® delayed the median time to first SRE in a prespecified integrated analysis across 3 head-to-head studies vs zoledronic acid1

PERCENTAGE OF PATIENTS WITHOUT SRE

Time to first SRE, evaluated in more than 5,600 patients1,2 XGEVA® 120 mg Q4W (n = 2,862) zoledronic acid 4 mg Q4W (n = 2,861)

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

HR = 0.83 (95% CI: 0.76–0.90) P < 0.0001†

0 0

3

6

9

12

15

18

21

24

27

30

Reduction in risk of first SRE in 3 individual studies • Breast cancer: 18% vs zoledronic acid (P = 0.010, superiority)3 • Prostate cancer: 18% vs zoledronic acid (P = 0.008, superiority)3 • Other solid tumors* or multiple myeloma: 16% vs zoledronic acid (P < 0.001, noninferiority; P = 0.060, NS for superiority)3 – Subanalysis of other solid tumors*: 19% vs zoledronic acid (P = 0.034, superiority)2 – XGEVA® is not indicated for the prevention of SREs in patients with multiple myeloma *Excluding breast and prostate cancer. † P value for superiority.

STUDY MONTH Data from three international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.3

SUBCUTANEOUS INJECTION

NO DOSE ADJUSTMENTS

PRECISE ACTION

XGEVA® is not cleared by the kidneys and does not require dose adjustments, regardless of renal function3-8

XGEVA® acts precisely to bind XGEVA® is administered once to RANK Ligand, a key mediator every 4 weeks as a single, 120 mg of bone resorption, to inhibit subcutaneous injection3 osteoclast activity3

Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.3

Pregnancy • Women should be advised not to become pregnant when taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

During post approval use, severe symptomatic hypocalcemia, including fatal cases has been identified.

Please see brief summary of Prescribing Information on the following page.

REFERENCES: 1. Lipton A, Siena S, Rader M, et al. Comparison of denosumab versus zoledronic acid for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials. Ann Oncol. 2010;21(suppl 8):viii380. Abstract 1249P and poster. 2. Data on file, Amgen. 3. XGEVA® (denosumab) prescribing information, Amgen. 4. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women.

J Bone Miner Res. 2004;19:1059-1066. 5. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis.

Biologics. 2008;2:645-653. 6. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies.

Clin Pharmacokinet. 2010;49:493-507. 7. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010;24:23-39. 8. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50:793-807.

T:9.5â&#x20AC;?

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information).

DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions).

Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment.

Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva.

Patients who are suspected of having or who develop ONJ while on Xgeva should immunogenicity. Using an electrochemiluminescent bridging immunoassay, less receive care by a dentist or an oral surgeon. In these patients, extensive dental than 1% (7/2758) of patients with osseous metastases treated with denosumab surgery to treat ONJ may exacerbate the condition. doses ranging from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 weeks for up to PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant 3 years tested positive for binding antibodies. No patient with positive binding woman. Based on ďŹ ndings in animals, Xgeva is expected to result in adverse antibodies tested positive for neutralizing antibodies as assessed using a reproductive effects. In utero denosumab exposure in cynomolgus monkeys chemiluminescent cell-based in vitro biological assay. There was no evidence resulted in increased fetal loss, stillbirths, and postnatal mortality, along with of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical response associated evidence of absent peripheral lymph nodes, abnormal bone growth and with binding antibody development. The incidence of antibody formation is decreased neonatal growth (see Use in SpeciďŹ c Populations). There are no highly dependent on the sensitivity and speciďŹ city of the assay. Additionally, adequate and well controlled studies with Xgeva in pregnant women. Women the observed incidence of a positive antibody (including neutralizing antibody) should be advised not to become pregnant when taking Xgeva. If this drug is test result may be inďŹ&#x201A;uenced by several factors, including assay methodology, used during pregnancy, or if the patient becomes pregnant while taking this drug, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab the patient should be apprised of the potential hazard to the fetus. with the incidence of antibodies to other products may be misleading.

ADVERSE REACTIONS: The following adverse reactions are discussed below DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted and elsewhere in the labeling: with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva t )ZQPDBMDFNJB TFF 8BSOJOHT BOE 1SFDBVUJPOT

was administered in combination with standard anticancer treatment. Serum t 0TUFPOFDSPTJT PG UIF +BX TFF 8BSOJOHT BOE 1SFDBVUJPOT) denosumab concentrations at 1 and 3 months and reductions in the bone turnover The most common adverse reactions in patients receiving Xgeva (per-patient marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, were similar in patients with and without prior intravenous bisphosphonate therapy. and nausea (see Table 1). The most common serious adverse reaction in patients There was no evidence that various anticancer treatments affected denosumab receiving Xgeva was dyspnea. The most common adverse reactions resulting in systemic exposure and pharmacodynamic effect. Serum denosumab concentrations discontinuation of Xgeva were osteonecrosis and hypocalcemia. at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone Clinical Trials Experience. Because clinical trials are conducted under widely therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar varying conditions, adverse reaction rates observed in the clinical trials of a drug between patients receiving concomitant chemotherapy and/or hormone cannot be directly compared to rates in other clinical trials and may not reďŹ&#x201A;ect the therapy (see Clinical Pharmacology [12.2] in full Prescribing Information). rates observed in practice. The safety of Xgeva was evaluated in three randomized, USE IN SPECIFIC POPULATIONS: double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Information) in which a total of 2841 patients with bone metastasis from prostate Xgeva can cause fetal harm when administered to a pregnant woman based cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple on ďŹ ndings in animals. In utero denosumab exposure in cynomolgus monkeys myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were resulted in increased fetal loss, stillbirths, and postnatal mortality, along with randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid evidence of absent lymph nodes, abnormal bone growth and decreased every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium neonatal growth. There are no adequate and well-controlled studies with Xgeva (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance in pregnant women. Women should be advised not to become pregnant when 30 mL/min or greater. Patients who had received IV bisphosphonates were taking Xgeva. If this drug is used during pregnancy, or if the patient becomes excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an pregnant while taking this drug, the patient should be apprised of the potential active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, hazard to the fetus. Women who become pregnant during Xgeva treatment are or any planned invasive dental procedure. During the study, serum chemistries encouraged to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or including calcium and phosphorus were monitored every 4 weeks. Calcium and their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 â&#x20AC;&#x201C; 41) and median duration on-study was 13 months (range: 0.1 â&#x20AC;&#x201C; 41). Of patients who received 9HFWB XFSF GFNBMF &JHIUZ mWF QFSDFOU XFSF 8IJUF )JTQBOJD -BUJOP Asian, and 3% Black. The median age was 63 years (range: 18 â&#x20AC;&#x201C; 93). SeventyďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.

DOUS2X0319_T_4Pg Tabloid_Update_Aug_12_BS_r8.indd 1

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and beneďŹ ts in continuing or discontinuing treatment with Xgeva.

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information).

OVERDOSAGE: There is no experience with overdosage of Xgeva.

HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat.

Avoid vigorous shaking of Xgeva.

PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: t 4ZNQUPNT PG IZQPDBMDFNJB JODMVEJOH QBSFTUIFTJBT PS NVTDMF TUJGGOFTT twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) t 4ZNQUPNT PG 0/+ JODMVEJOH QBJO OVNCOFTT TXFMMJOH PG PS ESBJOBHF GSPN UIF jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) t 1FSTJTUFOU QBJO PS TMPX IFBMJOH PG UIF NPVUI PS KBX BGUFS EFOUBM TVSHFSZ (see Warnings and Precautions) t 1SFHOBODZ PS OVSTJOH (see Warnings and Precautions and Use in SpeciďŹ c Populations) Advise patients of the need for: t 1SPQFS PSBM IZHJFOF BOE SPVUJOF EFOUBM DBSF t *OGPSNJOH UIFJS EFOUJTU UIBU UIFZ BSF SFDFJWJOH 9HFWB t "WPJEJOH JOWBTJWF EFOUBM QSPDFEVSFT EVSJOH USFBUNFOU XJUI 9HFWB Advise patients that denosumab is also marketed as ProliaÂŽ. Patients should inform their healthcare provider if they are taking Prolia.

Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 Š2012 Amgen Inc. All rights reserved. Printed in USA.

68257-R1-V3

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T:13â&#x20AC;?

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied Severity (Trials 1, 2, and 3) in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?).

Xgeva Zoledronic Acid In cynomolgus monkeys dosed subcutaneously with denosumab throughout Body System n = 2841 n = 2836 pregnancy at a pharmacologically active dose, there was increased fetal loss during % % gestation, stillbirths, and postnatal mortality. Other ďŹ ndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal GASTROINTESTINAL bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and Nausea 31 32 tooth malalignment; and decreased neonatal growth. At birth out to one month of Diarrhea 20 19 age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects GENERAL on bone quality and strength returned to normal; there were no adverse effects Fatigue/ Asthenia 45 46 on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes INVESTIGATIONS were present, though small; and minimal to moderate mineralization in multiple )ZQPDBMDFNJBb 18 9 tissues was seen in one recovery animal. There was no evidence of maternal 32 20 )ZQPQIPTQIBUFNJBb harm prior to labor; adverse maternal effects occurred infrequently during labor.

NEUROLOGICAL Maternal mammary gland development was normal. There was no fetal NOAEL (no )FBEBDIF 13 14 observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of RESPIRATORY denosumab) also caused fetal lymph node agenesis and led to postnatal impairment 18 Dyspnea 21 of dentition and bone growth. Pregnant RANKL knockout mice showed altered Cough 15 15 maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

1, 2, and 3, and meeting one of the following criteria: Measurable concentrations of denosumab were present in the maternal milk t "U MFBTU HSFBUFS JODJEFODF JO 9HFWB USFBUFE QBUJFOUT PS of cynomolgus monkeys up to 1 month after the last dose of denosumab t #FUXFFO HSPVQ EJGGFSFODF FJUIFS EJSFDUJPO PG MFTT UIBO BOE NPSF UIBO (â&#x2030;¤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and 5% greater incidence in patients treated with zoledronic acid compared to because of the potential for serious adverse reactions in nursing infants from placebo (US Prescribing Information for zoledronic acid) Xgeva, a decision should be made whether to discontinue nursing or discontinue b Laboratory-derived and below the central laboratory lower limit of normal the drug, taking into account the importance of the drug to the mother. Maternal [8.3 â&#x20AC;&#x201C; 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL (0.71 â&#x20AC;&#x201C; 0.9 mmol/L) for phosphorus] signaling pathway that have shown altered maturation of the maternal mammary Severe Mineral/Electrolyte Abnormalities HMBOE MFBEJOH UP JNQBJSFE MBDUBUJPO QPTUQBSUVN )PXFWFS JO DZOPNPMHVT t 4FWFSF IZQPDBMDFNJB DPSSFDUFE TFSVN DBMDJVN MFTT UIBO NH E- PS MFTT monkeys treated with denosumab throughout pregnancy, maternal mammary than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% gland development was normal, with no impaired lactation. Mammary gland of patients treated with zoledronic acid. Of patients who experienced severe histopathology at 6 months of age was normal in female offspring exposed to hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia denosumab in utero; however, development and lactation have not been fully and 16% experienced 3 or more episodes (see Warnings and Precautions and evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information).

Use in SpeciďŹ c Populations).

Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and t 4FWFSF IZQPQIPTQIBUFNJB TFSVN QIPTQIPSVT MFTT UIBO NH E- PS MFTT UIBO effectiveness of Xgeva in pediatric patients have not been established. Treatment 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of with Xgeva may impair bone growth in children with open growth plates and patients treated with zoledronic acid. may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target Osteonecrosis of the Jaw of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in at doses â&#x2030;¤ 10 mg/kg was associated with inhibition of bone growth and tooth 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic eruption. Adolescent primates treated with denosumab at doses 5 and 25 times acid group (see Warnings and Precautions). When events occurring during an (10 and 50 mg/kg dose) higher than the recommended human dose of extended treatment phase of approximately 4 months in each trial are included, 120 mg administered once every 4 weeks, based on body weight (mg/kg), had the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Postmarketing Experience. Because postmarketing reactions are reported decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and voluntarily from a population of uncertain size, it is not always possible to reliably mesenteric lymph nodes. Some bone abnormalities recovered once exposure estimate their frequency or establish a causal relationship to drug exposure. was ceased following birth; however, axillary and inguinal lymph nodes remained The following adverse reactions have been identiďŹ ed during post approval absent 6 months post-birth (see Use in Pregnancy). use of Xgeva: Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) t )ZQPDBMDFNJB Severe symptomatic hypocalcemia, including fatal cases. were 65 years of age or older. No overall differences in safety or efďŹ cacy were Immunogenicity. As with all therapeutic proteins, there is potential for observed between these patients and younger patients.

ASCOPost.com | DECEMBER 15, 2012

PAGE 55

Direct from ASCO

Shaping the Future of Oncology: Envisioning Cancer Care in 2030 ASCO Board shares outcomes of planning process, seeks member input

O

ver the course of the last year, and learning from vast amounts of the ASCO Board of Direcreal-world data ■■ Cancer “panomics”: Undertors worked to identify “drivers of standing the complex combichange” that will have the greatest nation of genes, proteins, moimpact on the oncology field over lecular pathways, and unique the next two decades. patient characteristics that “We are on the verge of a new together drive the disease of age of cancer care, in which emergcancer, as well as understanding scientific, technical, and ecoing how to target these factors nomic trends are likely to alter our in combination to develop prework more significantly in the next vention strategies and curative 20 years than in the prior 50 years therapies of modern oncology. As a profes■■ Delivering value: Confrontsion, we must anticipate and harness ing unsustainable cost increases these changes to improve the care of and furthering our patients,” said improvements in ASCO President We are on the verge quality metrics to Sandra M. Swain, promote cost efMD, FACP, of a new age of cancer and Medical Director, care, in which emerging fectiveness “value” in health Washington Canscientific, technical, and care cer Institute, MedThe report also Star Washington economic trends are lists obstacles to Hospital Center. likely to alter our work achieving posiThe Board tive outcomes identified the more significantly in related to each three main drivthe next 20 years than of the three drivers of change ers of change and through a stratein the prior 50 years of suggests actions gic planning promodern oncology. needed to ensure cess that includ—Sandra M. Swain, MD, FACP that the field is ed a virtual town well-positioned hall meeting for the future. with ASCO volunteers, in-depth interviews with Member Input Needed experts both inside and outside of “The Vision Statement represents oncology, Board discussions, and our vision of the future. This docufeedback from ASCO members via ment is intended to be the starting an interactive online article on ASpoint for ongoing conversations with COconnection.org. The identified ASCO members about where our drivers of change that present the field is headed and where we want to field with both challenges and opbe in 20 years,” said ASCO Immediportunities are: ■■ “Big data”: Collecting, analyzing, ate Past President Michael P. Link, MD. Over the next 12 months, ASCO Members Shaping the Future of are encouraged Oncology: Envisioning Cancer Care in 2030 to comment on Outcomes of the ASCO Board of all aspects of Directors Strategic Planning and Visioning Process, 2011-2012 this vision statement on ASCOconnection.org.

Members will also have opportunities to weigh in on the plan at State Affiliate

meetings and at ASCO’s Annual Meeting.

Together, the vision statement combined with member input will help ASCO determine future needs and solutions.

“With the number of cancer patients projected to grow dramatically both in the U.S. and internationally, it is imperative that the Society do everything possible to ensure that we are well-positioned to deliver the care patients will need,” said Dr. Link.

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY

To review the complete report, including detailed information on the three “drivers of change,” visit asco.org/vision. To comment, visit ASCOconnection.org and select “Magazine,” then “Online Exclusives.”

■

Originally published on ASCOconnec� tion.org. © American Society of Clinical Oncology.������������������������������� (“Shaping the Future of Oncol� ogy: Envisioning Cancer Care in 2030.” www.ASCOconnection.org 07 November 2012). All rights reserved.

5 most-accessed Top 10Top most-accessed articles recently in published articles published 2011 in in Journal of Clinical Oncology Journal of Clinical Oncology

Official Journal of the American Society of Clinical Oncology

What’s Hot in

JCO

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

www.jco.org

JCO.org Late Cardiac Effects of Cancer Treatment

By Daniel J. Lenihan, et al

Monoclonal Antibody-Based Therapies: A New Dawn in the Treatment of Acute Lymphoblastic Leukemia

By Hagop Kantarjian, et al

Seven-Year Follow-Up Assessment of Cardiac Function in NSABP B-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel (ACP) With ACP Plus Trastuzumab As Adjuvant Therapy for Patients With Node-Positive, Human Epidermal Growth Factor Receptor 2– Positive Breast Cancer

By Edward H. Romond, et al

Randomized Trial of Short-Course Radiotherapy Versus Long-Course Chemoradiation Comparing Rates of Local Recurrence in Patients With T3 Rectal Cancer: Trans-Tasman Radiation Oncology Group Trial 01.04

By Samuel Y. Ngan, et al

Long-Term Results of the Randomized Phase III Trial EORTC 18991 of Adjuvant Therapy With Pegylated Interferon Alfa2b Versus Observation in Resected Stage III Melanoma

By Alexander M.M. Eggermont, et al

The ASCO Post | DECEMBER 15, 2012

PAGE 56

Direct from ASCO

Clinical Cancer Advances 2012: ASCO’s Annual Report on Progress Against Cancer

C

linical research is continuously delivering new treatments that lengthen and improve the lives of patients with cancer. The abundance of advances reported in the past year illustrates our steady progress in cancer treatment and care.

Clinical Cancer Advances 2012: ASCO’s Annual Report on Progress Against Cancer reviews the year’s most important clinical cancer research.

About the CCA Report Clinical Cancer Advances (CCA), now in its eighth year, is unique in that it describes the most significant advances of the year, offering the public a window into the achievements, trends, and challenges in oncology. The CCA is intended for anyone with an interest in cancer care, including, patients, caregiv-

ers, concerned family and friends of cancer patients, oncologists and other medical professionals, policymakers, and cancer advocacy organizations.

This year’s report was compiled and edited under the guidance of 21

renowned experts in specific fields of cancer research. The editors reviewed research published in peer-reviewed scientific or medical journals and presented at major scientific meetings over a 1-year period (October 2011–September 2012). Research reviewed in the CCA covers the full range of clinical research disciplines: epidemiology, prevention, screening, early detection, treatment, patient and survivor care, biomarkers, tumor biology, and cancer disparities. The report this year includes two new sections highlighting research progress in the areas of tumor biology and quality cancer care.

Major Advances in Cancer Care The 2012 CCA features a total of 87 studies, 17 of which are considered major, meaning they represent re-

search results that are practice-changing, published in a peer-reviewed journal, and/or are reports on treatments that received FDA approval in the past year. In the last 12 months, the FDA approved 7 new anticancer drugs and expanded indications for 5 existing agents based on encouraging results from large clinical trials.

Significant strides were made this year in precision medicine and overcoming treatment resistance. Many of these advances involve therapeutic strategies that stem from our growing understanding of the complex biology of cancer. Major advances from this year include: ■■ New targeted drugs for patients with advanced colorectal and prostate cancers, skin cancer, and treatment-resistant forms of thyroid cancer and soft tissue sarcoma continued on page 57

Research of Three Conquer Cancer Foundation Grantees Featured among Top Cancer Advances of the Year

E

very year, the Conquer Cancer Foundation of the American Society of Clinical Oncology funds research grants that provide critical start-up funding for young physician-scientists, with the goal of enabling them to develop successful careers in cancer research so that they can bring new treatments into the clinic and improve the lives of patients with cancer. Clearly, the programs are working: Three of the studies featured in the recently released Clinical Cancer Advances 2012: ASCO’s Annual Report on Progress Against Cancer, which identifies the top advances of the year

Arti Hurria, MD

in clinical cancer research, were funded in part by Conquer Cancer Foundation of ASCO Career Development Awards (CDAs). All three researchers are also past recipients of the Foundation’s Young Investigator Award (YIA).

Major Advances Highlighted Identified as a major advance in the report, a study led by Arti Hurria, MD, (2002 YIA, 2005 CDA) reveals factors that predict risk for chemotherapy side effects in older adults. Older patients with cancer are generally more vulnerable to harmful adverse effects of chemo-

Paul Paik, MD

Mark Dickson, MD

therapy, but there are no objective factors to determine which elderly patients are at elevated risk. This study proposes a predictive model to address this concern and provides a sorely needed tool to inform chemotherapy decision-making for elderly patients with any type and stage of cancer.

A study led by Paul Paik, MD, (2011 YIA, 2012 CDA) identifies new therapeutic targets for squamous cell lung cancer through molecular testing of tumor specimens.

Squamous cell carcinoma accounts for approximately 40% of lung cancer cases, and the development of targeted drugs for this cancer has been slow compared with development of drugs for other cancers, because few druggable targets have been discovered, until now.

A phase II trial led by Mark Dickson, MD, (2009 YIA, 2011 CDA) shows that the targeted drug PD0332991, a CDK4 inhibitor, has

promising effects in a subset of patients with liposarcoma, which is the most common soft tissue sarcoma in adults. After 12 weeks of treatment with PD0332991, 70% of patients on the trial had no disease progression, which exceeded what was anticipated from historical controls.

To learn more about the advances led by these three Foundation-funded researchers, read the 2012 report recently published in the Journal of Clinical Oncology at www.jco.org or at www.cancerprogress.net/cca. For more information about the Career Development Award visit www.conquercancerfoundation.org/cda.

■

© 2012. American Society of Clinical Oncology. All Rights Reserved.

ASCOPost.com | DECEMBER 15, 2012

PAGE 57

Direct from ASCO

Clinical Cancer Advances continued from page 56

■■ New combination therapies for patients with breast cancer, chemotherapy-resistant ovarian cancer, esophageal and gastroesophageal junction cancers, and advanced lung cancer ■■ A maintenance therapy to delay multiple myeloma relapse ■■ A potential new screening modality for colorectal cancer ■■ Promising treatments for chemotherapy-induced nausea and pain ■■ Factors to consider before administering chemotherapy to elderly patients

Cancer Policy Priorities The “The Policy Environment: ASCO in Action in 2012” section of the report outlines important policy developments that have affected oncology over the past year and highlights related ASCO initiatives aimed at creating an environment where faster progress can be made against cancer. Many of the significant developments highlighted in this report were achieved through federally funded clinical research, which is currently under threat due to the challenging economic climate and federal budget concerns. ASCO

The Latest News on Quality Cancer Care: What It Means for Patients

D

irect your patients to www.cancer.net/qualitysymposium to learn about the research highlighted at the 2012 Quality Care Symposium in the special online newsletter Cancer Advances: News for Patients from the 2012 Quality Care Symposium. Also, your patients can listen to a podcast of highlights from the symposium online or download it free of charge at www.cancer.net/podcasts.

■

© 2012. American Society of Clinical Oncology. All Rights Reserved.

is using all means and channels possible to implore Congress to avert the disastrous impact of sequestration on patients with cancer. Additional topics covered in this section include ASCO’s initiative to build a rapid learning system for oncology, ASCO’s recommendations to tackle

drug shortages, and recommendations for improving quality and value in cancer care, such as the Choosing Wisely® campaign and ASCO’s Top Five list).

The Clinical Cancer Advances 2012: ASCO’s Annual Progress Against Cancer was published online

in the Journal of Clinical Oncology (www.jco.org) on December 3. The full report and additional resources are available at www.cancerprogress. net/cca.

■

© 2012. American Society of Clinical Oncology. All Rights Reserved.

The ASCO Post | DECEMBER 15, 2012

PAGE 58

Direct from ASCO

ASCO Underscores Importance of Quality and Value in Cancer Care at IOM Workshop analyze it, and provide feedback in realtime on what treatments work best for an individual patient,” Dr. Lichter said.

A full workshop summary is ex-

A

SCO leadership recently participated in the Institute of Medicine’s (IOM) National Cancer Policy Forum workshop titled “Delivering Affordable Care in the 21st Century.”

The workshop focused on examining the rising costs related to cancer care and potential ways to curb these costs while improving the quality of care.

Lowell Schnipper, MD, Chair of ASCO’s Cost of Cancer Care Task Force, spoke about ASCO’s Top Five list in oncology and its impact on improving value and quality of cancer care.

“Physicians inherently want to do the right thing. Part of that means not performing medical tests or treatments that have little or no clinical benefit,” Dr. Schnipper said. “Guidance like that provided by ASCO’s Top Five list also helps physicians in the exam rooms when discussing treatment options with patients.”

Dr. Schnipper also highlighted the need to measure and evaluate the impact of ASCO’s Top Five list. To that end, ASCO plans to incorporate the Top Five list into its measures set as part of the Quality Oncology Practice Initia-

tive® to demonstrate physician behavior and uptake of the Top Five list recommendations.

Oncology Community Must Work Together The IOM workshop also included panel discussions on policy issues related to the value, cost containment, and reimbursement of cancer care as well as the economic incentives for innovation and technology diffusion in cancer care.

Allen S. Lichter, MD, Chief Executive Officer of ASCO and panel participant, said that it is important that the oncology community work together to improve the quality of cancer care. Dr. Lichter emphasized that to improve the quality of care for all patients, the oncology community must be able to aggregate, share, and analyze patient data together to determine the highest value care for each patient. Using evidence-based medicine will help reduce inefficiencies and costs in the healthcare system, he said.

“We know cancer is complicated, and we’ve reached a tipping point where we must be able to collect data,

Volume 7, Issue 3

Top 5 articles Top 10 most-accessed recently published articles published in 2011 in in Journal of Oncology Practice Journal of Clinical Oncology

What’s Hot in

JOP

Report on the ASCO 2010 Provider-Payer Initiative Meeting

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

By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists

By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials

By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice

By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

—Lowell Schnipper, MD

■

© 2012. American Society of Clinical On� cology. All Rights Reserved.

The Authoritative Resource for Oncology Practices

Physicians inherently want to do the right thing. Part of that means not performing medical tests or treatments that have little or no clinical benefit.

Save the Date

May 2011

Journal of oncology Practice

pected to be published in 2013.

JCO.org National Oncology Practice Benchmark, 2012 Report on 2011 Data

By Elaine L. Towle, et al

Health Care Costs for Patients With Cancer at the End of Life

By Benjamin Chastek, et al

Oncology Practice Trends From the National Practice Benchmark

By Thomas R. Barr, et al

Ethics of Ongoing Cancer Care for Patients Making Risky Decisions

By Jeffrey Peppercorn

Implementing a Systematic Approach to Meeting Patients’ Cancer and Fertility Needs: A Review of the Fertile Hope Centers of Excellence Program

By Joyce D. Reinecke, et al

2013 Gastrointestinal Cancers Symposium

2013 Genitourinary Cancers Symposium

January 24-26, 2013

February 14-16, 2013

Moscone West Building

Rosen Shingle Creek

San Francisco, California

Orlando, Florida

ASCOPost.com | DECEMBER 15, 2012

PAGE 59

Direct from ASCO

ASCO Calls on Congress to Avoid Looming ‘Fiscal Cliff’

A

s Congress reconvenes for its lame duck session, ASCO calls on lawmakers to prevent devastating budget cuts to cancer care, research, and the drug review process citing the negative impact to millions of individuals who have cancer. The mandated cuts, known as “sequestration” under the Budget Control Act, will automatically go into effect on January 1, 2013—unless Congress acts. (See page 35 for more on sequestration.)

ASCO warns the sequestration cuts to cancer research, oncology practices, and the drug review process will affect the 1.6 million individuals newly diagnosed with cancer each year, 12 million Americans living with cancer, and many millions more who will receive a cancer diagnosis over the next decade.

“Cancer patients face a triple threat from the specter of these budget reductions,” said ASCO President Sandra M. Swain, MD, FACP. “Not only will critical cancer research sustain a devastating hit, but providers of cancer care who are already struggling to keep their practices open will be faced with significant cuts that will impede access to care. Seques-

“fiscal cliff ” if action isn’t taken,” said Dr. Swain. “Our country cannot afford to slow the tremendous progress that has occurred in cancer research and treatment. Lives depend on it.”

Editor’s note: As this issue of The ASCO Post went to press, Congress was working on proposals to address the automatic budget cuts.

For the most current developments

on this and other policy issues, visit ascoaction.asco.org.

■

© 2012. American Society of Clinical Oncology. All Rights Reserved.

We urge Congress to consider the millions of cancer patients who will be pushed over the edge of the ‘fiscal cliff’ if action isn’t taken.

—Sandra M. Swain, MD, FACP

tration will also hinder the federal review and oversight of new oncology treatments.”

According to the Office of Management and Budget, sequestration will reduce the National Institutes of Health and the Food and Drug Administration budgets each by 8.2% (about $2.5 billion and $318 million, respectively), and Medicare payments to physicians by 2% (more than $11 billion), beginning in January 2013.

“We urge Congress to consider the millions of cancer patients who will be pushed over the edge of the

Unified in our uncompromising commitment to improving patient care in renal cell carcinoma For more information visit www.aveopharma.com or www.astellas.com.

©2011 AVEO Pharmaceuticals, Inc. and Astellas Pharma US, Inc.

011L-073-4740

12/11

Printed in the USA

The ASCO Post | DECEMBER 15, 2012

PAGE 60

Issues in Oncology Cost of Care

The Ethics of Rationing Cancer Care

Soaring health-care costs have medical experts wondering whether modest benefits achieved from many new cancer drugs are worth the cost.

By Jo Cavallo

S

hould cost be a consideration when deciding on treatment for patients with cancer, and if so, what kind of ethical dilemma does that pose for oncologists?

With U.S. spending on oncology drugs expected to climb more than 20% annually over the next decade—reaching $173 billion by 2020, according to the pharmacy benefit management organization Ex-

limumab, which consists of four infusions over 3 months, is $120,000.

Health-care expenditures in the United States reached a budget-busting $2.6 trillion in 2010—more than 10 times the $256 billion spent in 1980,4 and growing faster than the national income.

This trend combined with reduced reimbursement for costly treatments and procedures by insurance companies, shifting more of those costs to consumers, is leading to the inevitable question: When evaluating cost vs benefit, how much is a

little more time worth?

“Generally, people are willing to pay more or place a higher value on life-prolonging treatments, so there is some value to that. But ultimately the question becomes, how much can we afford?” said David H. Howard, PhD, Associate Professor in the Department of Health Policy and Management at Emory University. “Chemotherapeutics very starkly raise the issue of trading off health and money in a way that you don’t find in other areas of medicine.”

Health-care Rationing Other industrialized countries already consider a treatment’s cost when deciding whether to pay for it.

For the most part, however, that discussion is not yet happening in the United States, where such a notion is equated with health-care rationing.

“There is a lot of huffing and puffing about rationing in the U.S. today that is all very politicized and misguided,” said Howard Brody, MD, PhD, Director of continued on page 65

How Other Countries Are Controlling Oncology Costs David H. Howard, PhD

press Scripts1—more and more oncologists are grappling with these questions.

The issue of soaring health-care costs and how to pay for them is coming under evercloser scrutiny as targeted therapies carrying hefty price tags and, in many cases, delivering only a modest benefit continue to come onto the market.

Case in Point One recent example of this phenomenon is pertuzumab (Perjeta), the newly FDA-approved drug in the treatment of metastasized HER2-positive breast cancer. The wholesale cost of pertuzumab is $5,900 a month, and the drug is used in combination with another HER2-targeted antibody, trastuzumab (Herceptin), which costs $4,500 a month, plus docetaxel chemotherapy. A full 18-month course of of this combination regimen costs a staggering $188,000. In a phase III clinical trial,2 patients who received the threedrug combination gained a median of 6 months’ progression-free survival compared with patients treated with trastuzumab and docetaxel alone.

In 2011, the FDA approved the immunotherapy ipilimumab (Yervoy), the first medication shown to prolong survival in metastatic melanoma. In a randomized clinical trial,3 patients treated with ipilimumab lived an average of 3.6 months longer than patients in the control group. The cost for a complete course of treatment with ipi-

T

he refrain is familiar: The United States spends more on health care than any other industrialized country, but the investment does not correspond to superior care. A recent study by The Commonwealth Fund, a health-care policy research foundation, shows just how stark the contrast is.

Instructive Data According to the report, “Explaining High Health Care Spending in the United States: An International Comparison of Supply, Utilization, Prices, and Quality,”1 of the 13 industrialized countries examined (the United States, Australia, New Zealand, Canada, Denmark, France, Germany, Japan, the Netherlands, Norway, Sweden, Switzerland, and United Kingdom), the U.S. spends $8,000 per person on health-care services, while the other countries spend between one-third (Japan and New Zealand) and two-thirds (Norway and Switzerland) as much. And while the U.S. had the highest survival rates in breast cancer, as well as the best survival rates, along with Norway, in colorectal cancer, survival rates for cervical cancer were worse than average and far below that of Norway. Rather than greater utilization of physician and hospital services, the biggest drivers of higher costs in the U.S. are prescription drug prices and greater use of expensive technology such as MRI and CT scanners, according to the study.

Universal Health Care The reason other industrialized countries are able to restrain health-care spending more effectively than the U.S.—although all are struggling with rising health-care costs—is that they provide universal health care and use cost-effectiveness analysis to form policy around their national health-care plans. As a result, expensive drugs or medical technologies that are not proven to be clinically beneficial and cost-effective are not covered under government health plans, even if they are approved for use.

“In Canada, where $5,800 per person is spent on health care, there are two levels of drug approval; one is for use, and one is for funding,” said Mary K. Gospodarowicz, MD, Medical Director of Princess Margaret Cancer Center in Toronto, and President of the Union for International

Cancer Control. “Health Canada approves drugs for use. We have evidence-based cancer care, and if the evidence is inadequate or the drug is found not to be costeffective, the Pan-Canadian Oncology Drug Review will turn down a drug for funding.”

If a drug is approved for use but not for funding, hospitals Mary K. Gospodarowicz, MD and clinics will not receive additional funding for the drug, although Canadians with private drug insurance can receive the drug in privately funded infusion clinics, explained Dr. Gospodarowicz. The main issue for Canadians, she continued, is the delay between the emergence of new evidence on a drug’s benefit and its approval for funding.

Although the Canadian system is not perfect, said Dr. Gospodarowicz, Canadians want the government to control health insurance. “Canadians may not like the execution— they would like care to be provided right away—but, in general, they accept some form of regulation to enjoy universal coverage. Although some people travel abroad to get health care, it’s a minority because of the high cost,” she said.

“I’m very fortunate to work in an environment in which the decision about cost vs benefit regarding treatment is made with the input of oncologists in the drug approval bodies,” Dr. Gospodarowicz added. “Generally speaking, we uphold our standards and use the agreed-upon guidelines to follow evidence-based recommendations when prescribing treatment.”

■

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

Reference 1. Squires DA: Explaining high health care spending in the United States: An international comparison of supply, utilization, prices, and quality. Issues in International Health Policy, May 2012. Available at www.commonwealthfund.org. Accessed November 12, 2012.

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splenomegaly and symptoms of MF

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*Intermediate or high-risk MF.

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

Jakafi is a registered trademark of Incyte Corporation. © 2012, Incyte Corporation. All rights reserved. RUX-1160A 07/12

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 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 × 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)

Jakafi demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2,a,b Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

150

40 20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

80

-100

50% Improvement Upper 50th Percentile

Placebo (n = 153)

Upper 50th Percentile

Jakafi (n = 145)

In these charts, each bar represents an individual patient’s response.

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

At Week 24, significantly more patients receiving Jakafi vs placebo had — A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a — A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive patients and JAK2 V617F-negative patients, relative to placebo2

Visit www.jakafi.com/regulate

for more information on Jakafi and MF, plus valuable educational resources.

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

a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom

scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. June 2012. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

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

JAK targeted to make a difference

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 trans16.8% 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 registered 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 © 2011-2012 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Issued: June 2012 RUX-1040a

ASCOPost.com | DECEMBER 15, 2012

PAGE 65

Issues in Oncology

Rationing Cancer Care continued from page 60

the Institute for the Medical Humanities and Professor of Family Medicine at The University of Texas Medical Branch at Galveston. “The fact is we already ration care. We ration care based on an individual’s ability to pay and what kind of insurance someone has, which determines ability to pay. The real questions are what type of health-care system do you have in place, and how fairly is care

Howard Brody, MD, PhD

rationed within that system? Those are the ethical questions.”

According to Dr. Brody, the ethical debate of rationing cancer care falls into two categories. The first is the situation in which a lot of health-care dollars are spent on services proven to provide little or no benefit to the average patient. “In theory at least, you have not denied these patients anything that’s beneficial, and that puts a different ethical slant on it,” he said.

The second category poses a greater ethical dilemma for physicians—and society. “In cancer care, you often can’t say there is no benefit derived from a specific treatment. You can say that the benefit may be very small compared to a very high cost. But that low benefit is the average, meaning that some people will have no measurable benefit, their life expectancy will be the same regardless of the treatment; a few people will die sooner and in misery due to treatment toxicities; and some people will benefit greatly, gaining a significantly extended life span. Ethically speaking, rationing this kind of care is a very different matter from rationing care where, to the best of our knowledge, the benefit is truly zero,” said Dr. Brody.

Shared Decision-making According to the Dartmouth Institute for Health Policy and Clinical Practice, 30% of health-care spending, or $800 billion a year, is wasted on ineffective measures, including treatments and diagnostic tests.5 One way to combat health-care waste, said Dr. Brody, is for physicians and patients

to have an honest conversation about the advantages and disadvantages of a prescribed therapy in a process he calls “shared decision-making.”

“The ethical ideal is tailoring a specific approach to a specific patient’s wishes once he understands the options and consequences of treatment.

If a patient is desperate for even an extra week of life and he doesn’t care how much he suffers—he just wants to live a little bit longer—that’s one thing. On the other hand, if he does not want to suffer and prefers to have quality of life, even if it means dying sooner, that’s a different story,” said Dr. Brody.

However, shared decision-making does not solve the ethical dilemma of how to equitably allocate limited health-care resources so everyone benefits, not just those with the ability to pay for costly therapy. “Right now we have a very unfair health-care system in which some people after considering their options are able to say, ‘On balance, I’d rather have that chemotherapy even though it costs $200,000,’ because

them what the available evidence tells us about how they are likely to benefit from treatment. But the exam room is not an opportunity to be an agent of societal change, because our moral obligation is to our patients,” said Dr. Schnipper.

“If the patient wants something the doctor feels is unethical or immoral, the doctor has the opportunity to excuse himself from the case,” he added. Nobody really does that with any frequency, but the doctor shouldn’t be forced to do something he feels is not appropriate.”

Reining in Costs Some national initiatives recently put in place should help stem exploding health-care costs, at least for a while. The Patient-Centered Outcomes Research Institute, which was created by the Patient Protection and Affordable Care Act, is funding comparative effectiveness research to provide physicians, patients, and caregivers with evidence-based data to help them make informed decisions on treatments and health outcomes.

We need to be very thoughtful about which drugs or technologies we provide and approve for use, meaning new agents and devices need to be a lot better than what is already available.

—Lowell E. Schnipper, MD

they are able to afford it, but many other people can’t. We have to address the social injustice of that,” said Dr. Brody.

Making Tradeoffs What should the tradeoffs be when weighing the cost of medical treatments and their benefits, and how should health-care resources be equitably distributed? These issues need to be decided by society, not by the physician, maintained Lowell E. Schnipper, MD, Chair of ASCO’s Cost of Cancer Care Task Force, Theodore W. and Evelyn Berenson Professor in the Department of Medicine at Harvard Medical School, and Clinical Director and Chief of Hematology/Oncology at Beth Israel Deaconess Medical School, Boston.

“In the exam room, the doctor is morally obligated to be the intermediary between the patient and his disease, with the goal being either to cure him or to help him live as well as possible with that disease. Informing patients of their options becomes key to helping oncologists learn what they want. Oncologists have to be their patients’ guide by telling

And last spring, as part of the American Board of Internal Medicine’s Choosing Wisely® initiative, ASCO issued its list of the Top Five common costly tests, procedures, and treatments that are not supported by evidence to have meaningful clinical benefit. The list includes unnecessary use of chemotherapy for patients with advanced cancers who are unlikely to benefit, use of costly imaging technologies for staging of early breast and prostate cancers and for detection of breast cancer recurrence, and overuse of drugs to stimulate white blood cell production in patients receiving chemotherapy.

According to Dr. Schnipper, the effort is already having positive results.

“ASCO’s initiative is penetrating the exam room and influencing the conversation between the doctor and patient, specifically in the circumstance in which a patient has advanced cancer and poor performance status. I’ve had colleagues say that having the Top Five list is adding a sense of legitimacy and credibility when they have to explain to patients that they are at a point where

active cancer treatment won’t have much or any likelihood of benefit,” said Dr. Schnipper. ASCO’s Cost of Cancer Care Task Force is now considering other high-cost procedures and treatments that have limited clinical benefit to add to the list.

Another initiative under the Affordable Care Act is a national pilot program on payment bundling that will be launched in January, in an effort to maximize health-care savings over the longterm. This program will test shifting to a health-care system in which all providers involved in treating a single illness, such as breast cancer, are paid under one negotiated fee rather than according to the current fee-for-service payment. The existing system often results in duplicative or unnecessary tests and the use of newer expensive treatments that may not provide greater benefit than older, cheaper chemotherapies. If these and other cost-saving initiatives prove successful, they may avert the need for severe mandatory restrictions on health care in the future.

“We need to think differently about how we ‘cost out’ technologies,” said Dr. Schnipper. “We need to be very thoughtful about which drugs or technologies we provide and approve for use, meaning new agents and devices need to be a lot better than what is already available. We might even need a model in which the drugs we use are paid for only if they provide the desired effect.”

■

Disclosure: Drs. Howard, Brody, and Schnipper reported no potential conflicts of interest.

References 1. Express Scripts Research & New Solutions Lab: 2011 Drug Trend Report, published April 2012. Available at www.expressscripts.com. Accessed November 12, 2012.

2. Baselga J, Cortes J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.

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

4. Centers for Medicare and Medicaid Services, Office of the Actuary, National Health Statistics Group: National Health Care Expenditures Data, January 2012.

Available at www.cms.gov. Accessed November 12, 2012.

5. Dartmouth Institute for Health Policy & Clinical Practice: Reflections on Geographic Variations in U.S. Health Care, updated May 12, 2010. Available at www. dartmouthatlas.org. Accessed November 12, 2012.

The ASCO Post | DECEMBER 15, 2012

PAGE 66

54th ASTRO Annual Meeting Genitourinary Oncology

Androgen-deprivation Therapy plus Radiation Proven as Standard of Care for High-risk Prostate Cancer

Use of radium-223 in this setting also addressed at ‘Innovation in Care’ session.

By Alice Goodman

A

combined-modality approach of androgen-deprivation therapy plus radiation therapy achieves a substantial survival benefit over androgen-deprivation therapy alone in patients with locally advanced prostate cancer according to final analysis of an intergroup randomized phase III study conducted by the National Cancer Institute of

Padraig Warde, MD

Canada, Southwest Oncology Group, and UK Medical Research Council.

At a median follow-up of 8 years, both

overall survival and disease-specific survival were significantly improved by combined-modality therapy, and the combined therapy was well tolerated, as reported at the 54th Annual Meeting of the American Society for Radiation Oncology (ASTRO).1

Radiotherapy in Prostate Cancer ■■ The addition of radiation to androgen-deprivation therapy in men with

high-risk/locally advanced prostate cancer prolongs overall and diseasespecific survival, and is well tolerated.

■■ Combined-modality therapy should be considered standard of care in this setting.

■■ Radium-223 improves survival and delays time to first skeletal-related event

Level 1 Evidence “Combined-modality therapy with androgen deprivation plus radiation should be considered the standard of care for locally advanced prostate cancer. The benefits of this therapy should be discussed with all patients,” said presenting author Padraig Warde, MD, Princess Margaret Hospital, Toronto, Canada. He said that combinedmodality therapy is the only guidelinerecommended primary therapy with level 1 evidence, and that the optimal duration of androgen-deprivation therapy remains to be defined.

The study randomly assigned 1,205

in men with metastatic castration-resistant prostate cancer.

■■ Pending FDA approval, radium-223 may be a new standard of care in this setting.

men with a median age of 69.7 years in a 1:1 ratio to androgen-deprivation therapy alone or androgen deprivation plus radiation. About 90% had T3/T4 disease and about 10% had T2 or lowerstage disease. About 81% had Gleason score ≤������������������������������ ����������������������������� 7. Continuous androgen-deprivation therapy was either bilateral orchiectomy or a luteinizing hormone–releasing hormone agonist. Radiation was delivered to the prostate, plus or minus

EXPERT POINT OF VIEW

A

lthough these two trials reported at the ASTRO Annual Meeting are seemingly different, they both establish the value of radiation-based therapy in prostate cancer, demonstrating overall survival benefit and favorable toxicity profiles in high-risk, locally advanced, and castrateresistant metastatic disease, stated formal discussant Jason A. Efstathiou, MD, DPhil, Massachusetts General Hospital, Boston.

According to some practice pattern databases, only 14% of patients with high-risk prostate cancer currently receive external-beam radiotherapy, whereas up to 46% may receive primary androgen-deprivation monotherapy, he noted. “These patients are undertreated and underserved,” he stated.

The final results of the Intergroup trial show that the answer to the question of whether radiation added to androgen-deprivation therapy improves survival in high-risk/ locally advanced patients “is a resounding yes,” Dr. Efstathiou told listeners. He added that the number needed to treat to save 1 life over 10 years is 17 patients (and to save 1 life from prostate cancer death is 9), and the treatment is very well tolerated. He noted that these results are consistent with another similarly designed large Scandinavian randomized trial, SPCG-7.

‘Gold Standard’ “[External-beam radiotherapy and androgen-deprivation therapy] should now be the gold standard against which interventions for high-risk and locally advanced prostate

cancer are compared, including radical prostatectomy. The role of pelvic irradiation, extent of androgen suppression, and the addition of more aggressive systemic therapy to radiation and androgen-deprivation therapy awaits results of ongoing trials,” he said.

In the metastatic setting, radium-223 prolonged over- Jason A. Efstathiou, MD, DPhil all survival and time to first skeletal-related event, with favorable safety. “If approved, radium-223 will be a first-in-class addition to a growing arsenal of new drugs exploiting novel therapeutic targets in castration-resistant prostate cancer and may lead to broad use of a radiopharmaceutical as a new standard,” he told the audience. Use of radium-223 in earlier disease settings, such as asymptomatic metastatic disease and in the prechemotherapy space, as well as in combination with other therapies, requires further study, he said.

“Taken together, these abstracts show that the use of radiation-based therapy endures, providing perhaps a gold standard and a new standard…. It improves overall survival in high-risk locally advanced and metastatic castrate-resistant prostate cancer. These two abstracts proudly proclaim that radiation is no quackery and no humbug,” he stated.

■

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

seminal vesicles with or without pelvic node irradiation. An antiandrogen was given for 2������������������������������ ����������������������������� weeks, with an option to continue; 72% in the combination therapy group had pelvic nodes irradiated.

Ten-year overall survival was significantly improved, from 49% in the androgen-deprivation therapy–alone group to 55% in the combined-modality group, representing a survival improvement that was statistically significant (P = .0003). Androgendeprivation therapy plus radiotherapy significantly improved disease-specific survival as well, with 134 deaths due to prostate cancer and/or its treatment on androgen-deprivation therapy alone and 65 deaths on the combinedmodality therapy arm, representing a 54% improvement with combinedmodality therapy (P < .0001).

Adding radiation to androgen-deprivation therapy resulted in a small detrimental effect on late gastrointestinal toxicity, specifically greater than grade 2 proctitis (0.3% on androgen-deprivation therapy alone vs 1% for combinedmodality therapy), but the difference was not statistically significant.

Radium-223 In another study presented at the “Clinical Trials and Innovation in Care” session, an updated analysis of the ALSYMPCA trial upheld the overall survival benefit of radium-223 vs placebo as well as delayed time to first skeletal-related event in patients with symptomatic castration-resistant prostate cancer with bone metastases.2 Skeletal-related events included spinal cord compression, pathologic fracture, and first use of external-beam radiation therapy for pain. The safety profile of continued on page 68

NOW FDA APPROVED new phase III trial data

The evolution continues.

See the new data at www.ALIMTAupdate.com

ALIMTA is available in 100 mg and 500 mg vials.

PM79999

11/2012 PRINTED IN USA © 2012, Lilly USA, LLC. ALL RIGHTS RESERVED. ALIMTA® is a registered trademark of Eli Lilly and Company.

The ASCO Post | DECEMBER 15, 2012

PAGE 68

54th ASTRO Annual Meeting Genitourinary Oncology

Sildenafil Improves Overall Sexual Function in Men with Prostate Cancer Treated with Radiation

By Alice Goodman

F

or the first time, a randomized controlled trial reported improved sexual function with 6 months of prophylactic sildenafil citrate before, during, and after radiation therapy in patients with prostate cancer.1 The paper was presented at the Plenary Session during the 54th Annual Meeting of the American Society for Radiation Oncology (ASTRO).

Proof of Principle “This trial demonstrates proof of principle that penile rehabilitation is important in the population of patients treated with radiotherapy. Prophylactic use of sildenafil improved overall erectile function and overall satisfaction with sexual activity and function,” said lead author Michael J. Zelefsky, MD, Memorial Sloan-Kettering Cancer Center, New York.

“The most significant improvements were seen at 6 and 12 months after treatment, with a slight dip at the 24-month mark, suggesting that future trials need to be conducted to demonstrate if longer treatment duration can further improve outcomes,” he continued.

The prospective, randomized, double blind, placebo-controlled trial included 295 patients with clinically localized prostate cancer who were treated with external-beam radiation therapy and/or

brachytherapy. At baseline, all patients had erectile function (International Index of Erectile Function [IIEF] score > 17 on the erectile function domain).

Study Design and Results Patients were randomly assigned in a 2:1 ratio to receive either sildenafil at 50 mg daily or placebo. Treatment was initiated 3 days before radiation treatment and continued daily for 6 months, when the drug was stopped.

After that, sildenafil could be used on an as-needed basis. Thirty-one patients were also treated with 6 months of androgen-deprivation therapy.

Sexual function was assessed at 3-month intervals for the first year, and thereafter at 18 and 24 months with the IIEF, and for urinary function, the International Prostate Symptom Score (IPSS) questionnaires. No benefit for prophylactic use of sildenafil was observed among the 31 patients who received androgendeprivation therapy, and this group of patients was excluded from the analysis.

Among 142 patients who completed these questionnaires and completed radiation therapy, overall sexual function was significantly improved with daily sildenafil vs placebo at all time points. IIEF scores were 58.6 for sildenafil vs 49.4 for placebo, respectively, at 6 months (P = .006); 56.3 vs 48.2 at

Sildenafil in Patients Undergoing Radiotherapy ■■ A randomized study provided proof of principle that prophylactic daily

sildenafil improves erectile function and sexual satisfaction in men with prostate cancer receiving radiation therapy.

■■ Daily sildenafil had no effect on men taking androgen-deprivation therapy.

Radium-223 continued from page 66

radium-223 was similar between treatment groups, with fewer adverse events reported in the active-treatment group.

“In symptomatic men with castration-resistant prostate cancer and bone metastases, radium-223 prolonged overall survival and median time to first skeletal-related event, and was well tolerated. This may be a new standard of care if it is approved by FDA,” said lead author Howard M. Sandler, MD, Cedars-Sinai Medical Center, Los Angeles.

Updated analysis of overall survival found an absolute difference

of 3.6 months favoring radium-223, representing a 31% improvement in survival that was statistically significant (P = .0001). Subgroup analysis showed a benefit for radium-223 in all prespecified subgroups, including prior docetaxel treatment.

Time to first skeletal-related event was significantly delayed in the radium-223 group (median of 13.6 months vs 8.4 months for placebo, P = .0005).

Radium-223 delayed the time to first use of external-beam radiotherapy for pain: a median of 17 months vs 10.9 months, respectively (P = .004). Radium-223 halved the rate of spinal cord compres-

EXPERT POINT OF VIEW

C

ommenting on this paper, Thomas Pisansky, MD, the Mayo Clinic, Rochester, Minnesota, reminded listeners that about 50% of patients treated with external-beam radiation therapy and about 33% of those treated with brachytherapy already have erectile dysfunction prior to treatment. After radiation therapy [with either technology], about one-third will develop erectile dysfunction, so this problem is widespread.

“Erectile dysfunction before radiotherapy is an Thomas Pisansky, MD early warning of increased risk of cardiovascular and stroke-related death. Our obligation is to make sure these patients are assessed appropriately. Also, erectile dysfunction is associated with depression, anxiety, and loss of self-esteem, quality of life, and intimacy, so avoiding it has important implications for general well-being” Dr. Pisansky said.

Radiation-related erectile dysfunction is incompletely understood, but may be partly explained by adverse effects on the vasculature. Androgen-deprivation therapy can also reduce the likelihood of erectile dysfunction, he continued. “The surgical literature shows that use of a phosphodiesterase type 5 inhibitor [like sildenafil] improves erectile function. This is a well designed study with minor limitations that do not detract from the conclusion that once-daily sildenafil improves erectile function in patients undergoing radiation. It would be good to know the experience of partners of these subjects, but this was not assessed in the study,” he said.

■

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

12 months (P = .02); and 54.9 vs 47.6 at 24 months (P = .04). Significant improvement in overall satisfaction and erectile function were observed with sildenafil vs placebo. Overall IPSS scores were also significantly improved with sildenafil vs placebo (P < .001).

A multivariate logistic regression analysis controlled for age and baseline IIEF scores found that sildenafil significantly improved sexual satisfaction and IIEF scores.

Disclosure: Dr. Zelefsky stated that Pfizer provided the drug for the study and provided limited funding for research assistance.

sion from 6% with placebo to 3%.

“No difference in hematologic toxicity was reported between the two arms, suggesting that radium-223 spares the bone marrow,” Dr. Sandler told listeners.

As part of the development program, a phase I trial is evaluating radium-223 plus docetaxel, and radium-223 is also being studied in patients with breast cancer and bone metastases.

References 1. Gospodarowicz MK, Mason M, Parulekar W, et al: Final analysis of intergroup randomized phase III study of androgen deprivation therapy (ADT) ± radiation therapy in locally advanced prostate cancer (NCICCTG, SWOG, MRC-UK, INT: T94-0110; NCT00002633). 54th ASTRO Annual Meeting. Abstract 8. Presented October 28, 2012.

2. Sandler HM, Nilsson S, Parker C, et al: Radium-223 chloride safety and use of external beam radiation therapy (EBRT) in the phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) and bone metastases. 54th ASTRO Annual Meeting.

Abstract 7. Presented October 28, 2012.

■

■

Disclosure: Dr. Warde reported no potential conflicts of interest. Dr. Sandler has consulted for Bayer and Algeta in regard to radium-223, but has no related leadership positions, employment, or ownership.

Reference 1. Zelefsky MJ, Shasha D, Kollmeier M, et al: Results of a prospective randomized double-blind placebo trial evaluating the use of prophylactic sildenafil citrate during radiation therapy in the treatment of prostate cancer. 54th ASTRO Annual Meeting.

Abstract 3. Presented October 29, 2012.

ASCOPost.com | DECEMBER 15, 2012

PAGE 69

54th ASTRO Annual Meeting Genitourinary Oncology

Stereotactic Body Radiation Therapy Produces Impressive Results in Organ-confined Prostate Cancer

By Alice Goodman

S

tereotactic body radiation therapy (SBRT) delivered via the CyberKnife can achieve excellent outcomes with minimal toxicity in patients with prostate cancer. Importantly, this technique delivers therapeutic doses of radiation in four to five fractions, which reduces the number of clinic visits from 8 weeks with standard intensity-modulated radiation therapy (IMRT) to 1 to 2.5 weeks for SBRT. This has huge implications for patient convenience and cost-savings to the health-care system, but experts agree that longer follow-up is needed. These findings of two prospective studies were reported at the 54th American Society for Radiation Oncology (ASTRO) Annual Meeting in Boston.

Stereotactic body radiation therapy refers to ultraprecise delivery of very-highdose radiation using converging, finely collimated beams (see sidebar, “Two Modes of Precision Radiotherapy”). The CyberKnife system, based on robotic technology, was used to deliver SBRT in both studies. Typically, a course of radiation with CyberKnife SBRT takes five sessions.

SBRT technology is currently available at about 150 centers in the United States.

Pooled Analysis In a pooled analysis of 1,100 patients with organ-confined prostate cancer treated with Cyberknife SBRT, actuarial

5-year biochemical control (undetectable prostate-specific antigen [PSA] level) was 95% for low-risk patients, 90% for intermediate-risk patients, and 80% for highrisk patients, reported Alan J. Katz, MD, Flushing Radiation Oncology, Flushing, New York.1 Results were similar in 150 of these patients who also received androgendeprivation therapy. Results were also similar with three different dose levels of SBRT (< 35 Gy vs 36–37 Gy vs 38–40 Gy).

For this analysis, Dr. Katz contributed data from 515 consecutive patients, and the other 585 patients were treated at one of seven other centers. Among all patients, 59% were low-risk, 30% were intermediate-risk, and 11% were high-risk.

Median follow-up was 36 months (range, 1–66); 465 of Dr. Katz’ patients had a minimum of 4 years of followup. Patients were treated from 2003 to 2010. Median dose was 36.25 Gy delivered in either four or five fractions.

“These results are 5% to 10% better than what is seen with standard IMRT, which takes 40 to 45 days to deliver. At this point, the statistics should encourage men with organ-confined prostate cancer to seek SBRT as an alternative to IMRT, brachytherapy, or prostate surgery,” he stated. Further, the results suggest that there is no need for androgen-deprivation therapy with SBRT, he added.

Regarding toxicity and the need for

EXPERT POINT OF VIEW

“T

hese were two nice presentations evaluating the ability of SBRT to control disease as well as toxicity. This is cutting-edge research. It is very exciting that we could treat prostate cancer patients with radiation inside of 2 to 2.5 weeks, and it is clearly cost-saving. We need longer follow-up on disease control and toxicities,” stated Colleen Lawton, MD, Vice-Chair, Department of Radiation Oncology, Clinical Director of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, and President of ASTRO. She Colleen Lawton, MD moderated the press conference where these abstracts on stereotactic body radiation therapy were discussed.

“We need to know across the board whether all radiation oncologists can use SBRT and achieve the same impressive results,” she continued.

A Radiation Therapy Oncology Group (RTOG) trial has been initiated to evaluate SBRT in 5-fraction and 12-fraction schedules. Results of that trial will help establish the role of SBRT, but longer-term results are needed.

“The devil is in the details. We need to be sure we are depositing the dose of radiation to the target and protecting normal structures,” she stated.

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

■

Two Modes of Precision Radiotherapy ■■ Intensity-modulated radiation therapy (IMRT) is a technique that uses

computer-controlled linear accelerators to deliver precise doses of radiation to a tumor, conforming to the three-dimensional shape of the malignancy by controlling the magnitude of the radiation beam in multiple small volumes.

With IMRT, higher doses of radiation can be focused to regions within the tumor while minimizing the dose to surrounding healthy tissue, and with a shorter treatment duration than standard radiotherapy.

■■ Stereotactic body radiation therapy (SBRT) is another approach designed

to deliver highly focused radiation therapy to tumors anywhere in the body.

The technology used in SBRT allows the delivery of radiation to be pinpointed through precise positioning of the tumor in relationship to the body, with tumor movement taken into account based on the patient’s breathing pattern.

Like IMRT, the technique allows higher doses of radiation to be delivered to the tumor while sparing healthy tissue, and with the improved accuracy, treatment can be delivered in an even shorter period of time than IMRT.

longer follow-up, Dr. Katz said that he has patients out to 7 years, and experience suggests that patients who develop significant side effects generally develop them within 2 to 3 years. “At 7 years, we see no new toxicities,” he stated.

At a press conference, Dr. Katz said, “SBRT represents huge savings in time for patients with prostate cancer and in costs to payers. Medicare reimbursement for SBRT is a median of $22,000 vs $40,000 to $45,000 per patient, making SBRT 50% less costly than standard IMRT treatment.”

Related Presentation A second report focused on 129 patients with intermediate-risk, organconfined prostate cancer treated at 21 different institutions from December 2007 to April 2010.2 Median follow-up of patients in this prospective phase II study was 3 years (range, 2.5–4 years).

Urinary side effects in men treated with stereotactic body radiation therapy, as assessed by the Expanded Prostate Cancer Index Composite (EPIC), were evident early in the course of treatment, but by 6 months later, returned to baseline values, said Robert Meier, MD, Swedish Radiosurgery Center, Seattle, who gave this presentation. A similar pattern was seen in EPIC quality-of-life scores for bowel side effects, which were seen early in the course of treatment, began to improve by 6 months, and reached baseline values by 2��������������������������������������� �������������������������������������� years. Most urinary and bowel side effects were grade 1 or 2, Dr. Meier said.

Biochemical control was excellent (99.2%), with only 1 of 129 patients who had a 2 ng/mL rise in PSA after the current nadir.

“These results are extraordinarily good.

We typically see 10% to 20% biochemical failure at 4 years with IMRT and protonbeam therapy,” Dr. Meier stated.

■

Disclosure: Drs. Meier and Katz reported no potential conflicts of interest.

References 1. Katz A, Freeman D, Aronovitz, J, et al: Five-year biochemical control rates for stereotactic body radiotherapy for organ confined prostate cancer: A multi-institutional pooled analysis. 54th ASTRO Annual Meeting. Abstract 365. Presented October 31, 2012.

2. Meier R, Kaplan I, Beckman A, et al: Stereotactic body radiation therapy for intermediate-risk organ-confined prostate cancer: Interim toxicity and quality of life outcomes from a multi-institutional study.

54th ASTRO Annual Meeting. Abstract 366. Presented October 31, 2012.

SBRT vs IMRT ■■ Retrospective experience at

different centers suggests that stereotactic body radiation therapy (SBRT) delivered via the CyberKnife to patients with organ-confined prostate cancer is highly effective in disease control with minimal and transient urinary and bowel toxicity.

■■ SBRT can be delivered within 1 to 2 weeks, making it convenient for patients and cost-saving for payers.

■■ Current follow-up in prospective studies is about 3 years. Longerterm follow-up and further study are needed to establish this as a standard of care.

The ASCO Post | DECEMBER 15, 2012

PAGE 70

54th ASTRO Annual Meeting Genitourinary Oncology

Early Quality of Life Better with Proton-beam Therapy, but Late Effects Similar to Other Treatment Modalities for Prostate Cancer

By Alice Goodman

D

iffering patterns of patient-reported quality of life for threedimensional (3D) conformal radiotherapy, intensity-modulated radiation therapy, and proton-beam therapy were reported in a nonrandomized comparison of three modern cohorts of patients with prostate cancer. The study was presented at the 54th Annual Meeting of the American Society for Radiation Oncology (ASTRO) in Boston.

At the first follow-up 2 to 3 months following therapy, patients treated with proton-beam therapy reported minimal bowel problems; however, patients treated with 3D conformal radiotherapy and intensity-modulated radiotherapy reported modest yet significant problems with bowel function. At 2 years, all three techniques were associated with similar modest but significant bowel problems.

Quality-of-life decrements in the urinary obstruction domain were observed for all three techniques at the early assessment, but this was deemed clinically meaningful only in intensity-modulated radiotherapy–treated patients (though 3D conformal radiotherapy patients received lower total doses of radiation). Sexual function domain scores were lower with all three techniques at 2 years, but these changes were not deemed clinically meaningful.

Prospective Trial Needed “These distinct patterns of treatment-related [quality of life] suggest that [proton-beam therapy] may be associated with fewer immediate side effects. Given the inherent limitations of any retrospective study, a prospective randomized controlled trial to investigate these differences

will provide the most rigorous and valid comparison of these advanced technologies,” said lead author Phillip J. Gray, MD, a resident in the Harvard Radiation Oncology Program in Boston.

All three technologies are proven means of delivering high-dose radiation for localized prostate cancer with acceptable rates of acute and late toxicities. Intensity-modulated radiotherapy has largely overtaken

EXPERT POINT OF VIEW

C

ommenting on both radiotherapy studies and the use of proton-beam therapy in general, Jeffrey Bradley, MD, of Washington University in St Louis, agreed with both presenters that a randomized prospective trial is needed to justify the use of proton-beam therapy in prostate cancer.

Washington University is building its own proton-beam center, the first single-room system in the world. Dr. Bradley noted that at this point, Jeffrey Bradley, MD prostate cancer is not at the top of the list of diseases treated with proton-beam therapy.

“With limited resources, we will tend to use [proton-beam therapy] where there is a proven benefit—in children and to treat diseases near the base of the skull, brain, and eye. Proton-beam therapy may enable a shorter treatment time and spares normal tissue, but we need a randomized trial to establish its use in prostate cancer,” Dr. Bradley said.

■

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

Phillip J. Gray, MD

3D conformal radiotherapy as the technique of choice for prostate cancer treatment in the United States, but use of proton-beam therapy is on the rise, with 10 centers currently operating and at least 17 more planned.

Proton-beam therapy is more expensive than the other techniques, and improved quality of life may be a consideration in selecting therapy, Dr. Gray said.

Patients in this study were treated with radiation therapy according to the standard techniques of the participating hospitals. Quality-of-life data were collected prospectively using the Expanded Prostate Cancer Index Composite (EPIC) for 153 patients treated with intensity-modulated radiotherapy. The Prostate Cancer Symptoms Index (PCSI) instrument was used to collect quality-of-life data

Radiotherapy Techniques for Prostate Cancer Compared ■■ Two different abstracts presented at the ASTRO Annual Meeting suggest that late quality of life is similar with proton-beam radiation therapy and intensity-modulated radiation therapy, with a possible early benefit for proton-beam therapy.

■■ Proton-beam therapy is about twice as expensive as intensity-modulated radiotherapy.

■■ A randomized, controlled trial comparing the two techniques in prostate cancer is needed and has been launched by the Massachusetts General Hospital and the University of Pennsylvania.

on 123 patients treated with 3D conformal radiotherapy monotherapy and 94 patients treated with proton-beam therapy.

Mean scores at baseline, at first follow-up, and at 24 months were compared using paired t-tests. Clinically meaningful differences in quality-of-life scores were defined as those exceeding half the baseline standard deviation. Dr. Gray explained that score changes exceeding that threshold would be clinically evident to physicians.

A randomized, prospective phase III trial has recently been opened to compare intensity-modulated radiotherapy and proton-beam therapy for patients with localized prostate cancer. The study is led by Jason A. Efstathiou, MD, DPhil, and Justin Bekelman, MD, in partnership between the Massachusetts General Hospital and the University of Pennsylvania. Several other proton centers are expected to join the trial next year.

Medicare Analysis A second study presented at the same session called into question the growing use of proton-beam therapy.

That study was based on the Medicare Chronic Condition Warehouse database, which includes 100% of U.S. Medicare claims for patients with certain chronic conditions, in-

cluding prostate cancer. The investigators compared data for protonbeam therapy vs intensity-modulated radiotherapy and found minimal differences in toxicity between the two

James Yu, MD

techniques, with a much higher cost for proton-beam therapy. “[Proton-beam therapy] is an emerging treatment for men with prostate cancer, yet it is much more expensive than the standard of care, [intensity-modulated radiotherapy],” said James Yu, MD, Yale University School of Medicine, New Haven, Connecticut. “The results of our study suggest that we need a prospective large study comparing radiation techniques to justify widespread use of [proton-beam therapy] for prostate cancer,” he said.

The database included 27,647 men, aged 66 to 94 years, treated with intensity-modulated radiotherapy continued on page 78

Because Endocrine Monotherapy Can Only Take You So Far

In postmenopausal women with advanced HR+, HER2-negative breast cancer after failure of treatment with letrozole or anastrozole

Change the Treatment Paradigm With AFINITOR Plus Exemestane AFINITOR plus exemestane more than doubles median progression-free survival (PFS) over exemestane monotherapy1

Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

HR=0.45 [95% CI, 0.38-0.54] Log-rank P value: <0.0001

7.8 months Placebo plus exemestane: 3.2 months

AFINITOR plus exemestane:

PFS Probability (%)

80

60

Median PFS: 3.2 months

55%

Median PFS: 7.8 months

reduction in risk of progression or death2

40

20 AFINITOR plus exemestane (n/N=310/485) Placebo plus exemestane (n/N=200/239)

0 0

2

4

6

8

10

12

14

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20

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24

26

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Time (months)

• Median PFS was 7.8 months with AFINITOR® (everolimus) Tablets plus exemestane [95% CI, 6.9-8.5] vs 3.2 months with placebo plus exemestane

[95% CI, 2.8-4.1] (P<0.0001)1

PFS curves for the 2 treatment arms began to diverge at 6 weeks (the first tumor assessment)1,2 An independent central review confirmed a significant PFS improvement with AFINITOR plus exemestane treatment vs placebo plus exemestane1,2 • Median PFS was 11.0 months with AFINITOR plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6]

(HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

BOLERO-2=Breast Cancer Trials of Oral Everolimus; HR=hazard ratio.

T:14”

B:14.25”

S:13”

AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information.

• AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients • There have been reports of noninfectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR, some with

fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared with patients <65 years of age

• Oral ulceration is the most frequently occurring adverse event and occurred in 44% to 86% of AFINITOR-treated patients across the clinical trial

experience. Most of these events were grade 1/2. Grade 3/4 stomatitis was reported in 4% to 9% of patients

• Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have

also been reported; monitoring of laboratory tests is recommended

• The use of live vaccines and close contact with those who have received live vaccines should be avoided • AFINITOR can cause fetal harm when administered to a pregnant woman

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.

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

References: 1. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2012. 2. Data on file. Study CRAD001Y2301. Novartis Pharmaceuticals Corp; 2012.

• Careful monitoring and appropriate dose adjustments for adverse

Important Safety Information.

AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, patients should be managed with dose interruption until symptoms improve • The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 • AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred • Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR • Treatment of preexisting invasive fungal infections should be completed prior to starting treatment • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients • In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared to 2% in patients <65 years of age • Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2012 Novartis

reactions are recommended Laboratory Tests and Monitoring: • Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported • Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter • When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) • Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments Hepatic Impairment: • Exposure of everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman.

Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%) • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%)

Please see Brief Summary of Prescribing Information on adjacent pages.

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

10/12

AFB-1043056

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009

T:14”

B:14.25”

S:13”

Brief Summary of Prescribing Information. See full prescribing information for complete product information.

1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed.

Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis.

If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information].

For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose.

Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.

Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information].

In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions].

Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations].

Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions].

A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions].

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions].

Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information].

For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].

Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.

Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations].

6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively.

Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%).

Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo.

Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 e Median duration of treatment 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration

Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo c

Key observed laboratory abnormalities are presented in Table 3.

Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory Parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively.

• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively.

Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions].

Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions].

Agents That May Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information].

Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

T:14”

B:14.25”

S:13”

A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf).

Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions].

There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus.

In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Pediatric use of AFINITOR Tablets is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in diseaserelated symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown.

Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age.

The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least one serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo.

No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information].The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information].

Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions].

In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 and over.

Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information].

No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information].

Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information].

For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (ChildPugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

Manufactured by: Distributed by: Novartis Pharma Stein AG Novartis Pharmaceuticals Corporation Stein, Switzerland East Hanover, New Jersey 07936 © Novartis T2012-153 August 2012

The ASCO Post | DECEMBER 15, 2012

PAGE 78

35th ESMO Congress Gynecologic Oncology

Combination Bevacizumab/Chemotherapy Improves Outcomes in Platinum-resistant Ovarian Cancer

By Alice Goodman

T

For the overall trial, median prohe addition of bevacizumab gression-free survival was 6.7 months (Avastin) to chemotherapy for bevacizumab plus chemotherapy improved progression-free survival vs 3 months for chemotherapy alone. and response rates in patients with For the paclitaxel platinum-resistant cohort, median recurrent ovarBevacizumab progression-free ian cancer, acsurvival was 10.4 cording to an excombined with months vs 3.9 ploratory analysis chemotherapy should months; for the of the phase III be considered a new liposomal doxoAURELIA trial. rubicin cohort, The combinastandard option for median progrestion of paclitaxel platinum-resistant sion-free survival with bevacizumab was 5.4 months vs achieved very recurrent ovarian 3.4 months; and good results in cancer. for the topotecan terms of response —Andrés M. Poveda, MD cohort, median rate and progresprogression-free sion-free survival, survival was 5.8 but the effect of months vs 2.1 months. the addition of bevacizumab was According to lead author Andrés seen also with pegylated liposomal M. Poveda, MD, head of the Oncodoxorubicin (Doxil) and topotecan gynecology Department, Fundación and was of the same magnitude.

EXPERT POINT OF VIEW

F

ormal discussant of the AURELIA presentation, Nicoletta Colombo, MD, University of Milan Bicocca, European Institute of Oncology, Milan, Italy, said, “This is the only positive trial in patients with platinum-resistant recurrent ovarian cancer.”

Dr. Colombo was impressed with the activity of weekly paclitaxel plus bevacizumab (Avastin) in the subgroup analysis.

“At 6 months, 69% of patients were progression-free, and at 12 months, 33% were progression-free [in the weekly paclitaxel arm]. This convinces me of the activity of this combination with bevacizumab,” she told listeners.

“Weekly paclitaxel plus bevacizumab should be explored earlier in the course of ovarian cancer, since the combination is so active in platinum-resistant disease,” she stated.

■

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

Proton-beam Therapy continued from page 70

or proton-beam therapy for prostate cancer in 2008–2009; 2% received proton-beam therapy, and 98% were treated with intensity-modulated radiotherapy.

Patients treated with proton-beam therapy were younger, healthier, and from geographic areas of higher socioeconomic status than patients undergoing intensity-modulated radiotherapy. Dr. Yu noted that patients receiving

proton-beam therapy often traveled great distances to receive treatment, “with 15% traveling 500 miles or more.”

The median amount of reimbursement per patient by Medicare was $32,428 for proton-beam therapy and $18,575 for intensity-modulated radiotherapy, a difference of 57%, Dr. Yu said.

Proton-beam therapy was associated with a significant reduction in urinary toxicity at 6����������������� ���������������� months vs intensity-modulated radiotherapy (5.9%

Second-line Bevacizumab/Chemotherapy in Ovarian Cancer ■■ Bevacizumab plus chemotherapy improves progression-free survival and response rates in platinum-resistant recurrent ovarian cancer.

■■ Among three chemotherapy regimens studied in this setting, bevacizumab combined with weekly paclitaxel was most promising.

■■ The combination of weekly paclitaxel plus bevacizumab may be useful earlier in the course of disease.

Instituto Valenciano de Oncologia, Valencia, Spain, “Bevacizumab combined with chemotherapy should be considered a new standard option for platinum-resistant recurrent ovarian cancer.”

Study Design AURELIA randomly assigned 361 patients with platinum-resistant recurrent ovarian cancer to chemotherapy alone (investigator’s choice among weekly paclitaxel, liposomal doxorubicin, or topotecan) vs chemotherapy plus bevacizumab. Treatment was continued until unacceptable toxicity or progressive disease occurred.

All patients enrolled in the trial had platinum-resistant ovarian cancer that progressed on up to two prior chemotherapy regimens. Baseline characteristics were well balanced between the treatment arms. Median age was around 60 years, and about 90% had stage III/IV disease. Minor differences were observed, including higher number of prior regimens in the weekly paclitaxel groups.

Responses and Toxicities Superior response rates for all three chemotherapy options were seen in vs 9.5%), but by 1 year there was no difference between groups for this toxicity. No significant differences between the two groups in gastrointestinal or other toxicity were reported at 6 months and 1 year.

Limitations of this study noted at the ASTRO meeting include the fact that it is a claims-based analysis with no staging information and no data on the extent or field of radiation.

■

Disclosure: Drs. Gray and Yu reported no potential conflicts of interest.

bevacizumab and chemotherapy vs the chemotherapy alone arms, with the highest respons rates observed in the weekly paclitaxel cohort: 51.7%, vs 28.8e. Overall response rates in the other two cohorts were: 18.3% and 7.9%, respectively, for the liposomal doxorubicin cohort and 5.8% and 2.1%, respectively, for the topotecan cohort.

The toxicity profiles of the various cohorts were consistent with previous studies and basically similar between the two main treatment arms. Patients in the weekly paclitaxel cohort had a higher rate of peripheral neuropathy, and those in the liposomal doxorubicin cohort had a higher rate of handfoot syndrome.

■

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

References 1. Poveda AM, Selle F, Hilpert F, et al: Weekly paclitaxel (PAC), pegylated liposomal doxorubicin (PLD), or topotecan (TOP) + bevacizumab (BEV) in platinum (PT)-resistant recurrent ovarian cancer (OC). Analysis by chemotherapy (CT) cohort in the GCIG AURELIA randomized phase III trial. 2012 ESMO Congress.

Abstract LBA26. Presented September 30, 2012.

References 1. Gray PJ, Paly JJ, Yeap B, et al: Patientreported quality of life in prostate cancer patients treated with 3D conformal intensity modulated or proton beam radiation therapy. 54th ASTRO Annual Meeting.

Abstract 30. Presented October 28, 2012.

2. Yu JB, Soulos PR, Herrin J, et al: Proton radiotherapy for prostate cancer in the Medicare population: Patterns of care and comparison of early toxicity with intensity modulated radiation therapy. 54th ASTRO Annual Meeting. Abstract 31.

Presented October 28, 2012.

ASCOPost.com | DECEMBER 15, 2012

PAGE 79

Dermatologic Events in Oncology Prevention and Treatment of Multikinase Inhibitor– induced Hand-Foot Syndrome

By Mario E. Lacouture, MD

M

ultikinase inhibitors (sorafenib [Nexavar], sunitinib [Sutent], pazopanib [Votrient], axitinib [Inlyta], regorafenib [Stivarga]) block various proteins including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). They have been approved by regulatory agencies for the treatment of advanced renal cell cancers and colorectal carcinomas, in addition to gastrointestinal stromal and pancreatic neuroendocrine tumors. In addition to hypertension and diarrhea, skin toxicity is common with these agents (see Fig. 1).

A maculopapular rash occurs more frequently with sorafenib (40%), yet the most clinically significant dermatologic adverse event is hand-foot syndrome, with associated all-grade incidences of 60% (sorafenib), 30% (sunitinib), 5% (pazopanib), 29% (axitinib), and 46% (regorafenib). Handfoot syndrome induced by multikinase inhibitors may affect the palms, soles, and any other areas exposed to friction or trauma (eg, elbows, knees).

The reaction appears within the first 6 weeks in most patients, initially with painful blisters, followed after several weeks to months by thick, hyperkeratotic areas resembling calluses. Extremely painful lesions on the palms and soles usually occur in the fingertips, over the interphalangeal joints, and on the heels and forefeet. Skin biopsies demonstrate a band-like area of necrosis with an underlying inflammatory infiltrate.

Patients at higher risk for developing hand-foot syndrome include women, those with at least two metastases, and those with a white blood cell count > 5,500/mm3.

Treatment Recommendations Treatment for multikinase inhibitor–induced hand-foot syndrome includes topical agents (for grades 1/2) or a combination of topical and oral agents (for grade 3) to address the most important symptom—pain.

Prior to beginning therapy, key measures include removal of any calluses and minimization of any foot ma-

lalignment with the help of a podiatrist or orthotist, as well as the use of thick socks, gloves, and soft slippers or shoes.

Many over-the-counter products are available in the foot care section of most pharmacies. The prophylactic use of daily moisturizers containing urea 10% three times a day has been shown to prevent all-grade hand-foot syndrome resulting from sorafenib therapy by approximately 15%. I advise patients to start the application of a keratolytic moisturizer (salicylic acid 6%, urea 40%, ammonium lactate 12%) at least twice daily, starting the same day they begin their cancer treatment.

For painful blisters, patients should use high-potency topical corticosteroids (clobetasol, betamethasone) and topical anesthetics (lidocaine, prilocaine/lidocaine, lidocaine patches) several times a day. For hyperkeratotic (callused) areas, keratolyitic moisturizers are helpful in softening and thinning these lesions when used several times a day. Since pain is the most im-

Mario E. Lacouture, MD

Dermatologic Events in Oncol� ogy is guest edited by Mario E. Lacouture, MD, a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. He is an Associate Member at Memorial Sloan-Kettering Cancer Center, New York. The series is intended to offer oncologists guidance in recognizing and treating the skin toxicities associated with anticancer agents. portant symptom, oral analgesics (opioids, nonsteroidal anti-inflammatory drugs) should also be considered.

Kinase inhibitor dose interruptions or decreases are necessary in patients with grade 3 or intolerable grade 2 handfoot syndrome, and this is usually helpful in maintaining patients on therapy, as long as treatment of dermatologic symptoms continues during rechallenge.

Since hand-foot syndrome almost always occurs during the first 5 weeks of kinase inhibitor therapy, I advise patients to avoid strenuous physical activity during the first 6 weeks, after which exercise must be done with caution in order to prevent an exacerbation of hand-foot syndrome.

■

Fig 1: Typical skin toxicity seen with hand-foot syndrome related to multikinase inhibitor therapy. Courtesy of Mario E. Lacouture, MD.

Download The ASCO Post iPad App FREE from iTunes today!

Disclosure: Dr. Lacouture is a consultant for AstraZeneca, Bayer/Onyx, Pfizer, and GlaxoSmithKline.

CURRENTLY ENROLLING for RELAPSED or REFRACTORY MULTIPLE MYELOMA

A Multicenter, Single-arm, Open-label Treatment Use Program For Pomalidomide in Combination With Low-dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma Primary Objective To provide patients with relapsed or refractory multiple myeloma access to pomalidomide while the medication is not commercially available

Key Eligibility Criteria* • ≥18 years or older • Confirmed, measurable, relapsed or refractory multiple myeloma • Received ≥4 antimyeloma regimens (induction bone marrow transplant with or without maintenance therapy is considered 1 regimen)

N=350

Study Treatment† • Oral pomalidomide 4 mg on Days 1-21 of 28-day cycle • Oral dexamethasone 40 mg weekly on Days 1, 8, 15, and 22 of 28-day cycle

*Additional criteria apply. †

Patients may continue on study treatment until documented disease progression, discontinuation of study treatment for any reason, or pomalidomide becomes commercially available.

Investigational use of pomalidomide.

For more information, e-mail thepexiusstudy@celgene.com, visit www.thepexiusstudy.com, or scan the QR code to the left.

©2012 Celgene Corporation 8/12 US-CELG120091a

ASCOPost.com | DECEMBER 15, 2012

Year-in-Review

PAGE 81

2012

TOP 10 Most Viewed Articles on ASCOPost.com for 2012 1 Novel Multikinase Inhibitor

Improves Survival in Metastatic Colorectal Cancer

4 No Advantage to Longer Adjuvant

Chemotherapy in Women with Early Breast Cancer: CALGB 40101 Trial

8 PD-1 Immune Checkpoint

Inhibitors Look Promising in Multiple Solid Tumors

By Caroline Helwick

By Matthew Stenger

By Caroline Helwick

The novel tyrosine kinase inhibitor regorafenib, given as a single agent to patients with treatmentrefractory metastatic colorectal cancer, significantly improved overall survival and delayed disease progression in an international phase III trial presented at the 2012 Gastrointestinal Cancers Symposium. The ASCO Post, May 1, 2012

The ideal duration of adjuvant therapy for women with lower-risk primary breast cancer remains unknown. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-15 trial, reported more than 20 years ago, found no difference in outcomes between six cycles of cyclophosphamide, methotrexate, and fluorouracil and four cycles of doxorubicin plus cyclophosphamide (AC)—although some believed that the AC arm might have fared better had they received six cycles of AC. Since then, several trials of adjuvant therapy have compared four cycles vs four cycles and six cycles vs six cycles of various regimens, but until recently, none has compared four vs six cycles of identical regimens using the same dose per cycle and schedule of treatment. The ASCO Post, September 1, 2012

Antibody-mediated blockade of the programmed death 1 protein (PD-1) and its ligand (PD-L1) induces durable tumor regression and prolonged stabilization of disease in patients with advanced solid tumors, according to data presented at the 2012 ASCO Annual Meeting.1,2 Although the studies reported were only phase I investigations, and the drugs are known only as BMS-936558 and BMS-936559, the findings earned the investigators an appearance at an ASCO press briefing and were concurrently published in The New England Journal of Medicine. The ASCO Post, July 1, 2012

Presentation by Axel Grothey, MD Expert Points of View by Richard Goldberg and Herbert Hurwitz, MD

2 ASCO Issues New Guideline

on Chemotherapy Dosing for Obese Patients

By Jo Cavallo

In April, ASCO released a new clinical practice guideline on the appropriate dosing of chemotherapy drugs given to obese adult patients with cancer. The result of an analysis by a panel of experts assembled by ASCO, the guideline calls for the use of a patient’s actual body weight when calculating chemotherapy dosing, rather than limiting the dose or using an adjusted ideal body weight, as is commonly done. The panel looked at 56 studies on cytotoxic chemotherapy dosing strategies for overweight and obese patients with cancer. The review excluded leukemia studies and did not address dosing of novel targeted agents.

The ASCO Post, May 15, 2012 Interviews with Gary H. Lyman, MD, MPH, and Jennifer J. Griggs, MD, MPH

3 First Genomic-based Pediatric Trials

Launched in Neuroblastoma

By Jo Cavallo

Last 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 high-risk neuroblastoma survive long-term. The disease is responsible for one in seven pediatric cancer deaths. The ASCO Post, January 15, 2012 Interviews with Giselle Sholler, MD, Craig Webb, PhD, and James M. Coffin, PhD

5 Favorable Early-stage Hodgkin

Lymphoma and HD.6: The Take-Home and Don’t–Take-Home Messages

By Joachim Yahalom, MD

The Canadian HD.6 randomized study in patients with nonbulky early-stage Hodgkin lymphoma is mostly of historic interest. It has little relevance to current treatment standards or questions, and the risk for its inappropriate interpretation is of great concern. The ASCO Post, January 15, 2012

9 Two Novel Agents Prolong Survival

in Advanced Prostate Cancer

By Alice Goodman

Two novel agents with distinct mechanisms of action join ranks of treatments that extend survival for patients with castration-resistant prostate cancer: MDV3100 and radium-223. Both drugs achieved a survival advantage compared with placebo, with relatively benign side-effect profiles, according to results of two international phase III trials reported at the 2012 Genitourinary Cancers Symposium, held recently in San Francisco. The ASCO Post, March 1, 2012

10 Targeting KRAS in GI Cancers:

The Hunt for the Holy Grail in Cancer Research

By Caroline Helwick

6 BOLERO-2: Everolimus Thwarts Resis-

tance to Hormonal Therapy in Advanced Breast Cancer

By Susan London

Adding an inhibitor of the mammalian target of rapamycin (mTOR) to hormonal therapy for advanced breast cancer effectively circumvents resistance, suggest updated results of the randomized BOLERO-2 trial. The ASCO Post, January 1, 2012

The RAS oncogenes are the most frequently mutated class of oncogenes in human cancers, and this has prompted a search for Ras inhibitors to effectively treat tumors with these mutations. Despite intensive efforts, however, none has materialized clinically because K-Ras is proving to be a very vexing target, according to Channing J. Der, PhD, of the University of North Carolina at Chapel Hill, who gave an invited lecture on the topic at the 2012 Gastrointestinal Cancers Symposium. The ASCO Post, April 15, 2012

7 T-DM1 Proves More Effective, Less

Toxic Than Standard Treatment for Metastatic Breast Cancer

By Caroline Helwick

Positive results continue to be reported for trastuzumab emtansine (T‑DM1), the antibody-drug conjugate linking trastuzumab (Herceptin) to a cytotoxic agent. Early results of the international phase III EMILIA study, presented at the 2012 ASCO Annual Meeting, showed a 35% reduction in risk of progression among patients with advanced HER2-overexpressing breast cancer who received T-DM1, compared to standard treatment with capecitabine (Xeloda) and lapatinib (Tykerb). The ASCO Post, June 15, 2012

Visit ASCOPost.com

for the most viewed articles published during 2012.

See Page 119

The ASCO Post | DECEMBER 15, 2012

PAGE 82

35th ESMO Congress No Survival Advantage for Combination Chemotherapy in Advanced Soft-tissue Sarcoma

By Caroline Helwick

T

he addition of aggressively dosed ifosfamide to doxorubicin in the treatment of advanced soft-tissue sarcomas significantly delayed disease progression but did not improve survival in the randomized phase III EORTC 62012 trial conducted by the Soft Tissue and Bone Sarcoma Group of the European Organisation for Research and Treatment of Cancer. The study was presented at the 2012 European Society for Medical Oncology (ESMO) Congress.1

Winette van der Graaf, MD

“The combination of doxorubicin and ifosfamide doubled the response rate and significantly improved progression-free survival, but it did not significantly improve overall survival and it was considerably more toxic than doxorubicin alone,” reported Winette van der Graaf, MD, of Radboud University Nijmegen Medical Center in The Netherlands.

Study Rationale EORTC 62012 was initiated to address concerns that previous studies comparing single-agent doxorubicin vs doxorubicin/ifosfamide had used suboptimal doses of ifosfamide. Nonrandomized data had suggested that higher doses could increase responses and might impact survival, Dr. van der Graaf explained, but randomized data are necessary for proof.

The 455 patients (all age ≤ 60) had locally advanced or metastatic grade 2

or 3 soft-tissue sarcomas; in total, half of them were liposarcoma, leiomyosarcoma, and synovial sarcoma.

They were randomly assigned to receive either single-agent doxorubicin (75 mg/m2) or doxorubicin (75 mg/ m2) with ifosfamide (10 g/m2 over 4 days) with growth factor support as first-line treatment. Patients were treated every 3 weeks for a maximum of six cycles or until progression.

Major Findings At a median follow-up of 56 months, the primary endpoint—overall survival—was numerically greater at 1 year with doxorubicin/ifosfamide (60% vs 51%), but the difference did not achieve statistical significance. Median overall survival was 14.3 months with the combination and 12.8 months with doxorubicin alone (HR = 0.83; P = .076).

Virtually all of the patients who received doxorubicin alone subsequently received ifosfamide as second-line therapy, which could impact the overall survival results.

Median progression-free survival, however, was 7.4 months with the combination and 4.6 months with doxorubicin alone, for a 26% reduction in risk that was statistically significant (HR = 0.74; P = .003), she reported.

The objective response rate was 26.5% with the combination and 13.6% with doxorubicin. Progressive disease was noted for 13.2% and 32.5%, respectively.

Despite colony-stimulating factor support, the combination regimen produced more severe (> grade 3) hematologic toxicity, including febrile neutropenia (45.9% vs 13.5%), anemia (34.9% vs 4.6%), and thrombocytopenia (33.5% vs 0.4%). While more patients discontinued treatment due to progression with doxorubicin (41.7% vs 20.7%), more discontinued the combination regimen due to toxicity (17.6% vs 2.6%).

Treatment of Soft-tissue Sarcomas ■■ In a phase III EORTC trial, the addition of ifosfamide to doxorubicin did not

improve survival but did significantly delay progression by 26%, in patients with advanced soft-tissue sarcomas.

■■ Single-agent doxorubicin should be the standard of care, but

the combination may be beneficial in patients with symptoms or potentially resectable disease after chemotherapy (because of the higher response rate).

EXPERT POINT OF VIEW

I

nvited discussant of the abstract, George Demetri, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, noted that metastatic soft-tissue sarcomas present with variable clinical behaviors but are nearly always incurable with any approach. “Therefore, our intent is to palliate and to prolong life with the highest possible quality,” he said.

He said the question that has “dogged the field” for more than 35 years is, “What is the best George Demetri, MD first-line treatment for metastatic disease?” Other questions include: Can all soft-tissue sarcomas be “lumped together,” ie, which types have reasonably similar behaviors when metastatic? And does combination chemotherapy meaningfully improve clinical outcomes, compared with single-agent chemotherapy?

The overall survival results were disappointing, although progression-free survival was prolonged by 3-plus months with the combination, he pointed out. Since the typical patient with metastatic soft-tissue sarcoma lives 13 months, “the results mean that sarcoma is controlled for approximately 20% longer with combination chemotherapy,” and this is meaningful to the patient, Dr. Demetri offered.

Targeting Specific Patients There is a need to be able to target patients who derive benefit from tumor response and control despite the regimen’s toxicities, he said. “And we do need to take quality of life into account as we think of how to use these data,” he added.

Dr. Dimitri suggested that “the clinical question” should be changed, from “What is the best first-line therapy?” to “What is the best first-line therapy for a specific patient.” EORTC 62012 offers “solid data” upon which clinicians can make informed choices about this, he said.

Based on the findings, he would prescribe single-agent doxorubicin for asymptomatic patients. For patients who are symptomatic or if tumor shrinkage is required, he believes combination doxorubicin plus ifosfamide is often the preferred choice.

■

Disclosure: Dr. Demetri has been a consultant for Novartis, Pfizer, Sanofi-Aventis, GlaxoSmithKline, Johnson & Johnson, Merrimack Pharma, Foundation Medicine, Merck, ZioPharm, N-of-One, and Champions Biotechnology. He has received research support from Novartis, Pfizer, Sanofi-Aventis, GlaxoSmithKline, Johnson & Johnson, Merck, and Amgen. He is a member of the scientific advisory board for ZioPharm, N-of-One, Koltan Pharmaceuticals, and Blueprint Medicines.

According to the investigators, the findings do not support the routine use of the intensive combination of doxorubicin plus ifosfamide in the setting of advanced incurable disease.

They added, however, that the higher response rate suggests this regimen might be justified in select patients aged ≤ 60 if tumor shrinkage is critical, with the caveat that it is significantly more toxic than doxorubicin alone.

While the regimen should not be universally applied, Dr. van der Graaf said the study’s results “make it is easier to have discussions with patients, as to

which treatment is optimal in which situation.”

■

Disclosure: Dr. van der Graaf reported no potential conflicts of interest.

Reference 1. van der Graaf WTA, Judson I, Verweij J, et al: Results of a randomized phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma: A survival study by the EORTC Soft Tissue and Bone Sarcoma Group. 2012 ESMO Congress. Abstract LBA7. Presented October 1, 2012.

NOW APPROVED for the treatment of patients with metastatic

castration-resistant prostate cancer (mCRPC) who have previouslyy received docetaxel

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AND...

• 37% reduction in risk of death vs placebo

(P < 0.0001; HR = 0.63 [95% CI, 0.53, 0.75])1

• XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1

—

In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1

• Oral, once-daily dosing1 • The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1

• Seven patients (0.9%) out of 800 treated AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.

Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved.

Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial

with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1

were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs.

If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

Learn more at XtandiHCP.com Reference: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. © 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012I-076-6330 9/12 XTANDI is a registered trademark of Astellas Pharma Inc. Astellas and the flying star logo are trademarks of Astellas Pharma US, Inc.

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; DECEMBER 15, 2012

PAGE 84

Announcement

Karen E. Knudsen, PhD, Named New Editor-in-Chief of AACR Journal Molecular Cancer Research

T

he American Association for Cancer Research (AACR) recently announced that Karen E. Knudsen, PhD, Professor and Hilary Koprowski Chair in the Departments

of Cancer Biology, Urology, and Radiation Oncology at Thomas Jefferson University in Philadelphia, and Deputy Director for Basic Science of the NCI-designated Kimmel Cancer

Center will be the new Editor-in-Chief of Molecular Cancer Research, one of its seven major peer-reviewed journals. â&#x20AC;&#x153;I am honored and excited for the opportunity to lead Molecular Cancer

Research,â&#x20AC;? said Dr. Knudsen, who will serve as the journalâ&#x20AC;&#x2122;s Editor-in-Chief for 5 years. â&#x20AC;&#x153;I hope to establish the journal as the seat of outstanding basic research related to cancer.â&#x20AC;?

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information.

------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel.

--------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@.

-------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures.

The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

--------------------------------- ADVERSE REACTIONS ------------------------------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 WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo.

All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.

7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders

9.0 44.4 9.3 Asthenic Conditionsa Peripheral Edema

1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4

24.3 4.0 Arthralgia

17.3 1.8 Musculoskeletal Pain

1.3

0.3 Muscular Weakness 9.8

6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1

0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9

0.0

Dizzinessb Spinal Cord 7.4 6.6

3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0

0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0

0.3 Upper Respiratory Tract Infectiond Lower Respiratory

2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0

Anxiety

0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8

1.0 Pollakiuria 4.8 0.0

0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin

0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH

Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo.

Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms.

Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; DECEMBER 15, 2012

PAGE 85

Announcement

Dr. Knudsen will officially begin her term in January 2013.

Molecular Cancer Research is an online and print journal that publishes original, novel, and well-designed studies on the molecular and cellular aspects of cancer biology. Papers selected for publication represent new information in basic research that has

implications for cancer therapeutics in angiogenesis, metastasis, or genomics.

The first issue of the journal was published in November 2002.

Expertise and Accomplishments â&#x20AC;&#x153;Dr. Knudsen brings a wealth of expertise to the position of Editor-in-

Chief of Molecular Cancer Research,â&#x20AC;? said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. â&#x20AC;&#x153;We are confident that her experience with the peer review process, coupled with her extensive knowledge of basic cancer research, will build on the journalâ&#x20AC;&#x2122;s success and impact in the field.â&#x20AC;?

Dr. Knudsenâ&#x20AC;&#x2122;s scientific accomKaren E. Knudsen, PhD

MEDPC9886 - Xtandi Brief PI Colors: 4CP Trim/live: DO NOT PRINT Bleed: 8.625"w Ă&#x2014; 11.375"h Trim: 8.125"w Ă&#x2014; 10.875"h Output @ 100% Giant Creative Strategy

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers.

Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ

DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @.

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @.

-------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, 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 Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment.

Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@.

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

Live: 7"w Ă&#x2014; 10"h

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose.

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8&

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\

XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember.

If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

plishments include the authorship of more than 80 peer-reviewed publications in cancer and biomedical science journals. In addition, she has authored numerous book chapters focusing on transcription and cell-cycle regulation in hormone-dependent cancers.

Dr. Knudsenâ&#x20AC;&#x2122;s research interest is predominantly prostate cancer and the molecular mechanisms that underlie tumor progression.

Throughout her career, Dr. Knudsen has been involved in both national and international scientific committees, and has held numerous leadership roles in scientific publishing, including Cancer Research. She recently received the Excellence in Mentoring Award from Thomas Jefferson University, the Richard E. Weitzman Laureate Award from the Endocrine Society, and the Ron Ross Award from the Pacific Rim Breast and Prostate Cancer Foundation.

â&#x2013;

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Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ ,QF 6DQ )UDQFLVFR &$ Issued: August 2012 $ (1= %56 Rx Only Š 2012 Astellas Pharma US, Inc. XTANDIŽ is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

@ASCOPost

The ASCO Post | DECEMBER 15, 2012

PAGE 86

35th ESMO Congress Genitourinary Oncology

Lenalidomide Trial Negative in Metastatic Castration-resistant Prostate Cancer

By Alice Goodman

L

enalidomide (Revlimid) failed to improve survival and increased toxicity when added to docetaxel and prednisone in men with chemotherapy-naive, progressive, metastatic castration-resistant prostate cancer in the phase III MAINSAIL trial reported at the 2012 ESMO Congress in Vienna.

This study joins several others failing to show benefit when another agent is added to docetaxel in this setting.

“Lenalidomide did not improve overall survival, and the three-drug regimen caused more toxicity. Docetaxel every 3 weeks remains the standard of care for metastatic castration-resistant prostate cancer,” stated lead author Daniel Petrylak, MD, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York.

Study Details MAINSAIL was an international, multicenter, randomized, doubleblind, placebo-controlled trial of firstline treatment for metastatic castration-resistant prostate cancer. Patients with progressive disease were randomly assigned to lenalidomide plus docetaxel/prednisone or docetaxel/ prednisone alone. Treatment cycles were repeated every 21 days until disease progression, and patients were followed for 5 years.

EXPERT POINT OF VIEW

“T

Daniel Petrylak, MD

Median overall survival was 19.25 months. Progression-free survival was similar between the two arms, with a 1-week difference that favored docetaxel/ prednisone (46 vs 45 weeks). Declines in prostate-specific antigen level were similar in both arms, and the objective response rate was about 25% in both arms.

Toxicity was greater with lenalidomide; in particular, diarrhea was more frequent in the lenalidomide-containing arm.

■

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

Reference 1. Petrylak DP, Fizazi K, Sternberg CN, et al: A Phase 3 study to evaluate the efficacy and safety of docetaxel and prednisone with or without lenalidomide in patients with castrate-resistant prostate cancer (CRPC): The MAINSAIL trial.

2012 ESMO Congress. Abstract LBA24.

Presented September 30, 2012.

Role of Lenalidomide in Prostate Cancer Therapy ■■ Adding lenalidomide to docetaxel/prednisone did not improve survival and was more toxic in men with metastatic castration-resistant prostate cancer.

■■ Future phase III trials should be built on a stronger rationale, perhaps

he data speak for themselves,” stated Robert Jones, MD, of the Beatson West of Scotland Cancer Center, Glasgow, UK, during discussion of the MAINSAIL trial at the 2012 ESMO Congress.

The study raises some important questions, he continued: What are the implications for designing future trials? Could failure have been avoided?

How should we interpret the seemingly detrimental effect of lenalidomide? Are there other lessons Robert Jones, MD for the future?

“As far as implications go, there is no future for this combination in metastatic castration-resistant prostate cancer. There is probably no future for lenalidomide in prostate cancer in any context. Further, there are direct consequences for patients who took part in the experimental arm. We lost 1,059 patients who participated in this trial for future trials,” Dr. Jones told listeners.

Avoidable Consequences Using the benefit of hindsight, Dr. Jones believes the negative consequences could have been avoided. He said, “Preclinical data showed enhanced cytotoxicity of docetaxel plus lenalidomide, with overlapping toxicity profiles.

There is no proof of concept for the lenalidomide-plus-docetaxel combination in prostate cancer, with no randomized phase II data for support. The prior hypothesis for the combination was by no means proven prior to the trial. Further, the planned interim analysis was conducted too late, after the last patient entered the trial, which wouldn’t have prevented patients from receiving the drugs if no benefit were found.” He added that the explanation for the detrimental effect of lenalidomide is not clear.

There are some lessons for future trials, Dr. Jones continued. “All phase III trials combining docetaxel with novel agents have been negative to date. This is also the fourth negative trial that fails to harness the power of antiangiogenic therapy in prostate cancer,” he noted.

“I believe future combination studies should demand proof of concept.

We have an obligation to patients to minimize avoidable risks. Randomized phase II trials should probably be required prior to initiating phase III studies.

We could consider better use of early stopping rules. We are still challenged by lack of a robust endpoint for early stopping,” Dr. Jones told listeners.

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

based on randomized phase II trials.

Contact The ASCO Post EDITORIAL CORRESPONDENCE James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654

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

■

FOR PATIENTS WITH ADVANCED BCC

IS IT TIME FOR A CHANGE? The first and only FDA-approved Hedgehog pathway inhibitor

Turn the page to see more...

Indication Erivedgeâ&#x201E;˘ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS See full prescribing information for complete boxed warning.

Erivedge can result in embryo-fetal death or severe birth defects. Verify pregnancy status prior to initiation of Erivedge. Advise male and female patients of these risks. Advise females of the need for contraception and advise males of the potential risk of Erivedge exposure through semen.

Please see additional Important Safety Information, including BOXED WARNING, on following page and Brief Summary of Prescribing Information on back.

Simulated image based on locally advanced BCC patient at Week 24.

Indication Erivedge™ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

Boxed Warning and Additional Important Safety Information Embryo-Fetal Death and Severe Birth Defects • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge.

Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen • Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant

• Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555

Blood Donation • Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge

Nursing Mothers • Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother

Adverse Reactions • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea,

TRANSFORM THE TREATMENT OF ADVANCED BCC Erivedge— a unique treatment option • Systemic therapy that targets dysregulated Hedgehog pathway signaling, a known driver of BCC1,2 • One 150-mg capsule a day until disease progression or unacceptable toxicity1 • Erivedge reduced lesions in patients with advanced BCC1,3

Objective response rates (ORR) by IRF from ERIVANCE1,3* laBCC (n=63)

mBCC (n=33)

43% (n=27) (30.5-56.0)

30% (n=10) (15.6-48.2)

Complete response

21% (n=13)

0%

Partial response

22% (n=14)

30% (n=10)

7.6 months (5.7-9.7)

7.6 months (5.6-NE)

ORR (95% CI)

Median response duration (95% CI)

* Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy. Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.

IRF=Independent Review Facility. laBCC=locally advanced BCC. mBCC=metastatic BCC. CI=confidence interval. NE=not estimable.

diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) Please see Brief Summary of Prescribing Information on following page.

References: 1. Erivedge™ (vismodegib) capsule Prescribing Information.

Genentech, Inc. January 2012. 2. Epstein EH. Nat Rev Cancer. 2008; 8:743-754. 3. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012; 366:2171-2179.

© 2012 Genentech USA, Inc.

All rights reserved.

HED0001171901

See what you can offer your patients with advanced BCC at www.Erivedge.com

The ASCO Post | DECEMBER 15, 2012

PAGE 90

Announcement

American Society of Hematology Launches ASH Foundation

T

he American Society of Hematology (ASH) has announced the creation of the ASH Foundation dedicated to curing blood diseases. The new foundation will complement and build on the work of the Society by harnessing the generosity of donors to expand

the reach of successful ASH programs and develop new initiatives to address critical issues facing hematology researchers and clinicians.

Through contributions from ASH members and supporters, the ASH Foundation will support a spectrum of

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

MedDRA Preferred Term2 Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information.

WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations.

Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].

1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)].

ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules.

If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed.

Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)].

5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 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 clinical practice.

ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer.

The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1).

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

-

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

-

All aBCC1 Patients (N = 138) All Grades 3 Grade 3 Grade 4 (%) (%) (%)

35 (25.4%)

3 (2.2%)

-

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

-

76 (55.1%) 15 (10.9%)

-

-

88 (63.8%)

-

-

aBCC = Advanced Basal Cell Carcinoma.

2 MedDRA = Medical Dictionary for Regulatory Activities.

3 Grading according to NCI-CTCAE v3.0.

Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)].

Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%).

1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole).

Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased.

Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown.

7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib.

In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits.

Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE 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 embryo or fetus.

Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)].

In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws).

8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

new or enhanced ASH programming in three broad categories, including research, career development, and quality care and education, such as ASH’s new Bridge Grants, as well as ASH’s Scholar Awards, Global Programs, Clinical Research Training Institute, and Minority

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, 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 ERIVEDGE capsule have not been established in pediatric patients.

In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose).

8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555.

Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus.

Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)].

Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib.

8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

• Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects.

• Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555.

• Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother.

• Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

ERIVEDGE™ [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832300

Recruitment Initiative. Because ASH covers all management and administrative costs for programs supported by the Foundation, 100% of donations will be allocated toward direct program expenses. Sustaining donor support for such programs is imperative for ASH to continue to move hematology forward, particularly during the current period of steadily declining federal support for hematology research through the National Institutes of Health (NIH).

Armand Keating, MD

“The ASH Foundation was created to ensure that there will be a new generation of hematology physicians and scientists to continue to build on the enormous progress that has been made in understanding the etiology of some of the most deadly blood diseases, and to develop new strategies for their prevention and treatment,” said ASH President Armand Keating, MD, of Princess Margaret Hospital in Toronto.

Bridge Grant Program Donors have the option of designating their gifts to support a specific programmatic area or contributing to the “Where Our Need is Greatest” fund, which will be directed toward ASHidentified programs that address the most pressing priorities and key issues facing the hematology community at any given time. The first initiative to be supported by this fund is the ASH Bridge Grant Program, launched in July 2012 by the Society to provide early-career hematologists who applied for an NIH R01 grant but were denied funding due to budget cutbacks with much-needed support needed to continue their research.

The ASH leadership has pledged $9 million in Society dollars to support the establishment of the ASH Bridge Grant Program through the ASH Foundation. Additional founding sponsors of the ASH Bridge Grant Program include Amgen, Inc; the Atlanta Convention and Visitors Bureau; Millennium: The Takeda Oncology Company; and Novartis Pharmaceuticals, Inc.

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ASCOPost.com | DECEMBER 15, 2012

PAGE 91

Initiatives

The Practice of More than One Art

The Weill Cornell Music and Medicine Initiative allows physicians to pursue dual passions.

By Jo Cavallo

T

he positive healing effects of music can be traced as far back as ancient Greece and the belief that Apollo was God of medicine and music. In his book De Anima, Aristotle wrote that flute music could purify the soul. By the end of the 19th century, researchers were showing a correlation between the use of music and its healing effects on patients in lowering their blood pressure, decreasing pulse rate, and increasing cardiac output. Today, music therapy is used as part of complementary care in the treatment of cancer—as well as other diseases—to help salve patients’ fears and anxieties and increase feelings of relaxation and calm.

Jenna Devare

The alluring power of music seems to extend to the practitioners of medicine as well. Last October, over 100 doctors, researchers, nurses, medical students, and other medical professionals from New York–area hospitals, including Memorial Sloan-Kettering Cancer Center, NewYork-Presbyterian Hospital/Weill Cornell Medical Center, and Rockefeller University, performed their first concert together, Mozart’s Requiem, to a sold-out audience at St. Bartholomew’s Church in Manhattan. The performers, members of the Music and Medicine Orchestra and Chorus (Fig. 1), are part of the Music and Medicine Initiative formed by Weill Cornell Medical College 4 years ago and comprise levels of musical ability from serious amateurs to conservatory-trained professionals.

Origins of Initiative The idea to launch the Music and Medicine Initiative grew from an observation that many applicants to Weill Cornell Medical College had a background in music. “I’m on the Admissions Committee, and I interview applicants to the Medical College,”

said David A. Shapiro, MD, Clinical Professor of Psychiatry at Weill Cornell Medical College and Founder and Chairman of the Music and Medicine Initiative. “It soon became clear to me that a significant number of the applicants—between 20% and 25%— had some degree of interest in music, from minor enthusiasts to graduates of conservatories.”

One of those applicants was Jenna Devare, now a fourth-year medical student, who is also a gifted violinist and helped organize the Music and Medicine Orchestra and Chorus and was among the Requiem concert performers. The concert was so well received, one attendee, famed neurologist and author Oliver Sacks, told New York magazine he was “carried away” by the performance and “thinking that I would like a performance of it in front of me as I was dying.”

The concert raised enough money to cover expenses and provide $10,000 to fund the student-led Weill Cornell Community Clinic, which provides free medical and psychiatric care to uninsured New Yorkers.

“The Clinic serves approximately 175 patients per year and has an annual operating cost of about $40,000.

The money we’re donating will significantly help fund the Clinic’s annual costs,” said Ms. Devare.

Mysterious Link Although there appears to be a clear link between the parallel pursuits of music and medicine, exactly what that link is remains a mystery. Some brain science studies have explored the music/ medicine connection, “but we don’t have any answers yet,” said Dr. Shapiro, who plays percussion instruments in a jazz group. “What we’ve noticed about our students and musicians is that these are very hardworking people who are very dedicated to these tasks, and the idea of practicing is a concept that is shared by both

professions. These are people with a capacity to achieve a certain kind of excellence.”

A look at the list of names on the Music and Medicine Initiative’s advisory board does in fact read like a

Breast Center, is also a member of the Music and Medicine advisory board and a serious musician. Dr. Shapiro called Dr. Norton when he was launching the Music and Medicine Initiative.

What we’ve noticed about our students and musicians is that these are very hard-working people who are very dedicated to these tasks, and the idea of practicing is a concept that is shared by both professions.

—David A. Shapiro, MD

Who’s Who of the best and brightest medical and musical talent in New York, including Richard Kogan, MD, Co-Director of the Human Sexuality Program at Weill Cornell Medical College and Vice Chairman and Artistic Director of the Music and Medicine Initiative. Dr. Kogan is also a concert pianist.

“Dr. Kogan is a graduate of the Juilliard School of Music and roomed with Yo-Yo Ma at Harvard. Hand injuries in undergraduate school led him to take a detour [in his musical pursuits], and he went to Harvard Medical School to study medicine,” said Dr. Shapiro.

Larry Norton, MD, Deputy Physician-in-Chief for Breast Cancer Programs at Memorial SloanKettering Cancer Center and Medical Director of the Evelyn H. Lauder

Fig. 1: Music and Medicine Orchestra and Chorus

“Dr. Norton plays about 10 instruments and can’t imagine his life without being a musician. He was immediately onboard with the Initiative,” said Dr. Shapiro.

Integrating Music and Medicine The current plan is for the Music and Medicine Orchestra and Chorus to perform one or two major concerts a year. In addition, many of these medical students are developing ways to integrate their two passions into their daily lives, such as performing at patients’ bedsides and holding monthly mini-concerts for those in need of palliative care.

For more information about the Music and Medicine Initiative, visit weill.cornell.edu/music.

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The ASCO Post | DECEMBER 15, 2012

PAGE 92

Book Review

Ambitious Call to Arms Seeks a Shift in Priorities to Eradicate Cancer

By Ronald Piana

I

t has been more than 4 decades since our nation loaded its medical cannons and declared war on cancer, self-assured that money and American scientific resolve would lead to victory.

But cancer has proved to be a humbling enemy. The war is now fought in targeted skirmishes; the weaponry is a growing array of hugely expensive biologics—a battlefield where a prolonged stalemate is considered victory.

According to Margaret I. Cuomo, MD, author of the recently published book, A World without Cancer: The Making of a New Cure and the Real Promise of Prevention, the threadbare military metaphor, “war on cancer,” has contributed to scientific attrition that has “put generals in charge who think we should start talking about living with cancer as the ‘new normal.’”

From the outset of the book, Dr. Cuomo, a board-certified radiologist, makes clear that she is not in the “turning cancer into a chronic, treatable disease” camp. Her clarion call for change is articulated in the introduction: “For years, I have been observing the ‘cancer culture’ in the United States, and I have become convinced that it is not structured to do what we most need: to determine how to prevent cancer and then implement our discoveries.”

Turn the page, and Dr. Cuomo’s ambition is distilled even further: “My driving commitment to shift the national approach to cancer from treatment to prevention is at once urgent and personal.”

Unfolding Thesis The first part of A World without Cancer—using anecdotes from her years in practice and a brief history lesson—serves as a rationale for her general thesis, which unfolds in highly readable, well organized chapters, some of which might raise eyebrows within the oncology community. For instance, chapter 4, “Cut, Poison, and Burn: A Look at Today’s Treatment Options,” explicates the trials, tribulations, and successes of the three oncologic disciplines.

Although Dr. Cuomo’s reservations about the direction of oncology are visible on each page, she is never strident, tempering her concerns by noting the advances. “Nevertheless,” she concedes at one point, “imatinib can be considered a success story. If only we had more of these.”

Despite highlighting the success stories, Dr. Cuomo is quick to point out that our sluggish progress suggests we aren’t taking the right approach.

She punctuates the futility of the cut, poison, and burn methodology with a quote from cancer pioneer, James F. Holland, MD, one of many luminaries who appear throughout the book.

“Even one cancer cell can lead to death,” says Dr. Holland. “Relapse is always possible until we can guarantee that there are no cancer cells in the body.”

Problems and Solutions The book gains full momentum at the midway mark, as Dr. Cuomo’s observations drill into the marrow of today’s contentious health-care debate

approach to cancer requires two broad commitments.

First, our research focus has to shift from treatment to prevention.… Second, we need to look hard at the flaws in our existing research infrastructure.”

Dr. Cuomo then wrestles with the problems of our disconnected research apparatus. This is well-documented terrain, but she deftly uses the NASA approach to “set a specific goal and a specific deadline for accomplishing it,” to make her point that ironclad collaboration produces effective team science, which escalates a targeted research environment.

Even a super-energized team effort can be brought to a grinding halt, she points out, by two other culprits: failed

A World without Cancer not only deserves to be read, but its ambitious call to arms deserves to become part of the ongoing health-care dialogue. with a chapter titled, “Paying More, Settling for Less.” Here Dr. Cuomo looks at value vs cost, taking aim at some of the extravagant new biologics, a subject she hopes will resonate with doctors and policymakers alike.

To add gravitas to this argument, she brings in policy heavyweight Ezekiel J. Emanuel, MD, PhD. He comments, “We should differentiate between drugs that make a small difference and drugs that make no difference at all. A lot of cancer drugs are not worth very much in terms of prolongation of life.”

Once Dr. Cuomo has laid out the fatal flaws in the cancer care system, she sets her sights on a solution by advocating a dramatic shift of focus. “Taking on the many weaknesses to our current

data management and a flawed clinical trial system. Dr. Cuomo exhorts the players in the field, noting, “Career success, and the promotions that come with it, must be defined by allegiance to team science, not personal ambition.” It is a lofty goal, one that will require moon shot–like leadership to reach.

Bold New Initiative It is cure by prevention where Dr. Cuomo finds her sturdiest footing; it is obvious that advocating prevention strategies is her bailiwick. And she wastes no time getting to the point: The long-term prevention studies are in; it’s time for action!

“After evaluating the impact of ‘research-proven strategies and inter-

Title: A World without Cancer: The Making of a New Cure and The Real Promise of Prevention Author: Margaret I. Cuomo, MD Publisher: Rodale Books Publication date: October 2, 2012 Price: $26.99; Hardcover, 304 pages ventions,’” researcher Graham Colditz, MD, DrPH, “concluded that more than half of all cancers need not occur,” she writes. Even to those long in the cancer-care trenches, it’s a sobering statistic. Dr. Cuomo gives a detailed prescription on public health dos and don’ts. To her credit it is not a lecture, but rather, a cleanly drawn blueprint on how, as a society, we can help ourselves not develop cancer.

The centerpiece of Dr. Cuomo’s prevention realignment strategy is the creation of a “bold new initiative: the National Cancer Prevention Institute (NCPI).” As part of NIH, the NCPI would “coordinate the many cloistered activities throughout the federal government and lead the way into new arenas.”

Although readers might sigh at first at the mention of yet another government agency, Dr. Cuomo makes a convincing argument that if we are truly earnest about cutting cancer deaths by more than half, the NCPI might give us the needed infrastructure to move forward. Considering the stakes, it’s worth consideration from policymakers on the Hill. Lives and huge amounts of money could be saved.

Adding another book about cancer to a long list of predecessors takes the chance that it will get lost in the crowd.

However, A World without Cancer not only deserves to be read, but its ambitious call to arms deserves to become part of the ongoing health-care dialogue.

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See page 115 for an interview with Margaret I. Cuomo, MD.

ASCOPost.com | DECEMBER 15, 2012

PAGE 93

Awards

American Cancer Society Honors Waun Ki Hong, MD, for Outstanding Clinical Research

D

istinguished physician, scientist, mentor, and leader Waun Ki Hong, MD, recently accepted the American Cancer Society 2012 Medal of Honor Award in recognition of his novel, high-impact clinical research that has extended the frontiers of cancer treatment and prevention. Dr. Hong is Vice Provost for Clinical Research and Head of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston.

sulted in removing the larynx and losing the ability to speak.

Recounting subsequent research at MD Anderson, Dr. Hong said, “We proved the principle of chemopreven-

tion, that the course of cancer developB:8.625” ment can be reversed, and second priT:7.625” mary cancers couldS:6.75” be prevented.”

Reflecting on personalized medicine, he added, “As we increasingly un-

derstand cancer-promoting molecular targets and identify people who are at high risk for it, we can use targeted therapy to prevent cancer by blocking those pathways.”

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Cabozantinib (XL184) phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases CabOzantinib MET Inhibition CRPC Efficacy Trials

Waun Ki Hong, MD

“I’ve been very lucky. I’ve been at the right place, working with the right people, with great support from my colleagues and this institution,” Dr. Hong said. “I enjoy a challenge, and innovative clinical research requires perseverance, articulating an agenda and assembling the right team,” he added.

“And you must look at things from the positive side. There are pros and cons in any worthwhile project, but if you talk too much about the downside, you can’t break through barriers to prolong and improve the quality of our patients’ lives,” he said.

Dr. Hong has mentored hundreds of oncologists and clinician-scientists and authored more than 685 scientific publications. In three major areas—organ conservation, chemoprevention, and targeted therapy—he conceived, designed, and completed clinical trials that enlarged the scope of lifesaving possibilities.

KEY ELIGIBILITY CRITERIA •Diagnosis of CRPC •Presence of bone metastases •Prior treatment with docetaxel • Prior treatment with abiraterone and/or MDV3100 (enzalutamide) •No limit to the number of prior therapies

COMET-1

COMET-2

PRIMARY ENDPOINT

PRIMARY ENDPOINT

Overall Survival

Confirmed Pain Response CRPC (N=246)

CRPC (N=960) • Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies

Cabozantinib (60 mg qd) Randomization Prednisone

Research Highlights As Chief of Medical Oncology at the Boston Veterans Administration Medical Center in the early 1980s, Dr. Hong conceived and led a series of landmark clinical trials showing that patients with laryngeal cancer fared just as well when treated with chemotherapy and radiation as those who underwent surgery that ultimately re-

Randomized, double-blind, controlled trial

• Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies • Pain related to bone metastases

Cabozantinib (60 mg qd) Randomization Mitoxantrone + Prednisone

Randomized, double-blind, controlled trial

Visit www.COMETClinicalTrials.com/ASCOPost or call 1-855-85-COMET to learn more about these trials. © 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 05/12

The ASCO Post | DECEMBER 15, 2012

PAGE 94

Letters to the Editor

Updates on Ruxolitinib from ASCO and ASH 2012, including Long-term Survival Data

R

uxolitinib ( Jakafi), a novel, oral JAK1 and JAK2 inhibitor, was approved by the FDA on November 16, 2011 for patients with intermediate- or high-risk myelofibrosis. The approval was based on its efficacy in reducing spleen size and improving disease-related burdensome symptoms. In the brief In the Clinic commentary, “Ruxolitinib: Novel Drug for Myelofibrosis,” which appeared in the November 15 issue of The ASCO Post, there were important and clinically relevant discrepancies with the published literature, as well as the collective clinical experience with the JAK1/JAK2 inhibitor ruxolitinib used for the treatment of myelofibrosis.

Survival Benefit This year, long-term follow-up data from two randomized controlled phase III trials (COMFORT-I and – II), with greater than 500 patients in over 150 study sites internationally, became available, and demonstrate a possible survival benefit. These novel data were presented at the 2012 American Society of Hematology (ASH) Annual Meeting and are summarized in the abstracts,1,2 showing that patients on ruxolitinib had significantly improved survival compared with both placebo (hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.36–0.95) and best available therapy (HR = 0.51; 95% CI = 0.26– 0.99).

In addition, results from an independent analysis of the intermediate-2 or high-risk myelofibrosis patients treated at The University of Texas MD Anderson Cancer Center (N = 107) in the earlier phase I/ II study also support a survival advantage vs a matched (based on trial enrollment criteria) historical control group of 310 patients (P = .005).3 The survival benefits documented in these larger study populations were not observed in a smaller subset (n = 51) of patients from the phase I/II study treated at the Mayo Clinic, Rochester, compared to an unmatched historical control group, as reported in an earlier Letter to the Editor published in The New England Journal of Medicine.4 Furthermore, recently published analysis of the long-term outcomes

of 107 patients with myelofibrosis receiving ruxolitinib at MD Anderson on the phase I/II trial provided evidence of durable safety and efficacy.3 After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with

long-term follow-up of COMFORTI, there continued to be no evidence of a “withdrawal syndrome”.1 Finally, the FDA-approved prescribing information for ruxolitinib specifically states that “there have been isolated cases of patients discontinuing [rux-

We believe that with these updates on ruxolitinib’s long-term safety and efficacy, the drug is now the standard of care therapy for appropriate patients with myelofibrosis. an overall survival of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy.

Therapy was well tolerated; discontinuation rates were 24% at 1 year, 36% at 2 years, and 46% at 3 years.

Comparison of discontinuation rates and reasons for stopping the therapy to those reported for the aforementioned 51 patients in the phase I/II trial at Mayo Clinic, Rochester (described in the November 15 article in The ASCO Post) suggested that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including overall survival benefit.3

No Evidence of Withdrawal Syndrome The lingering question of whether interruption of ruxolitinib is associated with a “withdrawal syndrome” has been thoroughly investigated in the COMFORT program5,6 and reviewed by the FDA and other health authorities. In the placebo-controlled COMFORT-I study, patient symptoms returned to baseline levels within approximately 1 week after treatment interruption, independently of the ruxolitinib dose from which interruption occurred.7 Grade 3 or 4 toxicity as well as serious adverse events that occurred during treatment interruption were infrequent, similar in occurrence to a placebo-treated patients, and showed no pattern of a defined “withdrawal syndrome.”

These data are consistent with COMFORT-II, as well as the report from the MD Anderson–treated cohort from the phase I/II trial. In the

olitinib] during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; however, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients.” These isolated clinical cases were the focus of a separate brief report.8 Additional long-term efficacy and safety results from COMFORT-I and –II were also presented at the 2012 ASH Annual Meeting. Our collective clinical experience with ruxolitinib when used outside the context of a research study is consistent with the above findings and conclusions. We believe that with these updates on ruxolitinib’s long-term safety and efficacy, the drug is now the standard of care therapy for appropriate patients with myelofibrosis.

—Srdan Verstovsek, MD, PhD Professor of Medicine Chief, Section for Myeloproliferative Neoplasms (MPNs), Department of Leukemia Director, Clinical Research Center for MPNs The University of Texas MD Anderson Cancer Center, Houston

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Ruben A. Mesa, MD Professor of Medicine Chair, Division of Hematology & Medical Oncology Deputy Director, Mayo Clinic Cancer Center Mayo Clinic, Scottsdale, Arizona Ronald Hoffman, MD Albert A. and Vera G. List Professor of Medicine

Director, Myeloproliferative Disorders Research Program Tisch Cancer Institute Mount Sinai School of Medicine, New York Jason Gotlib, MD Associate Professor of Medicine (Hematology) Director, Stanford MPN Center Stanford University School of Medicine/ Stanford Cancer Institute Stanford, California Rami Komrokji, MD Clinical Director Department of Hematologic Malignancies Moffitt Cancer Center, Tampa, Florida Hagop M. Kantarjian, MD Professor of Medicine Chairman, Department of Leukemia The University of Texas MD Anderson Cancer Center, Houston

Disclosure: Drs. Verstovsek, Mesa, and Hoffman have received research support from Incyte for conduct of clinical trials. Dr. Gotlib has received research support from Incyte for conduct of clinical trials and is a participant in physician advisory boards. Dr. Komrokji is a member of the speaker bureau for Incyte. Dr. Kantarjian reported no potential conflicts of interest.

References 1. Verstovsek S, Mesa RA, Gotlib J, et al: Long-term outcome of ruxolitinib treatment in patients with myelofibrosis: Durable reductions in spleen volume, improvements in quality of life, and overall survival advantage in COMFORT-I. 54th ASH Annual Meeting. Abstract 800. Presented December 10, 2012.

2. Cervantes F, Kiladjian J-J, Niederwieser D, et al: Long-term safety, efficacy, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy (BAT) for the treatment of myelofibrosis (MF). 54th ASH Annual Meeting. Abstract 801. Presented December 10, 2012.

3. Verstovsek S, Kantarjian HM, Estrov Z, et al: Long term outcomes of 107 patients with myelofibrosis receiving JAK1/ JAK2 inhibitor ruxolitinib: Survival advantage in comparison to matched historical controls. Blood 120:1202-1209, 2012.

4. Tefferi A, Litzow MR, Pardanani continued on page 95

ASCOPost.com | DECEMBER 15, 2012

PAGE 95

Letters to the Editor

The ‘True’ History of the Discovery of Prostate-specific Antigen

I

am frequently asked about the “true” history of prostate-specific antigen (PSA). As PSA has become more important, a controversy about its discovery has increased. I lived through much of this history and have known many of the “players.” Here are the relevant facts, as I believe them to be true.

In the late 1960s and 1970s, many researchers were searching for tumor-specific antigens that might be useful as biomarkers or targets for immunotherapy of cancer and other diseases.

PSA Milestones Before PSA, prostatic acid phosphatase was the most important blood test for prostate cancer, but it was useless for early detection of prostate cancer because it was elevated largely in men who already had bone metastases.

In the late 1960s and 1970s, many researchers were searching for

Updates on Ruxolitinib continued from page 94

A: Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med 365:1455-1457, 2011.

5. Verstovsek S, Mesa RA, Gotlib, J et al: A double-blind placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366:799-807, 2012.

6. Harrison C, Kiladjian JJ, Al-Ali HK, et al: JAK inhibition with ruxolitinib vs best available therapy in myelofibrosis. N Engl J Med 366:787-798, 2012.

7. Verstovsek S, Mesa RA, Gotlib JR, et al: Adverse events (AEs) and the return of myelofibrosis (MF)-related symptoms after interruption or discontinuation of ruxolitinib (RUX) therapy. 2012 ASCO Annual Meeting. Abstract 6624. Presented June 4, 2012.

8. Tefferi A, Pardanani A: Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 86:1188-1191, 2011.

tumor-specific antigens that might be useful as biomarkers or targets for immunotherapy of cancer and other diseases. Typical experiments involved searching for “antigens” by injecting extracts of human tissues

and body fluids into rabbits and testing the rabbit serum for antibodies against the antigens contained in the extracts. The earliest report on the properties of antigens in the prostate was by urologist Rubin Flocks in

1960.1 In 1966, a Japanese forensic scientist, Mitsuwo Hara, partially characterized and reported on a protein similar to what might have been PSA. continued on page 96

The ASCO Post | DECEMBER 15, 2012

PAGE 96

Letters to the Editor

‘True’ History of PSA continued from page 95

He called it “gamma-seminoprotein” and suggested its possible value as forensic evidence in rape cases in the Japanese Journal of Legal Medicine.

In 1970 and 1972, Richard Ablin reported finding two antigens that were specific to the human prostate, one of which was separate from acid phosphatase. I do not believe Dr. Ablin knew what the antigens were or contemplated their potential uses. In any case, he didn’t characterize the antigens further, but rather, moved on to studies of the possible induction of an antitumor immune response in the prostate gland by freezing the prostate.

In 1970, Tien Shun Li and Carl Beling, conducting research in male infertility reported there were antigens in human semen, some of which might have been PSA. In 1978, forensic scientist George Sensabaugh identified a protein in semen that was similar to one of Li’s that later was also shown to be similar to PSA.

Ambiguous ‘Antigens’ The debate about who really deserves credit for discovering PSA has focused on whether the reported

early “antigens” were actually PSA. Many did not exhibit all the properties that would be expected of PSA. The molecular weight and amino acid composition of gamma-seminoprotein as initially reported were different from those of PSA. Both Li and Beling and Sensabaugh reported their antigens were not of prostatic

characterized PSA, demonstrated its presence in normal, benign, and malignant prostate tissue, and showed that it was virtually prostate specific. Later they developed an immunoassay that could be used for blood testing and performed early studies exploring its potential clinical uses in prostatic diseases.

The debate about who really deserves credit for discovering PSA has focused on whether the reported early ‘antigens’ were actually PSA. origin. Ablin could not detect his antigen in semen or prostatic fluid where PSA should be easily detected.

Ultimately, Chu received the patent for the discovery of “purified human prostate antigen” in 1984, and has been honored on many occasions as the discoverer of PSA. In my opinion, the real credit for the “discovery” of PSA as a marker for prostate disease and for beginning to introduce it into clinical use belongs to T. Ming Chu and his research laboratory staff, notably Ming C Wang, at Roswell Park Memorial Institute (as it was known from 1946 to 1992) in New York. In 1979, they purified and

Monitoring and Screening What emerged from the early clinical studies by Chu’s group and by other researchers and was further demonstrated in 1987 by Thomas A. Stamey of Stanford University was that PSA is quite useful for monitoring the course of patients already known to have prostate cancer. However, it was not really appreciated that it could be used as a first-line screening test for prostate cancer, because PSA could be elevated in patients with benign prostate conditions and “normal” or low in patients with prostate cancer.

In 1991, I published the first results

of a study showing that the PSA test was the most accurate method of detecting prostate cancer.2 Using a PSA cutoff of 4 ng/mL, about 25% of men were found to have cancer. Moreover, PSA could detect many cancers that were missed by both the rectal exam and ultrasonography. Thus, I was the first to suggest that PSA could be used as a first-line screening test for prostate cancer.

I still believe that PSA is the best cancer blood test in medicine, and certainly the best we currently have for early prostate cancer detection. I believe that if it were used intelligently and were combined with high-quality, effective treatment, it could reduce the prostate cancer death rate by more than half.

—William J. Catalona, MD Professor in Urology Northwestern University Feinberg School of Medicine Chicago, Illinois

■

References 1. Rao AR, Motiwala HG, Karim OM, et al: The discovery of prostate-specific antigen. BJU Int 101:5-10, 2008.

2. Catalona WJ, Smith DS, Ratliff TL, et al: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 324:1156-1161, 1991.

Health-care Crisis Reconsidered

A

s an oncologist in private practice, I usually read with great interest the many articles in The ASCO Post on issues regarding the politics of oncology practice. These articles deal with the major topics of the day, ranging from the high cost of oncologic care to shortages of generic drugs, to alleged solutions of these complex problems. Most of the articles are written by academics and other so-called policymaking “experts.” Most cite studies from biased groups such as the World Health Organization and the Institute of Medicine to provide the bedrock upon which their “reforms” are based.

Most offer the same tired solutions of decision-making centralization and pressuring the practitioner to become a rationer of care, thereby fundamentally altering the doctorpatient relationship.

Root of the Problem None of these policymakers ever deal with the real etiology and root

cause of these problems. They cite “inappropriate incentives” for physicians to practice what is, in their opinion, appropriate care (ie, the profit motive). Most deny the existence of the sacred relationship between the practitioner and the usually anxious and often seriously ill patient and his or her family.

What has become clear to many of us who have practiced over the years

have been “abolished and obscured.”

This has led directly to an increase in demand for services with little connection to related costs. As in any system where this disconnect occurs (which includes most government programs), the distortion of the marketplace leads to massive increases in health-care costs, and in the case of generic drugs, shortages of the product.

The ‘original sin’ of the health-care crisis was the interdiction of the government and its surrogates in the insurance industry into the basic relationship between the patient and the physician. is that the “original sin” of the healthcare crisis was the interdiction of the government and its surrogates in the insurance industry into the basic relationship between the patient and the physician. As a result, market prices for health services and insurance

In the late 1980s, we were told that the diagnosis-related group (DRG) would solve all problems of overutilization and overbilling by hospitals.

Unfortunately, it perverted health-care delivery to such a degree that health care ceased to be about caring for sick

people and instead forced hospitals to become hotbeds of utilization reviews and charge capture, and consequently, moving patients out as quickly as possible to “make the DRG” for reimbursement purposes. As a result of this statist utopian solution, the government was forced to pass more legislation to penalize hospitals for kicking patients out too soon—ie, a new Medicare penalty system for readmissions.

Another example is the Medicare Modernization Act (MMA), which sought to right the wrongs of the past system of chemotherapy reimbursement but has now led to shortages in generic drugs because manufactures can’t make a “profit” on these cheaper drugs with this overregulated, non–free market– based system. Recently, the utopian electronic medical record (EMR) was cited as the cause for increases in hospital reimbursement due to physician up-coding through EMR templates. This incited our Attorney General and Secretary of Health and

ASCOPost.com | DECEMBER 15, 2012

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Letters to the Editor

Human Services to threaten hospitals and ultimately doctors, who in their esteemed estimations, up-code for profit.

The Real Challenge The real challenge for the experts should be how to wrestle the complexities of care away from those who wish to centralize all decision-making and find ways to give it back to the individuals directly involved in the interaction, ie, the patient and the doctor. This is the only humane and costeffective way to do this. Anyone with a modicum of intelligence can devise a plan that takes away individual choice and gives it to a centralized power, but the forward-thinking genius is the one who can figure out how to get it back to the individual.

Thus, I challenge ASCO to develop a

The Language of Cancer

committee that seeks market solutions to these difficult problems and eschews the tyranny of collectivization championed by so many policy experts in the medical community and so many powerful people in Washington, DC. Finally, regarding the article “Delivering Affordable Cancer Care: Is It Possible and What Will It Entail?”

which appeared in the November 15, 2012, issue of The ASCO Post, the “disclosure” section available online at ASCOPost.com notes that none of the individuals quoted for the piece reported a conflict of interest. I vehemently disagree with that statement.

Although there may be no drug companies involved, most of these speak-

For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

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

37%

changed

63% confirmed

I

am a member of ASCO and read with interest your piece entitled “The Language of Cancer” in the October 15, 2012, issue of The ASCO Post.

By way of introduction, I am an attending physician specializing in urologic oncology at Loyola University Medical Center. My group recently published an article in The Journal of Urology on the readability of prostate cancer materials on the Internet.1 Although the NIH mandates patient handouts to be at the 4th grade reading level, most of the materials online (and from cancer agencies, such as the American Urological Society) are written at the 12th grade level or above.

This poses a huge problem for physicians and allied health professionals who point their patients to outside reading materials. What are the patients going to understand? Could different treatment options have inherent readability differences, thus biasing their choices?

I am interested in hearing from others and seeing more on this topic in The ASCO Post.

—Gopal N. Gupta, MD Maywood, Illinois

■

Reference 1. Ellimoottil C, Polcari A, Kadlec A, et al: Readibility of websites containing information about prostate cancer treatment options. J Urol 188:2172-2176, 2012.

Send comments to editor@ASCOPost.com

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 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.

Now available for patients with ductal carcinoma in situ (DCIS) Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0712

ers are academic physicians or policymakers who stand to gain from the centralization of decision-making and the destruction of private practice oncology, which their policies must and will inevitably cause.

—Jonathan Schwartz, MD Oncologist Tucson, Arizona

■

The ASCO Post | DECEMBER 15, 2012

PAGE 98

Integrative Oncology Acupuncture: Does It Alleviate Symptoms Associated with Cancer Care?

By Barrie R. Cassileth, MS, PhD, and Ian Yarett Integrative Medicine Service Memorial Sloan-Kettering Cancer Center, New York

A

therapeutic modality of traditional Chinese medicine, acupuncture has been extensively investigated in Western medical settings. Its clinical use is increasingly common for the management of pain and other conditions. In the oncology setting, research demonstrates that acupuncture can significantly reduce symptoms associated with cancer and cancer treatments. This modality has proven to be very safe; serious adverse effects are rare or nonexistent among randomized controlled trials conducted to date.1 This overview presents results of high-quality clinical trials of acupuncture for symptom control in oncology.

What Is Acupuncture, and How Does It Work?

Acupuncture involves the placement of needles at specific points on the body, followed by manipulation with physical forces, heat, or electrical stimuli. According to Traditional Chinese Medicine, vital energy called Qi or Chi flows throughout the body along meridians. Blockages in this energy flow are thought to cause disease.

The insertion of needles at certain points along these meridians was believed to treat disease by restoring normal energy flow.

Research over recent decades has upheld acupuncture’s therapeutic value and provided a more modern understanding of its mechanisms.

Acupuncture is understood today to exert its effects by modulating the nervous system. There is no evidence that acupuncture has direct anticancer effects, but clinical research supports its importance in reducing common physical and emotional symptoms associated with cancer and its treatment.

As such, it is increasingly common for acupuncture to be integrated with mainstream cancer care in hospitals and other medical settings.2,3 A 1997 report of an NIH consensus conference supported the “efficacy of acupuncture in adult postoperative and chemotherapy nausea and vomiting and in postoperative dental pain.”

The report deemed acupuncture a promising treatment for “addiction, stroke rehabilitation, headache, menstrual cramps, tennis elbow, fibromyalgia, myofascial pain, osteoarthritis, low back pain, carpal tunnel syndrome, and asthma.”4

Nausea and Vomiting

More recent research supports the efficacy of acupuncture for cancer treatment-related nausea and vomiting. Two Cochrane reviews, published in 2006 and 2009, concluded that stimulation of the PC6 acupoint inside the wrist can effectively reduce chemotherapy-induced nausea and vomiting5 and prevent it postoperatively.6 Moreover, even simple, nonpuncturing acupoint interventions effectively control nausea. A randomized placebo-

I

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan-Kettering Cancer Center, New York.

The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective Barrie R. Cassileth, MS, PhD and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 260 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. controlled trial in craniotomy patients found that transcutaneous electrode stimulation at the PC6 acupoint before, during, and after surgery significantly reduced the incidence of nausea and vomiting at 24 hours postsurgery.7 Patients experienced a 40% lower incidence of nausea and a 60% decrease in vomiting compared to the placebo group, which received electrode stimulation at a nonacupoint.

Although acupuncture’s effectiveness when compared to usual care is documented in many studies, it also appears to have nonspecific effects. A 2011 investigation of acupuncture’s effects on radiation-induced nausea, for example, found no significant difference in nausea frequency and intensity between the groups receiving true and sham acupuncture, though both

groups experienced less intense nausea than patients receiving usual antiemetic care.8

Hot Flashes

Several recent systematic reviews have concluded that the existing evidence does not convincingly suggest that acupuncture is effective for reducing hot flashes related to breast cancer treatment.9-11 The only reviewed study that found a clear benefit compared true vs sham acupuncture in postsurgical patients taking tamoxifen and demonstrated a significant reduction in hot flash frequency in the true acupuncture group over 22 weeks.12 A qualitative follow-up study suggested that this acupuncture intervention may have had long-lasting benefits, as several women stated in a

Learn More About

Herbs, Botanicals, & Other Products Visit the About Herbs website at

www.mskcc.org/aboutherbs

ASCOPost.com | DECEMBER 15, 2012

PAGE 99

Integrative Oncology questionnaire conducted 2 years later that their hot flashes were still “fewer and milder.”13 Another efficacy trial, however, found that true and sham acupuncture both reduced hot flashes, with no statistically significant difference between groups.14

Xerostomia

Several studies have addressed acupuncture treatment for radiationinduced xerostomia in patients with head and neck cancer. A 2010 review found the existing evidence to be inconclusive but promising and worthy of further investigation.15 Neuroimaging findings strongly suggest that acupuncture may be useful in treating xerostomia; one study found that acupuncture at a relevant acupoint produced a distinct functional MRI pattern that was not observed with sham acupuncture, and that corresponded with an increase in salivary flow.16 A recent, high-quality trial demonstrated the preventive effects of acupuncture delivered concurrently with radiation treatment. This randomized, nonblinded trial of acupuncture vs usual care investigated the ability of acupuncture to prevent xerostomia in nasopharyngeal carcinoma patients.17 Acupuncture was administered thrice weekly for 7 weeks, and a statistically significant improvement in xerostomia and quality of life was reported starting in the third week and persisting for 6 months.

Pain

Acupuncture is a promising treatment for pain unrelated to cancer, with evidence supporting its effectiveness for low back pain, neck pain, and peripheral joint osteoarthritis, among others.18 Findings are mixed with regard to cancer-related pain.

Two recent reviews, including a Cochrane review, concluded that there is insufficient evidence to judge whether acupuncture is effective for cancer pain.19,20 Drawing on additional high-quality trials, however, another review suggested that acupuncture should be “recom-

mended as a complementary therapy if pain is poorly controlled and may offer utility as a primary treatment for cancerrelated pain.”21 A randomized efficacy trial compared true vs sham acupuncture at multiple body and auricular acupoints for the treatment of aromatase inhibitor–associated joint pain in patients with breast cancer, finding significant pain reduction at 6 weeks.22

Concluding Thoughts

As one of the most well studied complementary modalities, acupuncture’s therapeutic value has been documented by many high-quality randomized trials.

The most solid supporting evidence in oncology comes from studies of acupuncture for chemotherapy-related

Therapy for Cancer. Evidence-based Anticancer Complementary and Alternative Medicine. Dordrecht, The Netherlands, Springer Science+Business Media, 2012.

2. Stone JA, Johnstone PA: Mechanisms of action for acupuncture in the oncology setting. Curr Treat Options Oncol 11:118-127, 2010.

3. Deng G, Vickers A, Simon Yeung K, et al: Acupuncture: integration into cancer care. J Soc Integr Oncol 4:86-92, 2006.

4. Acupuncture. NIH Consens Statement 15:1-34, 1997.

5. Ezzo JM, Richardson MA, Vickers A, et al: Acupuncture-point stimulation for chemotherapy-induced nausea or vomiting. Cochrane Database Syst Rev:CD002285, 2006.

6. Lee A, Fan LT: Stimulation of the wrist acupuncture point P6 for preventing postoperative nausea and vomiting. Cochrane Data-

There is no evidence that acupuncture has direct anticancer effects, but clinical research supports its importance in reducing common physical and emotional symptoms associated with cancer and its treatment. nausea and vomiting. Evidence is less conclusive but suggests that acupuncture may be useful against hot flashes, xerostomia, and pain. There are also promising results from pilot studies of acupuncture for cancer-related fatigue and for chemotherapy-induced neutropenia and neuropathy, among others.1 In addition to its therapeutic value, acupuncture also may reduce costs.

One study noted a 30% cost savings per patient when acupuncture was used for radiation-induced nausea, compared to serotonin-receptor antagonists over the course of radiation treatment.8

■

Disclosure: Dr. Cassileth and Mr. Yarrett reported no potential conflicts of interest.

References 1. Deng G, Seto D, Cassileth B: Recent clinical trials of acupuncture for cancer patients, in Cho WCS (ed): Acupuncture and Moxibustion as an Evidence-based

base Syst Rev:CD003281, 2009.

7. Wang XQ, Yu JL, Du ZY, et al: Electroacupoint stimulation for postoperative nausea and vomiting in patients undergoing supratentorial craniotomy.

J Neurosurg Anesthesiol 22:128-131, 2010.

8. Enblom A, Lekander M, Hammar M, et al: Getting the grip on nonspecific treatment effects: emesis in patients randomized to acupuncture or sham compared to patients receiving standard care.

PLoS One 6:e14766, 2011.

9. Chao LF, Zhang AL, Liu HE, et al: The efficacy of acupoint stimulation for the management of therapy-related adverse events in patients with breast cancer: A systematic review. Breast Cancer Res Treat 118:255-267, 2009.

10. Lee MS, Kim KH, Choi SM, et al: Acupuncture for treating hot flashes in breast cancer patients: A systematic review. Breast Cancer Res Treat 115:497503, 2009.

11. Rada G, Capurro D, Pantoja T,

Download The ASCO Post iPad App FREE from iTunes today!

et al: Non-hormonal interventions for hot flushes in women with a history of breast cancer. Cochrane Database Syst Rev:CD004923, 2010.

12. Hervik J, Mjaland O: Acupuncture for the treatment of hot flashes in breast cancer patients, a randomized, controlled trial.

Breast Cancer Res Treat 116:311-316, 2009.

13. Hervik J, Mjaland O: Quality of life of breast cancer patients medicated with anti-estrogens, 2 years after acupuncture treatment: a qualitative study.

Int J Womens Health 2:319-325, 2010.

14. Deng G, Vickers A, Yeung S, et al: Randomized, controlled trial of acupuncture for the treatment of hot flashes in breast cancer patients. J Clin Oncol 25:5584-5590, 2007.

15. O’Sullivan EM, Higginson IJ: Clinical effectiveness and safety of acupuncture in the treatment of irradiation-induced xerostomia in patients with head and neck cancer: A systematic review. Acupunct Med 28:191-199, 2010.

16. Deng G, Hou BL, Holodny AI, et al: Functional magnetic resonance imaging (fMRI) changes and saliva production associated with acupuncture at LI-2 acupuncture point: A randomized controlled study.

BMC Complement Altern Med 8:37, 2008.

17. 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 118:3337-3344, 2012.

18. Ernst E, Lee MS: Acupuncture for palliative and supportive cancer care: A systematic review of systematic reviews.

J Pain Symptom Manage 40:e3-5, 2010.

19. Paley CA, Johnson MI, Tashani OA, et al: Acupuncture for cancer pain in adults. Cochrane Database Syst Rev:CD007753, 2011.

20. Hopkins Hollis AS: Acupuncture as a treatment modality for the management of cancer pain: The state of the science.

Oncology Nursing Forum 37:E344-E348, 2010.

21. Capodice JL: Acupuncture in the oncology setting: clinical trial update. Curr Treat Options Oncol 11:87-94, 2010.

22. Crew KD, Capodice JL, Greenlee H, et al: Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer. J Clin Oncol 28:1154-60, 2010.

The ASCO Post | DECEMBER 15, 2012

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2013 Oncology Meetings January 2013 3rd International Conference on Medical, Biological and Pharmaceutical Sciences January 4-5 • Bali, Indonesia For more information: www.psrcentre.org Breast-Gynecological International Cancer Congress January 17-18 • Cairo, Egypt For more information: www.bgicc.eg.net/ Highlights of ASH® San Diego, CA and Toronto, Canada January 18-19 • San Diego, CA and Toronto, Ontario, Canada For more information: www.hematology.org/meetings Case-based Clinical Hematology and Oncology 2013: The 10th Annual Review January 18-20 • Scottsdale, Arizona For more information: www.mayo.edu/cme 11th Oncology Update: Advances and Controversies January 18-21 • Steamboat Springs, Colorado For more information: www.mdanderson.org/conferences 2013 Gastrointestinal Cancers Symposium January 24-26 • San Francisco, California For more information: www.gicasymposium.org

3rd Annual San Antonio Breast Cancer Symposium Review January 26 • Omaha, Nebraska For more information: www.nebraskaoncology.org The 15th International Symposium on Anti-Angiogenic Therapy: Recent Advances and Future Directions in Basic and Clinical Cancer Research January 31-February 2 • San Diego, California For more information: www.mdanderson.org/conferences

February 2013 Highlights of ASH® Miami, FL and San Francisco, CA February 1-2 • Miami, Florida, and San Francisco, California For more information: www.hematology.org/meetings Interventional Pulmonology in Cancer Patients: An Intensive Hands-on Course February 7-9 • Houston, Texas For more information: www.mdanderson.org/conferences Advances in Orbital Oncology and Oculofacial Plastic Surgery February 8-9 • Houston, Texas For more information: www.mdanderson.org/conferences Integrative Medicine Program’s 1st Annual Integrative Oncology Healthcare Professional Training Conference February 8-9 • Houston, Texas For more information: www.mdanderson.org/conferences

T-cell Lymphoma Forum January 24-26 • San Francisco, California For more information: www.tcellforum.com

Methods in Cancer Research Workshop February 9-13 • Al Ahsa, Saudi Arabia For more information: mcrw.kacst.edu.sa

Highlights of ASH® Dallas, TX and New York, NY January 25-26 • Dallas, Texas, and New York, New York For more information: www.hematology.org/meetings

ASCO-MECC Palliative Care Workshop February 10-13 • Muscat, Oman For more information: www.asco.org/palliativecare

Genomics in Medicine: Individualized Care for Improved Outcomes February 11-12 • San Francisco, California For more information: www.triconference.com/genomicspersonalized-medicine Second Annual Targeting Cancer Stem Cells: Promising New Therapeutics for Oncology February 11-12 • San Francisco, California For more information: www.triconference.com/targetingcancer-stem-cells/ Quantitative Real-time PCR: Applications for Molecular Diagnostics February 11-12 • San Francisco, California For more information: www.triconference.com/ Quantitative-Pcr/ Molecular Med Tri-Con 2013 February 11-15 • San Francisco, California For more information: www.triconference.com American Psychosocial Oncology Society 10th Annual Conference February 14-16 • Huntington Beach, California For more information: www.apos-society.org 2013 Genitourinary Cancers Symposium February 14-16 • Orlando, Florida For more information: www.gucasymposium.org North Carolina Oncology Association & South Carolina Oncology Society Joint Membership Conference February 14-16 • Greenville, South Carolina For more information: www.ncoa-northcarolina.com Scripps Cancer Center’s 33rd Annual Clinical Hematology and Oncology Conference February 16-19 • San Diego, California For more information: www.scripps.org/events/clinicalhematology-and-oncologyfebruary-16-2013

2013 Multidisciplinary Head and Neck Cancer Update February 22-23 • Weston, Florida For more information: www.clevelandclinicmeded.com 2nd Novel Cancer Therapeutics Summit February 25-26 • Las Vegas, Nevada For more information: www.gtcbio.com

March 2013 International Congress on Targeted Anticancer Therapies March 4-6 • Paris, France For more information: www.tatcongress.org/tat13-home. html 24th Annual Cancer Progress Conference March 5-6 • New York, New York For more information: www.cancerprogressbyDH.com Inaugural Prostate Cancer Research and Translation Symposium March 6-7 • Winston-Salem, North Carolina For more information: northwestahec.wfubmc.edu NCCN 18th Annual Conference: Advancing the Standard of Cancer Care March 14-17 • Hollywood, Florida For more information: www.nccn.org Highlights of ASH® in Asia March 23-24 • Shanghai, China For more information: www. hematology.org/meetings 23rd Annual National Interdisciplinary Breast Cancer Conference March 23-27 • Las Vegas, Nevada For more information: www.breastcare.org/

April 2013 66th Urological Society of Australia and New Zealand Annual Scientific Meeting April 13-16 • Melbourne, Australia For more information: www.usanz2013.com/ continued on page 104

A N E W I N D I C ATI O N

COMING SOON Please see adjacent pages for current indication, Important Safety Information, and brief summary of full Prescribing Information.

Janssen Biotech, Inc. Š Janssen Biotech, Inc. 2012 8/12 08Z12244A

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information).

Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

www.zytiga.com Please see brief summary of full Prescribing Information on the following pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 8/12 08Z12244A

08Z11121R3

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castrationresistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. 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.

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter.

In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions].

Adrenocortical insufficiency [see Warnings and Precautions].

Hepatotoxicity [see Warnings and Precautions].

Food effect [see Warnings and Precautions].

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 clinical practice.

In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months.

The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA).

Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions].

Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities).

Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 26.2 3.0 Muscle discomfort3 General disorders 26.7 1.9 Edema4 Vascular disorders Hot flush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5 5.9 1.4 Fractures Cardiac disorders 6 Arrhythmia 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 Cardiac failure8 2.3 1.9 1 2 3

Placebo with Prednisone (N=394) All Grades Grade 3-4 % % 23.4 23.1

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

0

5.1 4.1

0.3 0

2.3

0

4.6 2.8 1.0

1.0 0 0.3

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms.

Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations.

In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated.

Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%).

Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebocontrolled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8.

Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo.

Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. 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 and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, 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: ZYTIGA is not indicated in children.

Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily.

If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

Manufactured by: Patheon Inc. Mississauga, Canada

Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044

© Janssen Biotech, Inc. 2012

Revised: July 2012

08Z12237B

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2013 Oncology Meetings continued from page 100

3rd ITLT Essen 2013 Interdisciplinary Treatment of Liver Tumors April 18-20 • Essen, Germany For more information: www.itlt.org 7th Conference on Experimental and Translational Oncology April 20-24 • Portoroz, Slovenia For more information: www.ceto.si

Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.asco.org

September 2013

May 2013

June 2013

Precision Medicines in Breast Cancer May 9-10 • London, United Kingdom For more information: www.precisionmedicines.com

12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch 6th International Nasopharyngeal Carcinoma Symposium June 20-22 • Istanbul, Turkey For more information: www.npc2013.org

The Psychological Impact of Cancer for Patients, Carers, and Families May 15 • Milton Keynes, United Kingdom For more information: www8.open.ac.uk/health-and-socialcare/main/research/research-events/ psychological-impact-of-cancer Iowa Oncology Society Spring Membership Conference May 17-18 • West Des Moines, Iowa For more information: www.ios-iowa.com The Bone Marrow Niche, Stem Cells, and Leukemia: Impact of Drugs, Chemicals, and the Environment May 29-31 • New York, New York For more information: www.nyas.org/bonemarrow

Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

Highlights of ASH® in Latin America April 25-26 • Santiago, Chile For more information: www.hematology.org/meetings

European Multidisciplinary Conference in Thoracic Oncology May 9-11 • Lugano, Switzerland For more information: www.esmo.org

ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna

MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com

July 2013 Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences

August 2013 Best of ASCO® Chicago August 9-10 • Chicago, Illinois For more information: boa.asco.org Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org

Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu 28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston, Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/ About+ASCO/International+Affairs/ International+Clinical+Trials+Works hops 4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in 18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas For more information: www.mdanderson.org/conferences 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

November 2013 EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de

October 2013

December 2013

Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences

55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org

ASCOPost.com | DECEMBER 15, 2012

PAGE 105

Journal Spotlight

Study Explores Use of Radiotherapy in Last 30 Days of Life

By Charlotte Bath

W

hile few patients receive radiation for cancer treatment in the last 30 days of life, almost 1 in 5 patients who do spend more than 10 of those days in treatment and more than half spend more than 5 days, according to a study published in the Journal of Clinical Oncology.1 The investigators used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases to analyze claims data for 202,299 patients dying as a result of lung, breast, prostate, colorectal, and pancreas cancers over a 5-year period.

“These cancers were chosen because they accounted for the top five most common causes of cancer deaths and comprised almost 60% of cancer deaths in 2010,” the researchers explained.

Among the 15,287 patients (7.6%) who received radiation therapy in the last month of life, 2,721 (17.8%) received more than 10 days of treatment and 53.7% received more than 5 days of treatment. Nonclinical factors associated with a greater probability of receiving radiotherapy for more than 10 days in the last 30 days of life included non-Hispanic white race, no hospice care, and treatment in a “freestanding” (vs hospital-associated) facility, the researchers reported.

“We found a decreasing use of radiotherapy in the last 30 days of life See Page 119 from 2000 to 2007, which corresponded to an increasing trend in hospice enrollment,” the authors noted. Other factors associated with significantly greater likelihood of receiving radiation therapy included lung cancer as the cause of death, younger age, male sex, being married, and living in an urban area.

Cost of Care “We found that the costs of care for patients who received radiotherapy at the end of life were higher than for those patients who did not,” the investigators stated. “Any debate about the costs of radiotherapy at the end of life must include acknowledgment of the palliative benefits to patients, such as decreased pain or improved neurologic functioning potentially offered through a course of conventional short-course radiotherapy. Also, increased costs could be due to complications of cancer that resulted in hospitalizations and need for radio-

therapy, rather than radiotherapy itself.”

The authors acknowledged that it is possible that the low percentage of patients who received radiotherapy in the last 30 days of life could reflect “under-

use of this modality in end-stage cancer care. However, dosing regimens that require dying patients to spend a significant proportion of their final days visiting a radiation therapy suite likely coun-

ters the overall aim of palliative care.”

Reference 1. Guadagnolo BA, et al: J Clin Oncol. November 12, 2012 (early release online).

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PAGE 106

Pioneers in Oncology Dr. Jimmie C. Holland’s Research Has Long Underscored the Importance of Caring for the Whole Patient

By Jo Cavallo

ing at the peak of the polio epidemic sweeping Boston in 1955.

“People were crippled with paralyzed limbs, and we had to clear out a whole ward to install iron lungs. I became very interested in what happened to these young people who were healthy one day and then paralyzed from the neck down the next day,” said Dr. Holland. “We began studying how these patients coped with catastrophe.”

Merging Specialties Jimmie C. Holland, MD

A

lthough internationally recognized today as the founder of the subspeciality of psycho-oncology, the field of psychiatry held no interest for Jimmie C. Holland, MD, when she entered Baylor College of Medicine in Houston, Texas, in the mid-1940s. Born in 1928 at the dawn of the Great Depression, Dr. Holland credits her mother with instilling in her a sense of optimism and a drive to help people that contributed to her decision to pursue a career in medicine. At Baylor, she was one of only three women admitted to a class of 80 students—most of whom were returning World War II veterans. With plans to return to her hometown of Nevada, Texas, after graduation and become a country doctor, she hoped to tend to the general medical needs of her rural community. However, a rotation in psychiatry during her internship at St. Louis City Hospital altered that future—and the future of cancer care.

“I wasn’t interested in surgery,” said Dr. Holland. “I didn’t want to cut up people’s bodies—that was clear to me early on—and I found treating illnesses like congestive heart failure with the same drugs over and over boring.

What really interested me was how people coped with their illness and how every patient had a different way of doing that.”

With her interest in psychiatry taking hold, Dr. Holland continued her residency at Massachusetts General Hospital in Boston, arriv-

It was during this time that she met James F. Holland, MD, then the Chief of Medicine at Roswell Park Cancer Institute, where he was researching chemotherapies for children with acute lymphoblastic leukemia. She moved to Buffalo, New York, where they married in 1956 and began raising a family of six children. Working part-time while the children were young, Dr. Holland began solidifying the focus of her work on the psychological care of the medically ill, especially patients with cancer.

Chief of the Psychiatric Consultation Services at Montefiore Hospital in New York. This is where the specialties of oncology and psychology began to merge, and the term “paradoxical anxiety” entered the medical lexicon.

“I started looking at how women with breast cancer reacted after going through surgery and radiation.

You would think that they would be happy after finishing treatment, but we found that women were more anxious because they were not being treated anymore and they feared that the tumor would come back,” said Dr. Holland.

Breaking Down Barriers In 1977, Dr. Holland launched the Psychiatry Service at Memorial SloanKettering Cancer Center in New York, the first of its kind in the country.

Nearly 2 decades later, she became the first Chair of the center’s Department of Psychiatry and Behavioral Sciences.

She is currently Attending Psychiatrist and holds the Wayne E. Chapman Chair at the cancer center.

I think we’re on the brink of seeing [psychosocial strategies in routine cancer care] really change in a good way in the next decade. But it’s slow going, and there’s plenty left to be done.

— Jimmie C. Holland, MD

She asked her husband, who was then Chair of the Cancer and Leukemia Group B, to launch a psychiatry committee within the group to study the effects of cancer and its treatment on the mental health of patients. “This is where I found my real heart,” said Dr. Holland. “Because that’s what I was interested in learning: How do people manage catastrophic illness?”

In the early 1970s, Dr. Holland spent a year in Moscow, where she served as a Special Consultant on a National Institutes of Health joint schizophrenic research project (while her husband was a consultant to the Soviet Union for cancer research). In 1973, after returning to New York, she became Assistant

Under her leadership, Memorial Sloan-Kettering’s Psychiatry Service became the country’s leading training and research program dedicated to the field of psycho-oncology, conducting randomized clinical trials to prove that interventions combatting the anxiety and depression associated with cancer care can work. During those early years, Dr. Holland also founded the International PsychoOncology Society and the American Psychosocial Society. All of these efforts helped break down cultural barriers, both for women wanting to purse a career in medicine and for the field of psychiatry.

“When we first came to visit patients, people would say, why are you here? These people are sick, why do

we need psychiatrists?” Dr. Holland said.

Today, hospitals and oncology practices across the country are adding programs to help patients cope with the psychological side effects of cancer, such as anxiety and major depression, which can influence how well patients fare. “Anybody who gets a cancer diagnosis is sad, but if you are so sad that you can’t get out of bed to get your chemotherapy and don’t adhere to treatment, it can alter outcome,” said Dr. Holland.

Measuring Distress According to research Dr. Holland has conducted, one-third of patients with cancer experience clinically significant mental distress. Distress, said Dr. Holland, is the “sixth vital sign” when assessing a patient’s condition, following pulse, breathing, temperature, blood pressure, and pain score.

To help oncologists easily evaluate patients’ distress levels, Dr. Holland and her colleagues at the National Comprehensive Cancer Network developed a “distress thermometer” that measures a patient’s distress on a 0-to-10 scale, similar to the pain scale oncologists use to assess pain. If a patient scores 4 or higher on the distress thermometer, it is a signal that the individual should be further evaluated and, if necessary, referred to a mental health-care specialist and monitored closely.

Long Way to Go In 2008, the Institute of Medicine (IOM) issued a report, Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs,1 which recommended the integration of psychological services into oncology care as a new quality standard for cancer care. The Commission on Cancer, which accredits centers that treat patients with cancer, has mandated that by 2015 providers must have a plan in place to evaluate patients for distress and refer them to programs for help.

How successful these efforts will be in garnering greater clinical attention to the psychological needs of patients remains to be seen. In a 2007 survey of 1,000 oncologists,2 only 14% said they

ASCOPost.com | DECEMBER 15, 2012

PAGE 107

Pioneers in Oncology used an evidence-based screening tool to measure stress in their patients.

“We still have a long way to go,” Dr. Holland admitted. “But [the 2015 mandate] is a foot in the door.”

The IOM report is already having an impact, with the Union for International Cancer Control, World Health Organization, and more than 45 other

TE A D E H SAVE T American Psychosocial Oncology Society

10th Annual Conference From Psychosocial Oncology to Oncology Supportive Care Services: New Evidence, Standards and Models for Patient-centered Care

February 14 - 16, 2013

Huntington Beach, California

For more information, visit

www.apos-society.org

international societies endorsing the IOM recommendation. Such support is helping to cement recognition of the importance of psychosocial strategies in routine cancer care.

“I think we’re on the brink of seeing things really change in a good way for us in the next decade,” said Dr. Holland. “But it’s slow going, and there’s

plenty left to be done.”

At 84, Dr. Holland plans to be around to witness the full success of her 4-decade-long effort.

“I’m still having too much fun to retire,” she said.

■

References 1. Committee on Psychosocial Services

to Cancer Patients/Families in a Community Setting; Adler NE, Page AEK (eds): Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs. Washington, DC, National Academies Press, 2008.

2. Pirl WF, Muriel A, Hwang V, et al: Screening for psychosocial distress: A national survey of oncologists, J Support Oncol 5:499-504, 2007.

The ASCO Post | DECEMBER 15, 2012

PAGE 108

Patient’s Corner Gastrointestinal Oncology

I Am Not a Victim

Cancer has given me a sense of urgency to make my life count.

By Margo Chevers, as told to Jo Cavallo

S

ix years ago, at age 62, I was feeling in great shape. The year before, I had taken over custody of my 2- and 3-year-old great-grandchildren and decided to change the course of my career from motivational speaker to motivational coach to be home more often with the kids. It was during one of our playtimes that I discovered I wasn’t in such great shape after all. I was on the floor with the children, and my greatgranddaughter straddled my stomach and sat down really hard. The pain I experienced was something I had never felt before. It was so unexpected and so unusual, I knew immediately something was wrong and saw my primary care physician.

Although my doctor could feel a mass in my lower-right intestinal area, neither a sonogram nor an MRI clarified the scope and exact location of the mass. Because the tumor looked like it was on my uterus, I was sent to a gynecologist, who then sent me to a gynecologic oncologist. A new CT scan showed that the tumor had moved from my right side to my left side, and it was growing. I was told I needed a complete hysterectomy.

As I was being prepped for surgery, and while I was under anesthesia, the tumor burst. Once the surgery began, my doctor discovered that the tumor

was actually located on my small bowel, and he called in another specialist who biopsied the tumor. The diagnosis was gastrointestinal stromal tumor (GIST).

Getting Disease Control Although my oncologist never gave me a prognosis, I later learned from my own research that overall survival with this cancer was usu-

currence. But six months after that, the tumor recurred on my bladder, and I was put on sunitinib (Sutent).

While the drug seemed to stabilize the growth of the tumor, it didn’t eliminate it, so I had a second surgery in 2008.

Since then, I’ve been whipsawing between imatinib and sunitinib to keep the cancer at bay, but the side effects from both drugs are difficult

I can advocate for better care by staying up to date on the latest advances in treatments for GIST and working with my oncology team to make the best medical decisions.

—Margo Chevers

ally less than 2 years. I’m glad I didn’t know that then.

Because my mutation status involved KIT exon 9, I was eligible to participate in a randomized doubleblind, placebo-controlled trial of imatinib (Gleevec). Six months into the trial, my oncologist called to say that I was on the placebo and that he wanted me to start taking the drug because the trial had shown that it helped reduce the risk of tumor re-

for me to tolerate. In January 2012, I had a third surgery to remove another tumor recurrence—this time back at the original site on my small intestine—and I’ve been on a lower dose of adjuvant sunitinib ever since. I’ll know soon whether it has kept the tumor from recurring.

Staying Ahead of Cancer I know that there is a possibility that sunitinib will fail, but I also know that

GIST is getting a lot more attention now and that there are several promising drugs being tested in clinical trials.

That gives me hope. Any anxiety or worry I have isn’t for me; I’m not afraid of dying. I see having cancer as one more challenge in my life, and I never ask, “Why me?”

My concern is for my great-grandchildren and making sure that I’m around long enough to see them through their adolescent years. I can’t change the fact that I have cancer any more than I can change the fact that I have blue eyes. But I can advocate for better care by staying up to date on the latest advances in treatments for GIST and working with my oncology team to make the best medical decisions—and even challenging my doctors when I don’t agree with what they want to do.

Although I expect to live a long time, I’m also realistic that that may not be possible. Having that realization has created a sense of urgency to live my life more fully, give back to my community through volunteerism, and enjoy every day. Raising my greatgrandchildren has given my life even more purpose and an even greater desire to make sure that I do whatever I have to do to stay well.

■

Margo Chevers is a motivational coach living in Wales, Massachusetts.

Contact The ASCO Post Advertising

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ASCOPost.com | DECEMBER 15, 2012

PAGE 109

Announcement

Dr. Lewis C. Cantley to Lead New Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital

L

eading cancer researcher Lewis C. Cantley, PhD, has been named Director of the newly established Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital. According to Weill Cornell Medical College’s new Dean, Laurie H. Glimcher, MD, and NewYork-Presbyterian Hospital’s CEO, Steven J. Corwin, MD, the recruitment and appointment of Dr. Cantley marks a critical step in the transformation and acceleration of personalized translational medicine, research, and clinical care for cancer patients at the two facilities on the Upper East Side of Manhattan.

Dean of Weill Cornell Medical College and Provost for Medical Affairs at Cornell University.

“We are thrilled about the formation of this new Cancer Center, as it

will propel us to greater heights in cancer research and patient-centered clinical care,” said Dr. Corwin. “Together with Weill Cornell Medical College, we are committed to making NewY-

ork-Presbyterian the preeminent academic medical center for cancer care in the country. The recruitment of Dr. Cantley puts us one step closer to making that goal a reality.”

■

INSIGHT

NEW IN EVERY ISSUE OF

JNCCN

NEW

Lewis C. Cantley, PhD

Read the December Issue of JNCCN: • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Rectal Cancer NEW

Dr. Cantley is the William Bosworth Castle Chair in Medicine and Professor of Systems Biology at Harvard and Director of the Cancer Center and Chief of the Division of Signal Transduction at Beth Israel Deaconess Medical Center, Boston. He is one of the world’s preeminent scientists in both basic and clinical research, having made significant advances stemming from his discovery of the signaling pathway phosphoinositide 3-kinase (PI3K) in the mid-1980s. For the past 3 decades, has worked to identify new treatments for cancers that result from defects in the pathway.

NCCN Guidelines® Insights: Non–Hodgkin’s Lymphomas In this new section, Panel members shed light on the process behind the creation of the NCCN Guidelines, clarifying why and how these important decisions are made.

• Strategies for Optimizing the Clinical Impact of Immunotherapeutic Agents Such as Sipuleucel-T in Prostate Cancer • Stereotactic Ablative Radiotherapy for Non–Small Cell Lung Cancer: Rationale and Outcomes • Controversies in Radiation for Upper Rectal Cancers

New Role As Director, Dr. Cantley will forge the Cancer Center into a collaborative, multidisciplinary research enterprise focused on gathering Weill Cornell’s basic, translational, and clinical research expertise under one umbrella, across faculty and departments, and converting cancer research breakthroughs into novel therapies that offer patients immediate access to the latest advanced care available and hope for the future.

“We are honored and delighted to have Dr. Cantley, a pioneering researcher in the field of cancer, join us to lead the new Cancer Center,” said Dr. Glimcher, who is Stephen and Suzanne Weill

Register for your free subscription at JNCCN.org

DOWNLOAD THE JNCCN APP Visit the iTunes store or use your QR code reader to download the JNCCN mobile application.

The ASCO Post | DECEMBER 15, 2012

PAGE 110

In the News Cost of Care

MSKCC’s Decision Not to Purchase New Cancer Drug Sparks Editorial and Unprecedented Actions

By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit.

This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

“A

t Memorial Sloan-Kettering Cancer Center, we recently made a decision that should have been a no-brainer: we are not going to give a phenomenally expensive new cancer drug to our patients.” That was the opening sentence of a New York Times op-ed piece written by three physicians from Memorial Sloan-Kettering Cancer Center (MSKCC) in New York.1 In an interview with The ASCO Post, one of those physicians, Leonard B. Saltz, MD, Chief of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center, expressed optimism that the article could itself serve to open a dialogue about the staggeringly high costs of some cancer drugs and the financial strains those costs impose.

Cancer Network (NCCN) do not say one drug is better than the other as an option for second-line therapy.

Dr. Saltz explained that the guidelines do note that the second-line choice should be either ziv-aflibercept or bevacizumab, but not one and then the other. He also said that there has been some “concern that ziv-aflibercept appeared to exacerbate the toxicity of the chemotherapy it was given with to a greater degree than we see in bevacizumab studies.”

Based on available data and comments from physicians who focus on gastrointestinal oncology at MSKCC and its network, Dr. Saltz recommended to the MSKCC Pharmacy and Therapeutics Committee, which he chairs, “that we defer adding it to the formulary at this time, until such time as there may be different data that would make us reconsider. That was the recommendation that the formulary committee accepted,” Dr. Saltz said. “This is somewhat unprecedented, to the best of my knowledge,” he said, “because I am not aware of another new FDA-approved drug for cancer that we have not made a formulary item at Sloan-Kettering.”

Shot Heard ’Round the World

Leonard B. Saltz, MD

Unprecedented Decision The op-ed article explained that physicians at MSKCC had chosen not to use ziv-aflibercept (Zaltrap) because the drug “has proved to be no better than a similar medicine we already have for advanced colorectal cancer,” identified as bevacizumab (Avastin), “while its price—at $11,063 on average for a month of treatment—is more than twice as high.” The authors noted that ziv-aflibercept and bevacizumab offered similar survival benefits to patients with advanced colorectal cancer, about 1.4������������������������� months ������������������������ compared to standard chemotherapy alone, and that major clinical guidelines such as those from the National Comprehensive

The physicians’ editorial has elicited strong responses. Harold J. Burstein, MD, PhD, a medical oncologist at Dana-Farber Cancer Institute in Boston and Editor-in-Chief of the Journal of the National Comprehensive Cancer Network, 2 stated in an editorial in that journal that “the decision at MSKCC, and more particularly its public declaration, may serve as a shot heard ’round the world for voluntary limits on the use of expensive oncology drugs.”

Less than 1 month after the op-ed article appeared in The New York Times, that newspaper reported that Sanofi, which together with Regeneron Pharmaceuticals, developed and markets ziv-aflibercept, would offer discounts of about 50% on the drug.3 The Sanofi statement quoted by The New York Times read: “We believe that Zaltrap is priced competitively as used in real-world situations. However, we recognize that there was some market resistance to the perceived relative price of Zaltrap in the U.S.—especially in light of low awareness of Zaltrap in the U.S. market. As

Expect Questions and Respond with Reasoned Explanations

“S

oaring spending has presented the medical community with a new obligation. When choosing treatments for a patient, we have to consider the financial strains they may cause alongside the benefits they might deliver,” three physicians from Memorial Sloan-Kettering Cancer Center (MSKCC) in New York asserted in an op-ed piece in The New York Times.1 Noting that 1 in 10 patients with cancer now reports spending more than $18,000 out of pocket for care, the MSKCC physicians also cited a study finding that 2% of patients with cancer were driven into bankruptcy by the disease and its treatment.

When patients bring up the costs of medications and say they are not filling prescriptions because they can’t afford it, these are usually the ancillary medications, such as low-molecular-weight heparin or advanced antinausea regimens, where the copays can be hefty, according to Leonard B. Saltz, MD, one of the article’s authors. “If the copays are for chemotherapy agents, then patients will be quite vocal with their doctors about whether they can afford to keep doing this or not.”

Honest and Open Discussion When that happens, “physicians can discuss honestly and openly with patients what the incremental benefits are of one approach vs another and try to work with them to better understand their options. Is this, in fact, a bill they’re unable to pay—in which case, what are the alternatives—or is this a bill they would rather not pay, but if looked at more closely, might be worth it to them?” Dr. Saltz asked.

“There are so many different scenarios,” he continued. “You could have a person who truly doesn’t have the means, or you could have a person who is quite well off but is just indignant about having to pay for some aspect of health care because, as Americans, we tend to think that whatever third party is paying ought to pay for everything.”

In the case where two agents offer similar benefits but differ in cost and toxicity, patients need to know the facts to make decisions for themselves. “To say to a patient, ‘I am going to save money by giving you a more toxic agent,’ is not something that most people would care to accept,” Dr. Saltz said. But if the patient was spending a lot of money on treatment and the less expensive agent offered “substantial savings and an acceptable toxicity,” then “you might have that kind of conversation,” Dr. Saltz said. In current practice, he added, that conversation is not very likely to occur.

■

such, we are taking immediate action across the U.S. oncology community to reduce the net cost of Zaltrap.”

Insufficient Solution A New York Times editorial4 called the offer to reduce the cost of the drug “a heartening sign that alert and aggressive physicians can potentially play a major role in helping to reduce the escalating costs of health care for treatments of marginal value.” Dr. Saltz, however, noted that giving discounts doesn’t adequately address the issue.

“When you give a discount, it doesn’t affect reimbursement from Medicare and it doesn’t affect copay,” Dr. Saltz explained. “Just to put it in round numbers

for a thought experiment, if you had a drug that sold for $1,000, Medicare pays 95% of that wholesale acquisition cost, so Medicare would reimburse the doctor $950. If the patient has a 20% copay, the patient’s copay would be $200.

Now if you lowered your wholesale acquisition cost down to $500, then the doctor would get reimbursed at 95% of that, and the patient would pay 20% of that,” he said. However, if the official wholesale acquisition price is kept at $1,000, then discounted 50%, “now the doctor is getting the drug for $500, but the doctor or the hospital, whoever is the purchaser, would still be reimbursed at $950, and the patient would still be continued on page 114

In metastatic melanoma

MAKE TREATMENT PERSONAL by testing for the BRAF V600E mutation with the cobas test 速

Test at diagnosis.

Test with the cobas 4800 BRAF V600 Mutation Test. 速

Only FDA-approved BRAF PCR diagnostic1 20% more accurate than Sanger Sequencing with fewer false negatives and invalid results1

Indication and Usage: ZELBORAF速 (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.

Please see Brief Summary of Prescribing Information and next page for Important Safety Information.

dEcodE metastatic melanoma.

ExtEnd

Significant improvement in OS vs dacarbazine in a randomized Phase III trial of BRAFV600E(+) patients (N=675)* OS at FDA approval (August 2011)†‡ 100

HR=0.44 (95% CI, 0.33-0.59), P<0.0001

Percentage surviving

80 60

Not reached

7.9

40

OS=overall survival HR=hazard ratio CI=confidence interval *Patients crossing over to ZELBORAF were censored.2

20 0

0

2

4

6

8

10

12

14

16

18

20

22

At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine.

‡

There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

24

OS (months) ZELBORAF (n=337)

†

Dacarbazine (n=338)

Median OS was not reached (NR) for ZELBORAF vs 7.9 months for dacarbazine (95% CI, 9.6 months-NR vs 7.3-9.6 months) The most common (≥30%) adverse reactions of any grade 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 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) The incidence of cuSCC, including both SCCs of the skin and keratoacanthomas, was 24%.

Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months after therapy. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care.

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

Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported.

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

QT prolongation Exposure-dependent QT prolongation has been reported, 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.

Monitor ECG and electrolytes before treatment and after dose modification. Monitor ECGs at day 15, monthly during the first 3 months of treatment, every 3 months thereafter, or more often as clinically indicated.

If the QTc exceeds 500 ms, temporarily interrupt ZELBORAF, correct electrolyte abnormalities, and control cardiac risk factors for QT prolongation. Re-initiate treatment 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.

Monitor liver enzymes and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation.

Photosensitivity Mild to severe photosensitivity has been reported.

Advise patients to avoid sun exposure and use adequate sun protection. For intolerable grade 2 or greater photosensitivity, dose modifications are recommended.

Ophthalmologic Reactions Serious ophthalmologic reactions, including uveitis and retinal vein occlusion, have been reported.

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

Routinely monitor patients for uveitis.

SURVIVAL Updated Significant OS improvement confirmed in an updated analysis3§ OS update at ASCO 20123||¶ 100

HR=0.70 (95% CI, 0.57-0.87), P<0.001

Percentage surviving

80 60

13.6 9.7

40

ASCO=American Society of Clinical Oncology

20 0

0

2

4

6

8

10

12

14

16

18

20

22

Patients crossing over to ZELBORAF were censored.3

||

At the time of updated analysis, median follow-up was 12.45 months (range, 0.4-24.0 months) for ZELBORAF patients vs 9.45 months (range, 0.0-22.5 months) for those taking dacarbazine.3,4

¶

At the time of the ASCO 2012 updated analysis, there were 199 deaths and 166 deaths in the ZELBORAF and dacarbazine arms, respectively.4

24

OS (months) Updated analysis of ZELBORAF

§

Updated analysis of dacarbazine

Median OS reached at 13.6 months with ZELBORAF: ~4-month improvement over dacarbazine median OS of 9.7 months (95% CI, 12.0-15.2 months vs 7.9-12.8 months)3,4

Additionally, blurry vision, iritis, and photophobia were observed.

New Primary Malignant Melanoma New primary melanomas were reported in the Phase III study.

Cases were managed with excision and patients continued treatment without dose adjustment; monitor for skin lesions as outlined on previous page [see cuSCC].

Use in Pregnancy: Pregnancy Category D Apprise patients who are pregnant or who may become pregnant that ZELBORAF may cause fetal harm.

BRAF Testing Confirmation of BRAFV600E(+) melanoma is required for appropriate patient selection. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma.

Most common adverse events The most common (≥30%) adverse reactions of any grade 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 accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

References: 1. cobas® 4800 BRAF V600 Mutation Test Package Insert. Roche Molecular Systems, Inc. August 2011. 2. Center for Drug Evaluation and Research. Clinical review—NDA 202429: ZelborafTM (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/ 202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed July 23, 2012. 3. Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. Presented at: the 48th Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 8502. 4. Data on file. Genentech, Inc.

© 2012 Genentech USA, Inc. All rights reserved. BRF0000653202 Printed in USA.

zelboraf.com

The ASCO Post | DECEMBER 15, 2012

PAGE 114

In the News

MSKCC Decision

Best Customer Gets Worst Price

continued from page 110

required to pay $200 on the copay.

What this does is to create, at best, an inducement—harsher words have been used—for a doctor to use the drug, and it isn’t something that deals on a societal level with the cost of the drug.”

ZELBORAF ® (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. 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

Dr. Saltz said the op-ed article received so much attention because “this was the elephant in the room that nobody was talking about. There is a tremendous amount of concern about the issue of cost, and it isn’t just reflective of one drug. This was a starting point for discussion,” he said.

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.

“We are trying to open a dialogue, not start a revolution,” he continued.

“But there have been enormous impediments to getting that dialogue going.”

One of the major impediments was spelled out in the op-ed article. “By law, Medicare must cover every cancer drug the FDA approves. (A 2003 law, moreover, mandates payment at the price the

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 Pruritus 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

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7

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12

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10

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14

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*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

BRF0000422001 Initial U.S. Approval: August 2011 © 2012 Genentech, Inc

manufacturers charge, plus a 6% cushion.) In most states, private insurers are held to this same standard,” he added.

“We have a situation where it is not a free market, and we can’t afford to pretend that it is,” Dr. Saltz said. “Virtually everything is bought by a third party, and the largest customer is the government.

We have laws that require the government to pay whatever wholesale acquisition costs the pharmaceutical company

[T]his was the elephant in the room that nobody was talking about. There is a tremendous amount of concern about the issue of cost, and it isn’t just reflective of one drug.

This was a starting point for discussion.

—Leonard B. Saltz, MD

sets. And we have laws that say that the government, which is the largest purchaser, is forbidden from negotiating for a better price. I don’t know any other scenario where your best customer gets the worst price. This is an illogical and unsustainable system,” he contended.

“I don’t think it is reasonable to expect that a publicly held pharmaceutical company with a fiduciary responsibility to its shareholders will, of its own volition, lower its price,” he added. “It would be nice if there were regulations that had some means of keeping controls on the price, but we don’t have that.”

Dr. Saltz said that he and the other authors of the op-ed piece, Peter B. Bach, MD, Director of the Center for Health Policy and Outcomes at MSKCC, and Robert E. Wittes, MD, Physician in Chief, considered it “unlikely that the conversation would start unless somebody took a leap and started it. We decided that we were appropriate people to do that.”

Confronting the Costs Confronting the reality of the high costs of cancer treatment means being willing to acknowledge that some treatments that seemed very promising may not prove to be such good ideas after all, and that everyone can’t get everything for free. From the public health standpoint, “the purpose of the copay is to create a continued on page 115

ASCOPost.com | DECEMBER 15, 2012

PAGE 115

Expert’s Corner Best Practices

Promoting a More Balanced Approach to Cancer Prevention and Treatment A Conversation with Margaret I. Cuomo, MD

Photo credit: Richard Marchisotto

By Ronald Piana

Margaret I. Cuomo, MD

M

argaret I. Cuomo, MD, is a boardcertified radiologist who served for many years as an attending physician in diagnostic radiology at North Shore University Hospital, Manhasset, New York. Dr. Cuomo is the daughter of former New York Governor Mario Cuomo and sister to Governor Andrew Cuomo.

She is also the author of the recently published treatise, A World without Cancer: The Making of a New Cure and the Real Promise of Prevention (see page 92). The ASCO Post spoke with Dr. Cuomo about the book’s thought-provoking themes.

Misplaced Priorities In your book, you state that you strongly believe our priorities [regarding cancer treatment] are misplaced. Please expand on that sentiment.

Another statement in the book that echoed mine is from Dr. Ronald Herberman: “We are stuck in a paradigm of treatment.” And many other prominent researchers that I interviewed shared the feeling that we are stuck in a status quo of treatment. However, we have enough financial and intellectual resources to address both issues, improving treatment and prevention.

What we have now is not a balanced

MSKCC Decision continued from page 114

certain amount of economic restraint on the decision to use or not use an agent,” Dr. Saltz said. “The idea is, if everything costs nothing, no one has any incentive to think carefully about whether it is an appropriate expenditure or not. The copay is designed to cause the patient, and therefore the doctor, to say, ‘Wait a minute. Is this worth it?’” he added.

“The harsh reality is, we can’t afford as a society to give everything to every-

approach, because we are not dedicating enough attention to prevention.

I also mentioned the President’s Cancer Panel, a body of three appointees who are charged with monitoring the nation’s cancer program. In 2010 and 2011, the panel held meetings built around the theme, The Future of Cancer Research: Accelerating Scientific Innovation. Their report found that the areas of cancer prevention and early detection are inadequately addressed.

Several years later, I see little to indicate that we’re implementing the changes advised by the President’s Cancer Panel. The NCI’s budget allocates only about 2% for cancer prevention. So there’s a real disparity in the way our resources are being allocated, leaving a lot of work to do in that area.

Drug Approval Considerations You stress the need for having value

instance, Memorial Sloan-Kettering Cancer Center has indicated that it would not give [ziv-aflibercept (Zaltrap)] to patients with colon cancer due to the drug’s exorbitant price—about $11,000 per month—and the associated meager improvement in median survival of only about 1.4 months. Memorial Sloan-Kettering made the point that [bevacizumab (Avastin)] offers the same survival time with less cost. So a major cancer center made a value decision, which is a huge step forward.

The larger point to be made on a national level is that current drug pricing practices are unsustainable. No other market works this way. If you were to make a product that is equal in value to another product but you charged twice the price, you’d go bankrupt. We need to have a serious discussion on the national level about introducing cost and value into our cancer drug pipeline.

It is up to the oncology community to advocate and lobby for the integration of preventive services as part of best practices. We have the resources; we just need the resolve.

—Margaret I. Cuomo, MD

and cost-effectiveness integrated into the drug approval process. Do you think that’s an achievable goal?

Yes, it is. For the book, I interviewed Dr. John Marshall and Dr. Ezekiel Emanuel, and they both stressed that of all the world’s industrialized nations, the United States stands alone as the only country that does not include an element of value in its drug evaluation process.

But value is trending upward. For

Moving Prevention Forward

one for free,” he reiterated. “There is no aspect of society in which we do that. We don’t do it for food. We don’t do if for shelter. We can’t do it for medicine.” To provide everyone access to basic health care, “we are going to need some means of making that health-care affordable, and that means we are going to have to be somewhat selective in deciding what health care we can afford,” Dr. Saltz said.

He noted that sometimes just the mention of controlling health-care costs “is labeled rationing, and rationing is

considered a bad thing. I don’t agree with that position. I believe that realistically in our economy, we ration everything. We look at the incremental cost and benefit of something, and we make decisions on how much as a society we are willing to pay for, and to what degree we are able to make it available to everybody, or alternatively, whether something should be available to someone who can afford it and not available to others.”

You make a strong case for prevention, noting that more than 50% of all cancers are preventable. Do we need moon shot– like leadership effort to move prevention forward?

We need a coordinated effort that is centralized under one roof, so to speak. That is why I proposed the National Cancer Prevention Institute, a federal entity that would focus our attention on prevention.

■

Disclosure: Drs. Saltz and Burstein reported no potential conflicts of interest.

This issue needs the kind of leadership that President Kennedy showed when he delivered his speech at Rice University in Houston, saying, “We choose to go to the moon … not because [it is] easy, but because [it is] hard.” He set a time frame of 10 years, and the mission was accomplished in 8 years. It happened because we rallied around a task and created a truly collaborative effort. That’s what we need in the cancer prevention arena.

Closing Thoughts Any last thoughts you’d like to share about your book?

In 2002, ASCO demonstrated its commitment to cancer prevention by establishing the standing Cancer Prevention Committee. The Society did that to ensure the integration of prevention into the practice of oncology. It was a progressive initiative. In 2004, the Cancer Prevention Committee conducted a survey of community oncologists, asking about the barriers they faced in offering prevention-oriented messages to patients.

Three-fifths of the oncologists cited economic barriers to offering those services—in other words, insufficient reimbursement.

That was 10 years ago. Is it any different today? The medical community is a major stakeholder in this issue, and it is up to us to advocate for adequate reimbursement for delivering prevention services. It is up to the oncology community to advocate and lobby for the integration of preventive services as part of best practices. We have the resources; we just need the resolve.

■

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

References 1. Bach PB, Saltz LB, Wittes RE: In cancer care, cost matters. New York Times.

October 14, 2012.

2. Burstein HJ: A “shot heard ’round the world” on cancer drug costs? J Natl Compr Canc Netw 10:1315-1316, 2012.

3. Pollack A: Sanofi halves price of cancer drug Zaltrap after Sloan-Kettering rejection. New York Times. November 8, 2012.

4. Incredible prices for cancer drugs (editorial). New York Times. November 12, 2012.

The ASCO Post | DECEMBER 15, 2012

PAGE 116

In the Literature

Emerging Clinical Data on Cancer Management GLIOMA Early Surgical Treatment of Low-grade Glioma Improves Survival vs Watchful Waiting In a comparison of surgical treat-

ment strategies for low-grade gliomas, patients in Norway treated at a hospital that generally favored early surgical resection had better overall survival than patients treated at a hospital that favored diagnostic bi-

opsy and watchful waiting, according to a study published in the Journal of the American Medical Association and presented at the Annual Meeting of the European Association of Neurosurgical Societies.

2012CLINICAL CANCER ADVANCES

The 2012 CCA Report is now available.

Get the full report today to learn about this year’s top cancer research findings and the policy updates shaping the future of care.

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Study Details The study included patients 18 years or older with diffuse low-grade gliomas (World Health Organization grade 2) treated at two Norwegian university hospitals with different treatment strategies—diagnostic biopsies and watchful waiting vs early resections. “Both neurosurgical departments are exclusive providers in adjacent geographical regions with regional referral practices,” the authors noted. Thus, they explained, the treatment strategy for a given patient has depended on where the patient lives.

Following a blinded histopathologic review to ensure uniform classification and inclusion, 153 patients with diffuse low-grade gliomas (91% of the screened cohort) were identified and included in the study; 66 patients (43%) from the center favoring biopsy and watchful waiting and 87 patients (57%) from the center favoring early resection.

“There were large regional differences in treatment strategies,” the researchers reported, “as biopsy and subsequent watchful waiting was the initial strategy in 47 (71%) of [lowgrade glioma] patients served by the center favoring biopsy and watchful waiting compared with only 12 (14%) served by the center favoring early resection (P < .001).” The researchers found “no significant differences in surgical complications (9% vs 8%; P = .82) or acquired deficits (18% vs 21%; P = .70) between centers. Later malignant transformation was more common when biopsy only was the favored initial management (56% vs 37%; P = .02).”

Overall survival was significantly longer for patients treated at the center favoring early resection, and the survival advantage increased with time. While 1-year survival rates were equal at 89%, the expected survival rates were 70% vs 80% at 3 years, 60% vs 74% at 5 years, and 44% vs 68% at 7 years. At the center favoring biopsy, median survival was 5.9 years, whereas at the center preferring initial resection, median survival had not been reached at the time of the report.

“Despite the clear survival advantage seen, clinical judgment is still necessary in individual patients with suspected [low-grade glioma] since results will depend on patient and disease characteristics together with

ASCOPost.com | DECEMBER 15, 2012

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In the Literature

surgical results in terms of resection grades and complication rates,” the authors stated. “Nevertheless, based on the observed regional survival difference in the present study, both involved centers now advocate early resections as the initial recommendation in most patients.” The researchers concluded that the survival benefit “significantly strengthens the data” supporting early resection in patients with newly diagnosed lowgrade glioma.

Commentary In an accompanying editorial, James M. Markert, MD. of the University of Alabama at Birmingham, wrote that “although class I evidence for surgical resection of [low-grade glioma] remains lacking,” National Comprehensive Cancer Network practice guidelines in oncology support the use of maximal safe resection as feasible first-line treatment for low-grade glioma. He added that most, but not all, studies published in the past 2 decades “support this approach as well,” and the current study “adds further evidence for this approach. A follow-up study of their cohorts, allowing for more definitive measurement of survival and more rigorous assessment of complications, neurologic deterioration, and malignant degeneration, would be valuable.”

Jakola AS, et al: JAMA 308:1881-1888, 2012.

Markert JM: JAMA 308:1918-19198, 2012.

BREAST CANCER Small Increase in Cardiac Events for Trastuzumab plus Anthracycline in HER2-positive Disease A 7-year follow-up of the phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-31 found that the cumulative difference in the rate of cardiac events was 3.1% between patients with HER2-positive, node-positive breast cancer who received trastuzumab (Herceptin) in addition to chemotherapy that included an anthracycline and taxane and those who did not receive trastuzumab. “The risk vs benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab,” the investigators concluded in the Journal of Clinical Oncology.

Study Design Patients were randomly assigned to receive four cycles of AC (doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2), followed by either four cycles of paclitaxel at 175 mg/m2 every 3 weeks or 12 weekly doses of paclitaxel at 80 mg/m2 (ACP), with or without weekly trastuzumab at 4 mg/kg loading dose, then 2 mg/kg (ACHP) for 52 weeks.

To be eligible for NSABP B-31, patients must have completed breast surgery and axillary dissection and have had no evidence of distant metastatic disease. Patients were not given trastuzumab if they developed symptomatic myocardial dysfunction during AC therapy, demonstrated an asymptomatic absolute decline in left-ventricular ejection fraction of more than 15% from baseline value after AC, or had a post-AC left-ventricular ejection fraction below the local institution’s lower limit of normal.

“As a result, the formal cardiac study was restricted to patients in either arm whose post-AC cardiac function met the criteria to allow initiation of trastuzumab,” the researchers noted. To be considered evaluable, patients must also have received at least one dose of post-AC therapy.

Key Data A cardiac event was defined as “a definite or probable cardiac death or congestive heart failure manifested by dyspnea with normal activity or at rest and associated with an absolute decrease in [left-ventricular ejection fraction] of greater than 10 percentage points from baseline to a value less than 55% or a decrease of more than 5% to a value below the lower limit of normal,” the authors noted.

Among 944 patients who received trastuzumab, 37 (4%) experienced a cardiac event. Among 743 patients who did not receive trastuzumab, 10 (1.3%) experienced a cardiac event, for a difference of 2.7%.

The relative risk of a cardiac event was 3.30 among trastuzumab recipients vs control patients (95% CI = 1.63–6.66; P < .001), the researchers reported. Only two cardiac events occurred more than 2 years after the initiation of trastuzumab therapy, and one cardiac-related death occurred in each group of patients.

“Most patients in B-31 who discontinued trastuzumab as a result of symptomatic or asymptomatic [cardiac dysfunction] have recovered [left-

ventricular ejection fraction] measurements ≥ 50%. In all, 36 patients (3.8% of the entire evaluable cohort) who discontinued trastuzumab for cardiac reasons have persistent [left-ventricular ejection fraction] values less than 50%,” the investigators reported.

Practical Implications While trastuzumab given concurrently with or after adjuvant chemotherapy has been shown to improve disease-free and overall survival patients with early-stage HER2-positve breast cancer, regimens including trastuzumab have been associated with cardiac dysfunction, especially when those regimens also include an anthracycline. “Given the demonstrated efficacy of trastuzumab, it is critical to identify risk factors that predispose patients to [cardiac dysfunction] and, conversely, to identify patients who may gain considerable clinical benefit from this regimen with minimal cardiac risk,” the researchers said.

On the basis of pretreatment risk factors for a cardiac event, the investigators developed a Cardiac Risk Score “that may provide a tool for estimating cardiac risk associated with the addition of trastuzumab to paclitaxel after AC. This model conforms closely with B-31 data but should be validated in other studies using similar chemotherapy regimens,” the researchers stated.

They noted that cardiac history forms continue to be submitted annually on patients enrolled in B-31 and that a long-term quality-of-life and cardiac assessment for those remaining disease-free is underway.

Reassuring Results “In summary, 7-year follow-up of NSABP B-31 demonstrates a striking and reassuring lack of longer-term cardiac events,” according to an editorial accompanying the study report. “Over the long run, we hope to see the development of highly efficacious adjuvant treatments for HER2-positive breast cancer with substantially less risk of toxicity than current standards,” the editorialists wrote. They noted that preliminary reports for “novel HER2directed agents,” including trastuzumab emtansine (T-DM1) and trastuzumab combined with pertuzumab (Perjeta) or with lapatinib (Tykerb) “have suggested a low risk of cardiac toxicity.”

Romond EH, et al: J Clin Oncol 30:37923799, 2012.

Mayer EL, Lin NU: J Clin Oncol 30:3769-3772, 2012.

SARCOMA Interval-compressed Chemotherapy More Effective with No Increase in Toxicity A randomized controlled trial among patients with newly diagnosed localized Ewing sarcoma found that “chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity,” investigators from the Children’s Oncology Group reported in the Journal of Clinical Oncology. At 5 years, eventfree survival, the primary endpoint of the trial, was 73% for patients receiving chemotherapy every 2 weeks, compared with 65% for patients receiving chemotherapy every 3 weeks (P = .048). This translates to a 22% decrease in risk of recurrence, the researchers noted.

Overall survival was 83% for patients in the 2-week group vs 77% for those in the 3-week group. “The superiority of the intensified arm in overall survival just misses conventional statistical significance (P =.056); although relapsed Ewing sarcoma is rarely cured, patients often survive from several months to a few years after relapse, causing survival to lag behind [event-free survival],” the researchers added.

“In the absence of new effective agents for Ewing sarcoma, the Children’s Oncology Group focused on improving outcome by increasing chemotherapy dose-intensity,” the investigators explained. Patients received a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with the cycles to start every 14 or 21 days provided patients had an absolute neutrophil count greater than 750 × 106/L and a platelet count greater than 75 × 109/L. Between cycles, patients received filgrastim (Neupogen, 5 mg/kg/d; maximum, 300 mg).

“Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm),” the authors explained. Each arm had 284 patients. “The primary continued on page 119

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PAGE 119

In the Literature

Emerging Clinical Data on Cancer Management continued from page 117

site could be bone or soft tissue, but not intradural soft tissues,” according to the eligibility criteria, and patients could have no evidence of metastatic disease.

“The use of filgrastim in our study was critical,” the researchers reported.

“Pegylated filgrastim (pegfilgrastim [Neulasta]) came to market shortly before this study opened. Although it offers the advantage of a single injection rather than a series of 10 to 14 daily injections, we forbade its use because of a lack of experience with either interval compression or children. It now seems that pegfilgrastim also permits interval compression with similar effectiveness to filgrastim in children.”

Womer RB, et al: J Clin Oncol 30:41484154, 2012.

LIVER CANCER Lower Risk of Recurrence in Patients with HBV-related Liver Cancer Receiving Nucleoside Analogs Patients with hepatitis B virus (HBV)-related hepatocellular carcinoma who received nucleoside ana-

logs after curative liver resection had an associated lower risk of hepatocellular carcinoma in a nationwide cohort study using data from the Taiwan National Health Research Data Base. The study was reported in the Journal of the American Medical Association and presented at the Annual Meeting of the American Association for the Study of Liver Diseases.

Study Rationale Higher HBV viral load is an independent risk factor for recurrence of HBV-related hepatocellular carcinoma, and nucleoside analogs are effective in suppressing HBV replication and ameliorating HBV-related liver disease, the researchers explained. Nevertheless, studies of nucleoside analog use in hepatocellular carcinoma recurrence “have been relatively limited and have yielded conflicting results,” they noted.

The researchers identified 4,569 patients with HBV-related hepatocellular carcinoma who received curative liver resection. The primary outcome measure for the study was the risk of first tumor recurrence between patients not taking nucleoside analogs (untreated group, n = 4,051) and patients taking nucleoside analogs (treated group, n���������������� ��������������� =�������������� ������������� 518). The median age of patients was 54 years, and

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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Position your device in front of the code so that it fills about half your screen.

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more than 80% of the patients in both groups were men.

The researchers found that the treated group had a higher prevalence of liver cirrhosis when compared with the untreated group (48.6% vs 38.7%; P < .001) but a lower risk of hepatocellular carcinoma recurrence (20.5% vs 43.6%), and lower overall death rate (10.6% vs 28.3%).

“After adjusting for competing mortality, the treated cohort had a significantly lower 6-year [hepatocellular carcinoma] recurrence rate,” the researchers reported, 45.6% vs 54.6% for untreated patients (P < .001). The risk of overall mortality was also significantly lower in patients in the treated vs untreated group (6-year cumulative incidence, 29% vs 42.4% (P < .001).

Multivariate analysis revealed that use of statins, nonsteroidal anti-inflammatory drugs (NSAIDs), or aspirin was associated with a lower risk of hepatocellular carcinoma recurrence, the investigators noted. While the protective role of statins in HBV-infected hepatocellular carcinoma has been previously reported, the “association between the use of NSAIDs or aspirin and a lower risk of [hepatocellular carcinoma] recurrence is a novel finding,” they wrote.

Interpreting the Data “The results of this study support findings from multiple smaller studies but are by no means definitive enough to answer the question of whether antiviral therapy after curative resection of hepatitis B-related [hepatocellular carcinoma] will prevent disease recur-

rence,” Anna S. F. Lok, MD, of the University of Michigan in Ann Arbor, stated in an accompanying editorial. “Given the long interval between cell damage, malignant transformation, and tumor development, it is unrealistic to expect that administration of antiviral therapy for 1 to 2 years can prevent [hepatocellular carcinoma] recurrence, particularly because early recurrence is likely due to previously undiscovered metastasis from the primary tumor.”

Nevertheless, Dr. Lok continued, nucleoside/nucleotide analogs “may decrease short-term mortality after liver resection, particularly among patients with underlying cirrhosis, high levels of HBV replication, or active hepatic inflammation.” For patients who do not show early hepatocellular carcinoma recurrence, continued therapy with these agents may prevent new primary tumors and further disease progression, thereby decreasing late recurrence and long-term mortality.

“Further studies with longer duration of treatment and better characterization of HBV replication status and liver disease are needed to determine the magnitude of benefit and to clarify whether nucleoside/nucleotide analogs should be administered to all or a subset of patients after curative treatment for HBV-related [hepatocellular carcinoma],” she concluded.

■

Wu C-Y, et al: JAMA 308:1906-1913, 2012.

Lok ASF: JAMA 308:1922-1924, 2012.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

© Leo Cullum / The New Yorker Collection / www.cartoonbank.com

The ASCO Post | DECEMBER 15, 2012

PAGE 120

Lab Notes

Ongoing Molecular Research in the Science of Oncology BIOMARKERS Role of Glutamate and Effect of Its Blockade in Prostate Cancer

Glutamate plays a role in oncogenic metabolic and signaling pathways. In a recently reported study, Koochekpour and colleagues from the Roswell Park Cancer Institute in Buffalo, NY, investigated potential correlations of

glutamate levels with prostate cancer in patients with primary or castrateresistant metastatic disease.

Univariate and multivariate analyses showed that serum glutamate levels were significantly higher in primary

Read the Expert’s Guide to the

Skin Effects of Cancer For Your

Patients

More people than ever before are living with and surviving cancer. However, even the most promising cancer treatments may cause unexpected side effects to the skin, hair, and nails.

How can your patients navigate these changes while staying on treatment and maintaining some quality of life?

Written for people living with cancer by Dr. Mario Lacouture, an expert in the dermatologic side effects of anticancer medications, this book offers your patients clear information and practical suggestions for preventing, treating, and living through these skin, hair, and nail changes.

Look inside for these important topics!

• Preparation for the rash, itching, or dry skin that may come with cancer treatment • Care for the fingernails, and suggested products that will contribute to their health • Awareness of the risks for hair loss, and resources your patients may need

prostate tumors with Gleason score ≥ 8 than in those with Gleason score ≤ 7, and higher in African Americans—who have a higher mortality rate from prostate cancer—than in Caucasian Americans. Overall, patients with metastatic disease had normal serum glutamate levels, but those with primary prostate cancer had significantly higher levels compared with healthy controls.

African Americans with metastatic disease had significantly higher serum glutamate levels than those with primary prostate cancer or benign prostate. In Caucasian Americans, serum glutamate levels were similar in normal subjects and in patients with metastatic disease.

Immunohistochemistry analysis showed weak or no expression of metabotropic glutamate receptor 1 (GRM1) in luminal acinar epithelial cells of normal or hyperplastic glands, but high expression in primary and metastatic cancer tissues. Glutamate deprivation or blockade with a glutamate receptor antagonist significantly decreased growth, migration, and invasion and induced apoptosis in both androgen-dependent and androgenindependent cancer cells.

As stated by the investigators, their findings suggest that “Glutamate expression is mechanistically associated with and may provide a biomarker of prostate cancer aggressiveness.”

■

Koochekpour S, et al: Clin Cancer Res 18:1-14, 2012.

• Suggested moisturizers and cosmetics that are appropriate for your patients’ use • Specific information for survivors

Available at:

or visit

drlacoutureskincare.com

The ASCO Post

About the Author Mario E. Lacouture, MD Associate Member Memorial Sloan-Kettering Cancer Center New York, NY Mario E. Lacouture, MD, is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. His clinical focus is the recognition and management of the side effects and conditions of the skin, hair, and nails that may arise in cancer patients and survivors as a consequence of surgery, chemotherapy, radiation, or transplantation. His research focuses on exploring new skin treatments that do not interfere with the effectiveness of anticancer medications.

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ASCOPost.com | DECEMBER 15, 2012

PAGE 121

In Memoriam

Past ASCO President, John Ridgway Durant, MD, Dies at 92

By Ronald Piana

John Ridgway Durant, MD

J

ohn Ridgway Durant, MD, ASCO’s 20th President, was born on July 29th, 1930, and died on October 28th, 2012. Dates that mark a person’s birth and passing are made all the more significant by how that person filled the days that link the two milestones. Dr. Durant will be remembered fondly as a man who filled his days and years as a doer-doctor whose clarity of thought and vision helped shape ASCO into the world’s leading professional cancer organization.

Education and Career Highlights Dr. Durant was born and reared in Ann Arbor, Michigan. After graduating from Lower Merion High School in 1948, Dr. Durant entered Swarthmore College in Swarthmore, Pennsylvania, where he earned his BA in 1952.

Pursuing his ambition to become a doctor, he received his medical degree

4 years later from Temple University Medical Center in Philadelphia. After Dr. Durant fulfilled his internship obligations at Hartford Hospital in 1957, he served as Junior Assistant Resident in Medicine at Hartford Hospital in Hartford, Connecticut. He then served as a Lieutenant in the U.S. Navy from 1958 to 1960, and after his discharge, he completed his residency program at Temple University Medical Center.

In 1968, Dr. Durant joined the University of Alabama School of Medicine, where, in 1972, he became the founding Director of the UAB Comprehensive Cancer Center. He is credited with developing the transdisciplinary team

he held from 1983 to 1988. He then returned to UAB as Senior Vice President for Health Affairs, retiring from that post in 1995.

Leadership Role at ASCO Retirement, however, was a shortlived pause in Dr. Durant’s future. Beginning in 1992, ASCO’s leadership under Robert C. Young, MD, then Chair of the ASCO Strategic Planning Committee, saw a need for consolidating the Society’s growing organization under one central roof. At that time, ASCO’s day-to-day activities were divided among three locations, which was beginning to stress the Society’s

Dr. Durant will be remembered fondly as a man who filled his days and years as a doer-doctor whose clarity of thought and vision helped shape ASCO into the world’s leading professional cancer organization. of clinicians and basic scientists that led to UBA’s cancer program being one the first eight institutions in the United States to be designated as a comprehensive cancer center by the National Cancer Act of 1971. After leading UAB for 14 years, Dr. Durant—one of the pioneers in initiating the use of combination chemotherapy—was named President and CEO of Fox Chase Cancer Center in Philadelphia, a position

burgeoning governance requirements.

The ASCO board determined that in order to transition from external management to self-operation, the Society would need a full-time officer to take a leadership role. They began an extensive search process that culminated in the appointment of Dr. Durant, ASCO’s first Executive Vice President, in 1995. From 1964, when the fledging Society’s membership was 66, the

 In Memoriam

John Ridgway Durant July 29, 1930 - October 28, 2012 

membership had swelled to more that 10,000 when Dr. Durant assumed his leadership role.

Under Dr. Durant’s steady hand and visionary craftsmanship, the Society quickly transitioned from multiple locations under the management of the Bostrom Corporation to a fully staffed, self-managed organization with its headquarters under one roof in Bethesda, Maryland. By the time he retired from his role as Executive Vice President, ASCO had relocated to a larger facility in Alexandria. Dr. Durant acknowledged the wisdom of the board’s decision to centralize ASCO’s widening scope of activities and services as one of the most important decisions in the Society’s history.

In his ASCO Presidential speech titled ASCO—As a Young Adult, Dr. Durant eloquently laid out a blueprint for the Society’s robust maturation, including challenges and potential dangers that lay ahead. His closing words were: “If our Society can meet the challenge, we will enter adulthood with the necessary and optimum blend of science and medicine, and thus serve our patients as truly compassionate clinician-scientists.”

The Society, now in its “adulthood,” continues to meet the challenge that Dr. Durant addressed in his 1985 Presidential speech, and nearly 3 decades later, his imprint on the fundamental ethos of ASCO remains firm. He will be missed.

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PAGE 122

The ASCO Post | DECEMBER 15, 2012

Perspective

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

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

compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

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

Screening for Ovarian Cancer continued from page 1

cancer. It is not unreasonable to assume that very few physicians will read the original article in the September 2012 issue of Annals of Internal Medicine.1 Indeed, many physicians will only see, for example, the bold-font headline on the MedPage Today website, “USPSTF Says No Routine Tests for Ovarian Ca”2 or similar headlines in The New York Times or their local newspaper, and conclude only that there are no screening tests for ovarian cancer in general.

Snippets of Headlines I do not dispute any of the USPSTF recommendations on ovarian cancer screening. What concerns me, though, is how the busy nononcologic physician processes the USPSTF recommendations based on seeing only snippets of headlines. Many physicians may misinterpret the USPSTF’s message and be inclined to ignore the recommendations generally.

A good example of this tendency is the reaction to 2012 USPSTF recommendations on screening for prostate cancer. Also published in Annals of Internal Medicine,3 the authors conclude, “The USPSTF recommends against PSA-based screening for prostate cancer.

This recommendation applies to men in the general U.S. population, regardless of age.” It is my understanding that many, if not most, urologists are generally ignoring the USPSTF recommendations.

Among the reasons many urologists ignore those recommendations is a recently published study by Scosyrev and coauthors.4 These investigators calculated that if PSA testing were not done in the modern era, rates of men presenting with metastatic prostate cancer—a highly fatal disease—would triple as compared to the pre-PSA era. If their conclusion is indeed correct, this could be a major tragedy in the making.

Complicating Factors Primary care physicians and gynecologists face other barriers in implementing the USPSTF recommendations to “not screen for ovarian cancer.” For example, a recent letter that I sent to a generalist obstetrician-gynecologist began as follows: Thank you for your referral of JL for an elevated CA125. Per your note, she asked you for CA125 because her sister, who had “problems” with her ovaries, told you to order the test. Your patient has no risk factors for ovarian cancer, but you were left in the difficult position of having to order a CA125….

Dr. K. probably had no choice but to order the test. Along similar lines, many doctors and women have received a widely circulated e-mail that claims, “the CA125 test is an effective ovarian cancer screening test.” For years, this e-mail has convinced many women to ask for the test.

Additional statistics add to the difficult decision-making for the nononcologic physician to screen or not for ovarian cancer: In 2012, a projected 226,870 new cases of breast cancer—the number 1 cancer in females—will be diagnosed, compared to only 22,800 cases of ovarian cancer—the ninth most common cancer in women. And yet, many women fear ovarian cancer more than any other cancer because of the lack of defined symptoms, the fact that 70% of ovarian cancer cases present with disease spread to the abdominal cavity, or because they know of someone who died of the disease.

Recommendations In my opinion, the USPSTF recommendations should not be ignored.

Rather, what is needed is a better method of communicating to primary care and nononcologic physicians what is presented in Annals of Internal Medicine, in an easy, concise format. Based on the above, my recommendations to the primary care physician and the general obstetrician-gynecologist are as follows: 1. Unless a patient has known risk factors including first- or second-degree relatives with ovarian cancer, a BRCA mutation, or family history of Lynch syndrome, there is little value in CA125 testing or transvaginal ultrasound, which are not highly sensitive or specific for the diagnosis of ovarian cancer and could lead to harmful major surgery.

2. For patients with a family history of ovarian cancer, BRCA mutation, or history of Lynch syndrome, screening with transvaginal ultrasound and CA125—even given the fact that they have a low sensitivity and specificity— should be done annually.

3. The USPSTF recommendations should not dissuade practicing physicians from using transvaginal ultrasound and CA125 testing in screening symptomatic women who present with a history of abdominal bloating, pelvic pain, or clothes that are too tight. If these tests are accurately evaluated, they can prevent women from having to undergo unnecessary abdominal surgery.

■

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

References available at ASCOPost.com

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 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

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

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6%

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies.

The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

• Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

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

The data below reflect exposure to Avastin in 4198 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin.

[See Clinical Studies (14).] The population was aged 18‑88 years (median 60 years), 43.6% male and 83.8% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment,

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AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.

In Study 5, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control))

Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3.

Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 7 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

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

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs.

19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.

In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

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

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) 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%).

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 5 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1– 4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 7. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

a

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

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity.

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

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility.

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

S:12.5"

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone.

The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were signficantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%).

Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

7% 5% 5%

T:13"

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

The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 7).

[See Warnings and Precautions (5.8).]

a

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%

Arm 2 IFL+ + Avastin (n = 392) 87%

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Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%).

Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 5, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%.

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

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

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).]

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations.

Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence

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

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

To confront the threat of angiogenesis in mRCC…

Think Avastin

Because anti-angiogenesis matters Avastin plus IFN improved median PFS by 89% over placebo plus IFN (10.2 vs 5.4 months) in AVOREN1

Proportion Progression Free

1.0

Median PFS:

10.2 vs 5.4 months

0.8

(HR=0.60 [95% CI, 0.49–0.72], P<0.0001)

0.6

Avastin + IFN (n=327) Placebo + IFN (n=322)

0.4 0.2 0.0

2

4

6

8

10 12 14 PFS (Months)

16

18

20

22

24

PFS benefit of Avastin plus IFN was observed as early as 2 months and was sustained through the duration of the study1,2 Median OS with Avastin plus IFN was 23 months, a nonsignificant increase vs placebo plus IFN (21 months, HR=0.86 [95% CI, 0.72–1.04], P=0.1291)1,3 mRCC=metastatic renal cell carcinoma; IFN=interferon alfa; PFS=progression-free survival; HR=hazard ratio; CI=confidence interval; OS=overall survival; ORR=objective response rate.

Indication

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.4%) — Proteinuria including nephrotic syndrome (<1%)

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All rights reserved.

AVA0000502301

Printed in USA.

Avastin plus IFN more than doubled ORR vs placebo plus IFN (30% vs 12%, P<0.0001), as confirmed by an independent review facility1,3

Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

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

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother The most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%)

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

References: 1. Avastin Prescribing Information. Genentech, Inc. September 2011. 2. Escudier B, Pluzanska A, Koralewski P, et al. Lancet. 2007;370:2103-2111. 3. Escudier B, Bellmunt J, Negrier S, et al. Slides presented at: Annual Meeting of the American Society of Clinical Oncology; May 29–June 2, 2009; Orlando, FL.

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