OncologyLive Targeted Therapy News

ASCO: A Focus on Personalized Medicine

06.12

Breaking news from clinical trials, educational sessions, and seminars at this year’s meeting will focus on the latest advances in and practical advice for the use of new targeted treatments.

Here’s what not to miss. (see page 22)

Targeted TherapyNews

TM

Patricia LoRusso, DO

For the Practicing Oncology Professional

In this issue...

Gastric and Colorectal Cancer • Imatinib Indication Expansion: Approval for GIST • Regorafenib May Offer Option for Metastatic Colorectal Cancer and GIST Hematologic Malignancies • Targeting the PI3K/Akt/mTOR Pathway for Lymphoma • Obinutuzumab Compares Favorably With Rituximab in NHL Trial • Nilotinib Beats Imatinib for CML in Two Phase III Trials Renal Cell Carcinoma • Approval of Axitinib Adds Another Therapy Option for Metastic RCC

Feature

Feature

The Rising Cost of Cancer Care in the Era of Individualized Therapy A Q&A With Thomas J. Smith, MD

By Anna Azvolinsky, PhD

E

merging targeted therapies are extending survival in many cancers, but the cost of these new treatments is often high. For example, sipuleucel-T (Provenge, Dendreon) for metastatic castration-resistant prostate cancer costs $93,000 a year. Ipilimumab (Yervoy, Bristol-Myers Squibb), the first treatment for metastatic mel-

The Mayflower Renaissance Hotel Washington, DC August 17-18, 2012

T

reatment of breast cancer is becoming “horrendously complicated,” said Brian Leyland-Jones, MD, PhD, director of the Winship Cancer Institute at Emory University in Atlanta, Georgia. According to Leyland-Jones, as research on breast cancer progresses, the disease is seen as a set of many different diseases, each with distinct molecular and clinical features.

In February, Leyland-Jones spoke at the 9th Annual Northern New Jersey Breast Cancer Conference, held at the John Theurer Cancer Center, Hackensack, New Jersey, where he gave a broad overview of the current progress and direction of optimal therapies for breast cancer—individualized treatment based on specific Brian Leyland-Jones, MD, PhD molecular targets. Leyland-Jones noted that research in the field, both clinical trial data and new preclinical studies, is progressing so rapidly that it is almost impossible to remember all of the new, targeted areas. “It is becoming clear that breast cancer has 50 to 80 targetable drivers,” he said. “This is a time of massive knowledge change in the entire field.”

(continued on page 27)

Gastric and Colorectal Cancer

Skin Cancer • New Laboratory Melanoma Research Supports Ongoing Clinical Trials

10th International Congress on Targeted Therapies in Cancer

Targeted Therapies in Breast Cancer: Increasingly Promising—and Complicated

Better Understanding of Gastric Cancer Subtypes Needed for Targeting Treatment

G anoma to improve overall survival in more than 10 years, costs $120,000 for four infusions over a span of just three months. Everolimus (Afinitor, Novartis), for renal cell carcinoma and pancreatic cancer, costs $10,000 a month.

Many of these medications are indicated at the final stage of cancer; on average, they extend lifespan by a

astric cancer is not one disease. This was the theme highlighted by Manish A. Shah, MD, director of Gastrointestinal Oncology at Weill Cornell Medical College/New York Presbyterian Hospital, in New York City, during his talk at the ASCO 2012 Gastrointestinal Cancers Symposium. Shah discussed the importance of developing new, targeted therapies for gastric cancer based on new delineations and definitions of gastric cancer subtypes.

Hypothesis-driven development of targeted therapies for gastric cancer is an important and yet elusive goal. Much more research is needed to define molecular subtypes of gastric cancer and identify appropriate targets for clinical use. Shah stressed that while it has been known for more than 40 years that there are distinct subtypes of gastric cancer, clinical practice and clinical trials continue to cluster these gastric cancer patients. Current progress includes the first targeted therapy for gastric cancer approved by the FDA in 2010: Trastuzumab (Herceptin) in combination with chemotherapy is now an option for gastric cancer that overexpresses HER2.

Aside from trastuzumab, little progress has been made in over a decade. “It may have been appropriate to group all gastric cancer patients together when cytotoxic

(continued on page 23)

(continued on page 7)

Thomas J. Smith, MD

www.TargetedTherapyOncology.com

In advanced prostate cancer...

TREAT fIRST LINE wITh PROVENGE TO

Activate PROVENGEactivated T cells

Resting T cell

PROVENGE activating a T cell

Amplify Prostate cancer cell

Attack Activated T cell attacks prostate cancer

EXTEND SURVIVAL

• PROVENGE extends median survival beyond 2 years1 • Only 1.5% of patients treated with PROVENGE in the pivotal trial discontinued treatment due to adverse events2 — The most common adverse events in PROVENGE trials were chills, fatigue, fever, back pain, nausea, joint ache, and headache2 • PROVENGE is the first and only FDA-approved immunotherapy for advanced prostate cancer • The NCCN recommends PROVENGE as a first-line treatment for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (NCCN Category 1 recommendation)3

visit us at Booth 22063

• Explore the PROVENGE Interactive Experience • Create a personalized patient educational poster for your office

IndIcatIon: provenge® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

Important Safety InformatIon: provenge is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the provenge group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (grade 3) acute infusion reactions were reported in 3.5% of patients in the provenge group. reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. no grade 4 or 5 acute infusion reactions were reported in patients in the provenge group.

The most common adverse events (incidence ≥15%) reported in the provenge group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.

For more information on provenge, please see Brief Summary of prescribing Information on adjacent page.

www.provenge.com

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION • For Autologous Use Only.

• The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals.

• Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine.

• Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag.

• Do Not Initiate Infusion of Expired Product.

• Infuse PROVENGE intravenously over a period of approximately 60 minutes.

Do Not Use a Cell Filter.

• Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use.

• Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction.

I n controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion.

Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed.

• Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed.

• Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied.

PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician.

Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician.

Dendreon may request additional information from the physician in order to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

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 safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells.

The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group.

Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.

PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.

Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).

Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Influenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3) 319 (53.1) 247 (41.1) 188 (31.3) 178 (29.6) 129 (21.5) 118 (19.6) 109 (18.1) 89 (14.8) 85 (14.1) 80 (13.3) 75 (12.5) 74 (12.3) 74 (12.3) 74 (12.3) 73 (12.1) 71 (11.8) 71 (11.8) 65 (10.8) 60 (10.0) 58 (9.7) 54 (9.0) 52 (8.7) 50 (8.3) 49 (8.2) 46 (7.7) 46 (7.7)

186 (30.9) 13 (2.2) 6 (1.0) 6 (1.0) 18 (3.0) 3 (0.5) 11 (1.8) 4 (0.7) 0 (0.0) 1 (0.2) 2 (0.3) 11 (1.8) 1 (0.2) 7 (1.2) 0 (0.0) 5 (0.8) 2 (0.3) 3 (0.5) 6 (1.0) 1 (0.2) 0 (0.0) 3 (0.5) 11 (1.8) 1 (0.2) 2 (0.3) 6 (1.0) 2 (0.3)

291 (96.0) 33 (10.9) 105 (34.7) 29 (9.6) 87 (28.7) 45 (14.9) 62 (20.5) 20 (6.6) 43 (14.2) 43 (14.2) 23 (7.6) 34 (11.2) 40 (13.2) 20 (6.6) 43 (14.2) 40 (13.2) 34 (11.2) 17 (5.6) 20 (6.6) 34 (11.2) 11 (3.6) 31 (10.2) 14 (4.6) 31 (10.2) 29 (9.6) 18 (5.9) 17 (5.6)

Grade 3-5 n (%) 97 (32.0) 0 (0.0) 4 (1.3) 3 (1.0) 9 (3.0) 0 (0.0) 5 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (2.3) 3 (1.0) 3 (1.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 2 (0.7) 3 (1.0) 0 (0.0) 3 (1.0) 3 (1.0) 1 (0.3) 1 (0.3) 3 (1.0) 0 (0.0)

(Table 1 continued on next page.)

From the Publisher

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)

3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)

0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)

17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)

0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)

Grade 3-5 n (%)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

2. PROVENGE [package insert]. Dendreon Corporation; June 2011.

3. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer.

V.1.2012. National Comprehensive Cancer Network Web site. www.nccn.org. Accessed March 6, 2012.

©2012 Dendreon Corporation.

All rights reserved. March 2012.

Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation.

P-A-03.12-066.00

3

Targeted Therapy News: The Premier Issue

I

n 2011, the FDA approved 35 new medicines—seven in oncology, including the first new treatment for Hodgkin lymphoma in 30 years. By the end of the first quarter of 2012, the FDA had approved two new cancer therapies. Many of the new oncology medications being approved are molecularly targeted therapies—and that has posed a challenge for practicing oncologists: Treating patients with targeted therapies requires new approaches to diagnosis, treatment, monitoring, and management of adverse events.

Targeted Therapy News is aimed at helping oncologists meet these challenges by providing the information and analyses they need to best use targeted therapies in clinical practice.

In this, our premier issue, we focus on the latest developments in targeted therapies. “ASCO: A Focus on Personalized Medicine” highlights key presentations to watch for at this year’s annual meeting of the American Society of Clinical Oncology, including educational seminars specifically designed to help oncologists successfully use novel therapies in patient care.

“The Rising Cost of Cancer Care in the Era of Individualized Therapy” takes a look at controversies over the costs of these emerging treatments, and “A New Look at Survival Data for Sipuleucel-T” goes beyond the original analysis of clinical trial data for sipuleucel-T to suggest that the prostate cancer vaccine may have delivered a greater overall survival benefit than previously described.

Finally, our news section includes coverage of breaking developments in a wide range of cancers, including gastric, colorectal, skin, and renal cell cancers, and hematologic malignancies.

In 2011, the FDA approved 35 new medicines—seven in oncology, including the first new treatment for Hodgkin lymphoma in 30 years.

Targeted Therapy News is one of the latest additions to our family of oncology-focused publications and websites, along with The International Journal of Targeted Therapies in Cancer, a new, peer-reviewed journal that also makes its debut this month.

We thank you for joining us, and we look forward to continuing to provide you with the information and resources you need to provide the best possible care to your cancer patients.

Peter Ciszewski

4

Editorial Board Jame Abraham, MD Section of Hematology/Oncology Mary Babb Randolph Cancer Center West Virginia University Morgantown, WV Ross Abrams, MD Department of Radiation Oncology Rush University Medical Center Chicago, IL Alex A. Adjei, MD, PhD Department of Medicine Roswell Park Cancer Institute Buffalo, NY Lawrence Afrin, MD Division of Hematology/Oncology Medical University of South Carolina Charleston, SC Sanjiv S. Agarwala, MD Division of Oncology/Hematology St. Luke’s Hospital & Health Network Bethlehem, PA Nita Ahuja, MD Surgery & Oncology The Johns Hopkins Hospital Baltimore, MD Lowell Anthony, MD Section of Hematology & Oncology Louisiana State University New Orleans, LA David Artz, MD, MBA Information Systems Memorial Sloan-Kettering Cancer Center New York, NY J. Robert Beck, MD Fox Chase Cancer Center Philadelphia, PA Tomasz Beer, MD Prostate Cancer Program Oregon Health & Science University Cancer Institute Portland, OR E. Roy Berger, MD North Shore Hematology Associates East Setauket, NY Ralph V. Boccia, MD Center for Cancer and Blood Disorders Bethesda, MD Jeffrey Bumpous, MD Division of Otolaryngology-HNS University of Louisville Louisville, KY Barbara A. Burtness, MD Head and Neck Medical Oncology Fox Chase Cancer Center Philadelphia, PA John Caton Jr, MD Medical Oncology Willamette Valley Cancer Center Eugene, OR Emily Chan, MD, PhD Vanderbilt University Nashville, TN Helen Chan, MD GI Surgical Oncology Lakeland Regional Cancer Center Lakeland, FL Tarek Chidiac, MD Mid-Ohio Oncology/Hematology Inc, dba The Mark H. Zangmeister Center Columbus, OH Patrick Wayne Cobb, MD Hematology-Oncology Centers of the Northern Rockies Billings, MT Ezra E. W. Cohen, MD Section of Hematology/Oncology University of Chicago Chicago, IL Richard Cohen, MD Cohen Hufford Koltzova Medical San Francisco, CA Allan Cohn, MD Rocky Mountain Cancer Center Denver, CO Sandra Cuellar, PharmD, BCOP Department of Pharmacy Practice University of Illinois at Chicago Chicago, IL

Targeted Therapy News • 06.12

Mary Daly, MD, PhD Population Science Fox Chase Cancer Center Philadelphia, PA Don Dizon, MD Program in Women’s Oncology Women & Infants Hospital Providence, RI Habib Doss, MD Tennessee Oncology, PLLC Nashville, TN Anthony Elias, MD Breast Cancer & Sarcoma Programs University of Colorado Cancer Center Aurora, CO Fadi Estephan, MD Medical Oncology Hutchinson Clinic Hutchinson, KS Evelyn Fleming, MD Gynecologic Oncology Dartmouth-Hitchcock Medical Center Lebanon, NH Michele Fox, MD Pathology Myeloma Institute for Research & Therapy University of Arkansas for Medical Sciences Little Rock, AR Sharon L. Francz, BHA, BS, O National Coalition of Oncology Nurse Navigators Rockville, MD David R. Gandara, MD Division of Hematology and Oncology UC Davis Cancer Center Sacramento, CA Leonard G. Gomella, MD Department of Urology Thomas Jefferson University Philadelphia, PA

Emad Kandil, MD Department of Surgery Section of Endocrine & Oncological Surgery Tulane Cancer Center New Orleans, LA Song Kang, MD Virginia Oncology Associates Sentara Careplex Hospital Hampton, VA

Adam I. Riker, MD Cancer Services Ochsner Cancer Institute New Orleans, LA Steven Rosen, MD Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, IL

Gary Lyman, MD, MPH, FRCP(Edin) Duke University Medical Center Durham, NC

Richard J. Rosenbluth, MD John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

David G. Maloney, MD, PhD Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, WA

Oliver Sartor, MD Department of Urology Tulane Cancer Center New Orleans, LA

Maurie Markman, MD Clinical Affairs & Medical Oncology Cancer Treatment Centers of America Philadelphia, PA

Lee Schwartzberg, MD The West Clinic Memphis, TN

Robert Meister, MD Arlington-Fairfax Hematology Arlington, VA Wilson Mertens, MD Cancer Services Baystate Health Springfield, MA Joseph Mikhael, MD Division of Hematology/Oncology Department of Internal Medicine Mayo Clinic Scottsdale, AZ Mohamed Mitwally, MD Department of Obstetrics & Gynecology University of Minnesota Minneapolis, MN

Maureen Sheehan, MD Kansas City Cancer Center Kansas City, MO Edibaldo Silva, MD, PhD Division of Surgical Oncology Eppley Cancer Center University of Nebraska Medical Center Omaha, NE David Spigel, MD Lung Cancer Program The Sarah Cannon Research Institute Nashville, TN Kellie Sprague, MD Bone Marrow Transplantation Tufts Medical Center Boston, MA

Janaki Moni, MD Michiana Hematology Oncology South Bend, IN

Richard Tenglin, MD Oncology Associates Rapid City Regional Hospital Rapid City, SD

Andre Goy, MD, MS John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Hyman Muss, MD University of Vermont and Vermont Cancer Center Hematology Oncology Unit Burlington, VT

J. Tate Thigpen, MD Division of Medical Oncology University of Mississippi Jackson, MS

David Graham, MD Clinical Trials Carle Clinic Association Urbana, IL

Leigh Neumayer, MD Integrated Breast Program Huntsman Cancer Institute Salt Lake City, UT

Katherine Tkaczuk, MD Medicine & Oncology University of Maryland Cancer Center Baltimore, MD

Gregory Griffin, MD Division of Hematology/Oncology Alfred I. duPont Hospital for Children Wilmington, DE

Anthony Nguyen, MD Medical Oncology Comprehensive Cancer Centers of Nevada-Siena Henderson, NV

Debu Tripathy, MD Women’s Cancer Program University of Southern California Los Angeles, CA

Reuben Guerrero, MD Division of Oncology/Hematology Straub Clinic & Hospital Honolulu, HI

Joyce A. O’Shaughnessy, MD Division of Breast Cancer Research Texas Oncology/US Oncology Dallas, TX

Philip Villiotte, MD Spectrum Medical Group Scarborough, ME

Mahendra Gupta, MD Medical Oncology Innovis Health Fargo, ND

Daniel A. Osman, MD Breast Cancer Surgeon Miami, FL

Daniel Hamstra, MD, PhD Pediatric Radiation Oncology Genitourinary Radiation Oncology University of Michigan Ann Arbor, MI Robin Hanson, MD, PhD Cardinal Kids Cancer Center St. John’s Mercy Medical Center Creve Coeur, MO Roy S. Herbst, MD, PhD Division of Medical Oncology Yale School of Medicine New Haven, CT William Hocking, MD Hematology/Oncology Marshfield Clinic Marshfield, WI Clifford A. Hudis, MD Breast Cancer Medicine Services Memorial Sloan-Kettering Cancer Center New York, NY Dennie Jones, Jr, MD New Mexico Cancer Care Alliance University of New Mexico Albuquerque, NM

Andrew L. Pecora, MD John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ Edith A. Perez, MD Department of Hematology/Oncology Mayo Clinic Jacksonville, FL Román Pérez-Soler, MD Division of Oncology Albert Einstein College of Medicine Bronx, NY Daniel P. Petrylak, MD Genitourinary Oncology Section Columbia University Medical Center New York, NY Aarati Rao, MD Division of Pediatric Hematology/Oncology University of South Alabama Mobile, AL Douglas Reding, MD, MPH Marshfield Center Marshfield, WI John Rhee, MD Medical Oncology & Hematology, PC Yale-New Haven Hospital New Haven, CT

Roland Walter, MD, PhD Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, WA

Ronald Walters, MD, MBA, MHA Medical Operations & Informatics Breast Medical Oncology MD Anderson Cancer Center Houston, TX Richard Wein, MD Department of Otolaryngology-Head & Neck Surgery Tufts Medical Center Boston, MA H. Jack West, MD Thoracic Oncology Program Swedish Cancer Institute Seattle, WA James Wheeler, MD Radiation Oncology Program Goshen Center for Cancer Care Goshen, IN Andrew D. Zelenetz, MD, PhD Department of Medicine Memorial Sloan-Kettering Cancer Center New York, NY Paul Zeltzer, MD Neurosurgery David Geffen School of Medicine University of California, Los Angeles Los Angeles, CA Jeffrey Zonder, MD Hematology/Oncology Karmanos Cancer Center Detroit, MI

In This Issue...

5

Publishing Staff Editorial & Production Vice President, Oncology and Managed Markets Lyn Beamesderfer lbeamesderfer@onclive.com Senior Editors Jason M. Broderick Beth Fand Incollingo Anita T. Shaffer

Oncology Special Projects Editor Devera Pine Oncology Projects Editor Anna Azvolinsky, PhD Web Editor Silas Inman

Associate Editor Ben Leach

Assistant Web Editor Stephanie Ogozaly

Assistant Editor Marissa Murtaugh

Art Director John Salesi

Sales & Marketing

Features

News

Erik Lohrmann elohrmann@onclive.com

22 ASCO: A Focus on

GASTRIC AND COLORECTAL CANCER

Senior National Accounts Manager Mike Hennessy, Jr mjhennessy@onclive.com

6R egorafenib May Offer Option for Metastatic Colorectal Cancer and GIST

National Accounts Manager Robert Goldsmith rgoldsmith@onclive.com

23 The Rising Cost of Cancer Care in

President Peter Ciszewski pciszewski@onclive.com

Directors of Sales Scott Harwood sharwood@onclive.com

Executive Vice President, Sales Jack Lepping jlepping@onclive.com Vice President, Sales & Marketing Lisa Greene lgreene@onclive.com Vice President, Integrated Special Projects Group David Lepping dlepping@mdmag.com

Vice President, Digital Media Jung Kim

Controller Jonathan Fisher, CPA Assistant Controller Leah Babitz, CPA

Corporate Chairman/Chief Executive Officer/President Mike Hennessy

Vice President, Executive Director of Education Judy V. Lum, MPA

Chief Operating Officer Tighe Blazier

Vice President, Group Creative Director Jeff Brown

Chief Financial Officer Neil Glasser, CPA/CFE

A Q&A With Thomas J. Smith, MD

By Anna Azvolinsky, PhD

7B etter Understanding of Gastric Cancer Subtypes Needed for Targeting Treatment

gynecologic malignancies

8 PARP Inhibitors Intriguing Despite Research Setbacks

head and neck cancer

9 Reolysin Trial Reaches Enrollment Milestone

By Anita T. Shaffer

27 Targeted Therapies in Breast Cancer: Increasingly Promising— and Complicated

Departments 35 Research Profile: Leonard M. Neckers, PhD 36 Trials in Progress

Office Center at Princeton Meadows, Bldg. 300 Plainsboro, NJ 08536 • (609) 716-7777

6 Imatinib Indication Expansion: Approval for GIST

26 A New Look at Survival Data for Sipuleucel-T

Operations & Finance

Director of Operations Thomas J. Kanzler

By Anna Azvolinsky, PhD

the Era of Individualized Therapy

Digital Media

Director of Circulation John Burke jburke@mdng.com

Personalized Medicine

40 E vidence-Based Oncology Breakthroughs in Targeted Therapies Not Applicable If Not Cost-Effective

By Marie Rosenthal, MS

9 Hypothyroidism Risks With MKIs Examined

HEMATOLOGIC MALIGNANCIES

12 Subcutaneous Dosing of Bortezomib Approved 12 Targeting the PI3K/Akt/mTOR Pathway for Lymphoma 13 Bruton’s Tyrosine Kinase Inhibitor PCI-32765: Durable Responses in Refractory CLL 13 Obinutuzumab Compares Favorably With Rituximab in NHL Trial 14 N ilotinib Beats Imatinib for CML in Two Phase III Trials

prostate cancer

19 Z ytiga Study Unblinded After Interim Analysis 19 S ipuleucel-T Stimulates Response in Localized Setting, Study Finds

RENAL CELL CARCINOMA The content contained in this publication is for general information purposes only. The reader is encouraged to confirm the information presented with other sources. Targeted Therapy News makes no representations or warranties of any kind about the completeness, accuracy, timeliness, reliability, or suitability of any of the information, including content or advertisements, contained in this publication and expressly disclaims liability for any errors and omissions that may be presented in this publication. Targeted Therapy News reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. Targeted Therapy News further disclaims any and all liability for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any material or information presented in this publication. The views expressed in this publication are those of the authors and do not necessarily reflect the opinion or policy of Targeted Therapy News.

20 Approval of Axitinib Adds Another Therapy Option for Metastic RCC

SKIN CANCER

21 New Laboratory Melanoma Research Supports Ongoing Clinical Trials 21 First-Ever Drug Approved for Advanced Form of Most Common Skin Cancer

Targeted Therapy News • 06.12

News

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Targeted Therapies: Gastric and Colorectal Cancer

Imatinib Indication Expansion: Approval for GIST

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n January of this year, the FDA approved the use of imatinib (Gleevec, Novartis Pharmaceuticals) for adult patients with CD117-positive gastrointestinal stromal tumors (GIST) following surgical removal. Updated clinical trial data supporting a longer treatment schedule were also disclosed; the label now includes study data showing prolonged overall patient survival and relapse-free survival over a 36-month adjuvant treatment compared with the standard-of-care, 12-month adjuvant

regimen in high-risk GIST patients.

Imatinib was first approved in 2001 for chronic myeloid leukemia. The drug was granted accelerated approval for advanced and metastatic GIST in 2002.

In 2008, a label was approved for adjuvant use in patients who had surgical removal of their GIST but who are at risk for recurrence.

The latest approval stems from the results of the SSGXVIII/AIO study, which were first presented at the annual American Society of Clinical On-

cologists (ASCO) meeting in June 2011.

The open-label, multicenter, randomized phase III study evenly divided 400 patients with KIT-positive GIST into two groups to receive imatinib for either 12 months or 36 months. The primary endpoint was recurrence-free survival.

After 54 months of follow-up, study results showed that patients who received imatinib for 36 months were 54% less likely to experience recurrence (hazard ratio [HR] 0.46; 95% confidence

interval [CI], 0.32-0.65; P < .0001) compared with patients who received the drug for 12 months. The study also found that the chance of death as a result of GIST was 55% lower in the group that received imatinib for 36 months (HR 0.45; 95% CI, 0.22-0.89; P = .019) compared with the group receiving the drug for 12 months. After five years, 92% of patients in the 36-month imatinib group were alive compared with 81.7% of patients in the 12-month arm of the study. TTN

Regorafenib May Offer Option for Metastatic Colorectal Cancer and GIST

Axel Grothey, MD

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esults from two phase III trials in metastatic colorectal cancer (mCRC) and unresectable gastrointestinal stromal tumors (GIST) that have progressed despite prior treatment indicate that the multi-tyrosine kinase inhibitor regorafenib may offer some benefit.

The phase III international CORRECT trial showed that regorafenib may be a new treatment option that achieves disease control in mCRC that has progressed on multiple lines of standard therapy including 5-fluorouracil (FU), oxaliplatin, irinotecan, bevacizumab, and cetuximab. The trial achieved a statistically significant improvement in

Targeted Therapy News•06.12

overall survival (OS). The trial was unblinded in October 2011 after an interim analysis of patients in the placebo arm were offered regorafenib therapy. The full results of the trial were presented at the American Society of Clinical Oncology (ASCO) 2012 Gastrointestinal Cancers Symposium in January 2012.

The trial has since been expanded to a phase IIIb open-label protocol for mCRC patients who have progressed following standard of care. Follow-up results will be presented at the upcoming ASCO Annual Meeting in June 2012.

A total of 760 patients with mCRC who had progressed despite therapy were randomized 2:1 to receive either regorafenib or placebo. Both study arms also received best supportive care. Patients received regorafenib 160 mg (n=505) or placebo (n=255) once daily for three weeks, followed by one week with no treatment.

Median OS was 6.4 months for regorafenib and 5.0 months for the placebo arm, an improvement of 29%. The estimated hazard ratio for OS was 0.773 (one-sided P = .0051). Median progression-free survival was 1.9 months and 1.7 months for the regorafenib and placebo arms, respectively. The most frequent grade 3 or higher adverse events included hand-foot skin reaction in 17%, fatigue in 15%, and diarrhea in 8% of patients. Some patients had their dosages reduced to manage side effects.

“This is the first small-molecule ki-

nase inhibitor with proof of efficacy in colorectal cancer and is a potential new standard of care in this patient population,” said lead author Axel Grothey, MD, Mayo Clinic, Rochester, Minnesota. “The main emphasis of these findings is that this drug delays disease progression, achieving a much higher disease control rate than placebo,” Grothey added. The disease control rate was 44% for regorafenib and 15% for placebo (P < .000001).

Regorafenib is a multikinase inhibitor that shows antiangiogenic activity against vascular endothelial growth factor receptor 2 (VEGFR2) and TIE2.

The inhibitor blocks various kinases involved in tumor cell proliferation, new blood vessel formation, and the interaction between tumor cells and the microenvironment.

Study findings showed no difference in response in patients treated with two versus three or four lines of prior therapy, according to Grothey. Previous smallmolecule multikinase inhibitors were investigated in conjunction with chemotherapy but showed no benefit in mCRC. Grothey believes that regorafenib worked because it was used as a single agent. He speculated that because tumors evolve due to therapy exposure, a “promiscuous” multitargeted therapy may be needed in a last-line setting.

The drug is under investigation in combination with FOLFIRI chemotherapy as a second-line treatment for mCRC in a

phase II trial.

“A lot of pharmaceutical companies shy away from this very sick patient population, but this is a population in need, and we can do drug development here,” Grothey said. He added that the CORRECT trial shows that placebo-controlled trials are feasible in a population with unmet needs, particularly refractory colorectal cancer.

Regorafenib also holds promise for patients with GIST. In April 2012 it was announced that the phase III GRID trial met its primary endpoint of a statistically significant improvment in progression-free survival in patients with metastatic and/or unresectable GIST whose disease had progressed despite prior therapy. Full trial results will be presented at the upcoming ASCO annual meeting in June 2012.

Finally, regorafenib is being investigated in phase II trials for treatmentnaïve patients with metastatic renal cell carcinoma and liver cancer. TTN Key Research Grothey A, Sobrero AF, Siena S, et al. Results of a phase III randomized, double-blind, placebocontrolled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. Presented at the ASCO Gastrointestinal Cancers Symposium; January 19-21, 2012; San Francisco, CA. J Clin Oncol. 2012;(suppl 4; abstr LBA385).

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Targeted Therapies: Gastric and Colorectal Cancer Gastric Cancer (continued from cover) therapeutics like 5-FU were being studied,” Shah said. “But when we talk about targeted therapies for gastric cancer, the subtypes matter, and they will matter more as we design trials for targeted therapies for this disease.”

According to the National Cancer Institute, there will be approximately 21,320 new cases of gastric cancer in 2012, and 10,540 patients are estimated to die of the disease. It is the seventh leading cause of cancer death in the US and the second leading cause of cancer death worldwide.

Epidemiology and risk factor studies, response to therapy, and genetic analyses all provide evidence that distinct

Manish A. Shah, MD

“When we talk about targeted therapies for gastric cancer, the subtypes matter, and they will matter more as we design trials for targeted therapies for this disease.”

–Manish, A. Shah, MD

Epidemiology and risk factor studies, response to therapy, and genetic analyses all provide evidence that distinct subpopulations of gastric cancer exist.

subpopulations of gastric cancer exist. Epidemiologic studies have shown that gastric cancer in Asian countries is different from gastric cancer in the US in terms of location of tumor, stage at diagnosis, postoperative mortality, response to therapy, and outcomes.

One step in the right direction is analysis of clinical trials based on patient subtypes in order to identify patients who are more likely to respond to treatment. Shah presented survival analysis according to gastric cancer subtype in the AVAGAST trial testing first-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced forms of the disease. The trial was a phase III worldwide trial, in which more than 50% of the patients were recruited from Asia. Subanalysis showed that patients from the Americas and Europe exhibited more evidence of benefit compared with patients from the Asia-Pacific region. Patient outcomes were also analyzed based on the molecular expression profiles for gastric cancer: proximal nondiffuse gastric cancer (type 1), diffuse (type 2), and distal nondiffuse (type 3). These three tumor subtypes have different genetic and histological patterns.

The presented subanalysis showed that patients with the type 3 subtypes had a better prognosis, independent of geography. Bevacizumab had a higher benefit in non-Asian patients with type 2 and type 3 gastric cancer. The data support the view that gastric cancer subtypes may be important predictors of outcomes and need to be investigated further.

Shah also described a study that compared gastric cancers among Koreans and Americans from one institution in each country. After adjusting for all known risk factors, disease-specific survival for Korean patients with gastric cancer was significantly higher than in the US patients by about 20% to 30%.

Results showed that the tumors in Korean patients were mainly in the middle and lower stomach. In contrast, the tumors of American patients were mainly in the gastroesophageal and upper gastrointestinal tract. Cancer was

generally diagnosed at an earlier stage in Korean patients, while the diagnosis was evenly split among four stages in the American patients. Postoperative mortality was 0.2% in Korean patients and 2% in American patients. Five-year disease-specific survival was 82% in Korean patients and 74% in American patients.

“This suggests a different biology [in Asians and Americans],” Shah said.

However, there may be inherent biological and genetic differences between Koreans and Americans that were not accounted for in this study.

A 2011 study by Wang et al analyzed 22 matched pairs of gastric cancer specimens and normal tissue. The authors showed that these tumors are genetically diverse, with the gastric cancer tissues exhibiting mutations in chromatin modifiers, cell junction genes, and cell cycle regulation genes.

A second group of investigators, Tan and colleagues, identified a 171-gene signature that could robustly classify tumors to predominantly intestinal or diffuse gastric cancer subtypes. “These authors were setting up a dichotomy,” Shah explained. The implication is that the different subtypes of the cancer respond differently and have different disease kinetics due to different molecular drivers and therapeutic targets.

The future of gastric cancer should be targeted therapies, said Shah.

Supporting the notion that gastric cancers, like many other cancers, consists of distinct subtype is a small phase II study by Shah et al of 44 patients with gastric cancer treated with antiangiogenic therapy at Memorial SloanKettering Cancer Center, New York City.

The study showed variation in the sixmonth progression-free survival (PFS) for the three subtypes of gastric cancer.

Proximal gastric cancers had the best PFS, distal tumors had intermediate PFS, and diffuse gastric cancers had the worst PFS. The study underscores the need to focus research on the genetic profiles of gastric cancer and to use the current knowledge about the three gastric subtypes to better design clinical trials. TTN

Key Research AVAGAST: A randomized, double-blind, placebo-controlled, phase III study of first-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer (AGC). Presented at the ASCO Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol.

2010;28:(suppl; abstr LBA4007).

Shah MA, Jhawer M, Ilson DH, et al. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma.

J Clin Oncol. 2011;29(7):868-874.

Strong VE, Song KY, Park CH, et al. Comparison of gastric cancer survival following R0 resection in the United States and Korea using an internationally validated nomogram. Ann Surg.

2010;251(4):640-646.

Tan IB, Ivanova T, Lim KH, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology.

2011;141(2):476-485.

Wang K, Kan J, Yuen, ST, et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet.

2011;43(12):1219-1223.

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News Targeted Therapies: Gynecologic Malignancies

PARP Inhibitors Intriguing Despite Research Setbacks

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Michael J. Birrer, MD, PhD

arly excitement over the potential for using PARP inhibitors in the treatment of patients with ovarian cancer has dissipated amid disappointing findings on overall survival, but the class of novel therapeutics remains under active investigation for patients with this tumor type.

At least three pharmaceutical companies are continuing development programs with various PARP agents, noted Michael J. Birrer, MD, PhD, professor of Medicine, Harvard Medical School and director, Gynecologic Medical Oncology, director, Gynecologic Cancer Research Program, Massachusetts General Hospital Cancer Center in Boston, in a recent interview. He spoke shortly after AstraZeneca announced its decision to halt studies of olaparib for maintenance treatment of serous ovarian cancer.

“I haven’t given up hope on this,” said Birrer, referring to the class of PARP inhibitors as a whole. “I think you’ll see trials with PARP inhibitors testing the ability and activity of bringing the PARP inhibitor up front in newly diagnosed patients in combination with chemotherapy. Most of those trials will also include a maintenance phase. In conjunction with that, there will be selective trials in BRCA1- and BRCA2-mutated patients with recurrent resistant disease.”

PARP, poly(adenosine diphosphate [ADP]–ribose) polymerase, plays an important role in the repair of single-strand DNA breaks. Birrer said single-strand breaks can become double-strand breaks that

are, in turn, repaired by a complex that contains BRCA1 and BRCA2. Thus, he said, researchers have theorized that inhibiting the PARP enzyme should selectively kill cells with those genetic abnormalities.

Earlier studies had demonstrated higher antitumor activity and objective response rates for patients with and without BRCA1/2 mutations, a phase II trial highlighted at the 2011 American Society of Clinical Oncology Annual Meeting did not require that mutation status. Eligible patients had recurrent, platinum-sensitive ovarian or fallopian-tube cancer or primary peritoneal cancer with high-grade (grade 2 or 3) serous features or a serous component.

The trial, which AstraZeneca sponsored, demonstrated that olaparib improved median progression-free survival by 65% among the 136 patients randomized to receive 400-mg doses twice daily, compared with 129 participants on placebo. Investigators believed the compound showed promise as monotherapy for this patient population.

In December, however, AstraZeneca announced the company would not move forward with phase III development in the maintenance setting after interim data “indicated that the previously reported progression-free survival benefit is unlikely to translate into an overall survival benefit, the definitive measure of patient benefit in ovarian cancer. In addition, attempts to identify a suitable tablet dose for use in phase III studies have not been successful.”

In March, researchers detailed those

Stage IIC Cancer Bladder Fallopian tube

Uterus Ovary Malignant cells in a peritoneal washing Tumor

Sigmoid colon

Targeted Therapy News•06.12

This illustration depicts ovarian cancer at stage IIC. One noteworthy PARP study included patients with grade 2 or 3 serous ovarian cancer.

results in The New England Journal of Medicine. They reported median progressionfree survival of 8.4 months with olaparib versus 4.8 months on placebo. Adverse events were more prevalent among those who received olaparib, but most of those events were grade 1/2, with nausea, fatigue, vomiting, and anemia among the most frequently reported effects.

However, the interim survival analysis, conducted after 38% of the participants had died, did not show a significant advantage for olaparib, which demonstrated a hazard ratio of 0.94 (95% confidence interval, 0.63-1.39; P = 0.75).

“Maintenance treatment with olaparib was associated with a significant improvement in progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer,” the researchers concluded.

“However, at the interim analysis, this did not translate into an overall survival benefit. As of this writing, 21% of the patients were still receiving olaparib (and 3% were still receiving placebo), which indicates that the disease is controlled for a prolonged period in some patients.”

Birrer said the trial results presented at ASCO were “remarkable,” but that the FDA would want to see an overall survival advantage before approving a new drug. He said there also remains “a fair amount of confusion” about what would be the best dosage for patients, with studies evaluating doses ranging from 100 mg to 400 mg twice daily.

Meanwhile, companies that are continuing to study PARP inhibitors in ovarian cancer include Abbott Laboratories, which is studying veliparib (ABT-888) as monotherapy for patients with relapsed ovarian cancer with a BRCA mutation; Clovis Oncology, which is exploring rucaparib (CO-338) in BRCA-associated ovarian cancer; and BioMarin Pharmaceutical Inc, which is investigating BMN-673 in patients with advanced or recurrent solid tumors, including ovarian cancers. TTN Key Research Ledermann JA, Harter P, Gourley C, et al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer. J Clin Oncol.

2011;29(suppl; abstr 5003).

Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer [published online ahead of print March 27, 2012]. N Engl J Med. doi: 10.1056/NEJMoa1105535.

Illustration courtesy of the American Society of Clinical Oncology

By Anita T. Shaffer

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Targeted Therapies: Head & Neck Cancer

Hypothyroidism Risks With MKIs Examined

By Ben Leach

Eric J. Sherman, MD

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retrospective analysis of the risks of hypothyroidism in patients in Germany who received sunitinib and sorafenib is gaining attention in the field of head and neck cancers, where the drugs are being evaluated for clinical use.

A study published in the European Journal of Cancer earlier this year found that 13.7% of patients on sunitinib and 6.3% of those who took sorafenib were treated with thyroid hormone (TH) therapy typically prescribed to treat hypothyroidism.

The study, with findings based on prescription data from 2509 patients, is believed to be the largest database examination of the endocrine disorder among people taking either of the drugs.

Both drugs are multikinase inhibitors (MKIs) that the FDA has approved for the treatment of advanced renal cell carcinoma (RCC). Sunitinib (Sutent) also is approved to treat certain gastrointestinal stromal tumors (GIST) and pancreatic neuroendocrine tumors while sorafenib (Nexavar) is additionally indicated for hepatocellular carcinoma.

A number of phase II trials are under way studying the efficacy of sunitinib and sorafenib in the treatment of thyroid cancer.

In reviewing the study, Eric J. Sherman, MD, Head and Neck Oncology, Memorial Sloan-Kettering Cancer Center, New York City, said the findings are notable in his field because MKIs represent a promising class of drugs for thyroid patients. “This study is clinically relevant to anyone treating a patient with thyroid cancer,” he said.

Using prescription data from more than 80% of German pharmacies, investigators started with an index of 6444 patients for whom one of the two anticancer therapies had been prescribed from July 1, 2006, through December 31, 2007. Clinical hypothyroidism requiring TH therapy was defined as thyroidstimulating hormone (TSH) levels >10 mIU/L. Patients who had been prescribed

TH before the study period, those who were not registered in the database, and those who received TH within 29 days of the initial index date were excluded.

Data for the remaining 2509 patients were examined based on TH prescriptions written during an observation period that began 30 days after the initial index date through August 31, 2009.

In all, 178 of 1295 patients taking sunitinib (13.7%) and 77 of 1214 patients taking sorafenib (6.3%) received TH therapy. Incidence rates were 24.2 per 100 person-years for sunitinib patients and 12.1 per 100 person-years for sorafenib patients, with the unadjusted hazard ratio for TH therapy calculated as 2.0 (95% confidence interval [CI], 1.5-2.6) for sunitinib as compared with sorafenib.

Sherman said hypothyroidism has been observed in patients, but that the study marks the first time that there are enough concrete data to make the necessary recommendations.

The German research team suggested clinicians exercise caution in prescribing TH for cancer patients with slightly increased serum-TSH levels who are not displaying symptoms. “If clinical hypothyroidism occurs, it can be treated with TH, which leads to fast and complete correction of increased TSH values and should not restrict the use

of sunitinib and sorafenib in malignant diseases in general,” they concluded.

The FDA-approved prescribing information (PI) for Sutent includes a recommendation for a baseline laboratory measurement of thyroid function prior to the start of treatment and advice about monitoring patients for signs of such problems. In May 2011, the PI was updated to include reports of higher rates of hypothyroidism than with placebo among small groups of patients.

The PI for Nexavar describes hypothyroidism as an “uncommon” adverse drug reaction and does not include it among the most serious reactions.

Sherman said that while hypothyroidism does pose a serious risk to the patient, it is also a very treatable condition. TH can be started as soon as hypothyroidism is identified, and dose rates are monitored throughout treatment. If a patient is taken off sorafenib or sunitinib, it is possible for thyroid levels to return to normal.

“It’s very easy to treat,” Sherman said.

“It’s just one of those things that you want to make sure you don’t miss.” TTN Feldt S, Schüssel K, Quinzler R, et al. Incidence of thyroid hormone therapy in patients treated with sunitinib or sorafenib: a cohort study [published online ahead of print February 28, 2012]. Eur J Cancer. doi:10.1016/j.ejca.2012.01.036.

Reolysin Trial Reaches Enrollment Milestone

Illustration courtesy of Oncolytics Biotech Inc.

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he first stage of enrollment has been completed in a phase III clinical trial that will examine the use of a human reovirus, in combination with chemotherapy, in patients with head and neck cancer. Oncolytics Biotech Inc. announced April 2 that it has enrolled 80 patients in the trial of Reolysin, a variant of the respiratory enteric orphan virus. The patients, who have platinum-refractory head and neck cancers, will receive Reolysin in combination with paclitaxel and carboplatin.

“This is an important milestone for this study,” Brad Thompson, PhD, president and CEO of Oncolytics in Calgary, Canada, said in a press release. “A data analysis that will involve examining evolving progression-free survival will now be performed on this patient group to determine the probability of success in the second stage of the study.”

The randomized, double-blind trial

will assess the intravenous administration of Reolysin with the two chemotherapy drugs versus chemotherapy alone in patients with metastatic or recurrent squamous cell carcinoma of the head and neck, or squamous cell cancer of the nasopharynx, who have progressed on or after prior platinum-based chemotherapy. It is being conducted in 80 centers in 12 countries in North America and Europe. The primary endpoint is overall survival.

Reolysin works by infecting patients with the reovirus, to which most people have been exposed by adulthood, and which typically causes few or no symptoms, the company said. Normal cells are able to fight the infection, but cancer cells with Ras gene mutations cannot, and the unchecked multiplication of the virus kills them by causing them to rupture.

Then, the virus moves on to destroy nearby tumor cells. (NCT01166542) TTN

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News Targeted Therapies: Hematologic Malignancies

Subcutaneous Dosing of Bortezomib Approved

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he FDA has approved subcutaneous injection as a safe method for delivering bortezomib (Velcade, Takeda Pharmaceuticals) for patients with multiple myeloma and mantle cell lymphoma who have received one prior therapy, expanding the potential number of patients who can receive the medication.

Bortezomib by intravenous injection is already approved (since 2003) to treat both multiple myeloma and mantle cell lymphoma. The subcutaneous delivery reduces the risk of adverse events associated with the intravenous form.

The new approval is based on a pivotal 222-patient, randomized phase III trial published in The Lancet Oncol-

ogy in May 2011. The trial compared subcutaneous and intravenous injections of bortezomib in patients with relapsed multiple myeloma who were bortezomib-naïve, finding similar efficacy regardless of the delivery method.

The patients receiving subcutaneous injections had an overall response rate (ORR) of 43% and a complete response (CR) rate of 7%. This is compared to a 42% ORR and an 8% CR in patients receiving the intravenous drug.

In addition to a noninferior efficacy compared with standard intravenous delivery, subcutaneous bortezomib injection had a lower incidence of peripheral neuropathy, a common side effect of bortezomib therapy.

This is an important benefit, according to Sundar Jagannath, MD, director of the Multiple Myeloma Program and professor of Medicine in Hematology and Medical Oncology at Mount Sinai Medical Center in New York City. “In a newly diagnosed myeloma patient at this time, we really don’t want to cre-

ate peripheral neuropathy if a better option is available,” Jagannath said. “I think this novel method of administration is really helpful.”

A total of 53% of patients in the intravenous arm experienced peripheral neuropathy of any grade, compared with 38% of patients in the subcutaneous arm; 16% of patients in the intravenous arm compared with 6% in the subcutaneous arm had grade 3 or higher peripheral neuropathy.

Additional grade 3 events included thrombocytopenia (19% vs 13% in the intravenous and subcutaneous arms, respectively) and neuralgia (9% vs 3% in the intravenous and subcutaneous, arms, respectively). TTN

Targeting the PI3K/Akt/mTOR Pathway for Lymphoma

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ne of the major developments in cancer treatment in recent years has been the potential of drugs that target the oncogenic phosphatidylinositol-3-kinase (PI3K)/Akt pathway and the mammalian target of rapamycin (mTOR), a downstream effector of the pathway. The intracellular pathway is central to cell proliferation, growth, and angiogenesis, so it’s no surprise that it’s implicated in a number of different tumor types, including breast, non-small cell lung, and renal cell cancer. Mutations and changes in expression have been found in every major node of the pathway. Typical mutations include mutation or amplification of PI3K, overexpression of the oncogene AKT, or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN). Research has shown that alteration of normal PI3K pathway signaling translates to a poor patient prognosis and resistance to available treatments. This makes the role of the PI3K pathway in tumor evolution particularly important to understand.

This multifunctional pathway has been recognized as a particularly attractive target for patients with lymphoma.

“The PI3K pathway appears continuously deregulated among lymphoma malignancies,” said Sonali M. Smith, MD, director of the Lymphoma Program at the University of Chicago Medical Center, Illinois. Molecular abnormali-

Targeted Therapy News•06.12

ties linked to abnormal PI3K pathway signaling have been demonstrated in mantle cell lymphoma (MCL), a mature B-cell non-Hodgkin lymphoma, as well as in Hodgkin lymphoma. Specifically, mTOR, a serine/threonine kinase that is a key downstream target of the PI3K pathway, as well as an important regulator of normal development, has been associated with lymphomagenesis. “[mTOR] appears to be an excellent target in MCL,” Smith said. “Overexpression of the protein cyclin D1 is the hallmark of mantle cell lymphoma. This protein is controlled in part by mTOR. So this is a very nice rationale for testing mTOR inhibitors in this cancer.”

Smith added that the entire PI3K/Akt/ mTOR pathway, not just mTOR, is valid as a target in MCL. Temsirolimus (Torisel, Pfizer), an mTOR inhibitor, has been studied in patients with MCL in phase II trials. The response rate in these trials was about 40% and lasted six months, according to Smith. This led to combination trials, including temsirolimus combined with rituximab (Rituxan, Genentech) and everolimus (Afinitor, Novartis) combined with the CHOP chemotherapy regimen.

In a phase III trial testing the efficacy of temsirolimus compared to choice of therapy in 162 heavily pretreated patients with relapsed or refractory MCL, temsirolimus significantly improved

progression-free survival (hazard ratio [HR] = 0.44; P = .0009) compared with the investigator’s choice. Objective response was 22% among patients receiving temsirolimus and 2% in the control group. The study established an effective clinical dose for temsirolimus monotherapy—the trial tested two different once-weekly dosages—and the results led to approval of the agent in Europe for relapsed or refractory MCL in 2009.

“The challenge with the classic mTOR inhibitors is that there is a lot of resistance,” said Smith, who was one of the investigators in the phase III study. It is not yet clear why only certain patients respond and why the responses are not durable. Smith believes that secondgeneration mTOR inhibitors, although still in early-stage trials, may be more promising for MCL. Another approach that exploits the PI3K/mTOR pathway is targeting PI3 kinase, the major switch that signals to mTOR. The compound GS-1101 (Gilead) specifically inhibits the delta isoform of PI3K and is in clinical trials for MCL and other types of lymphoma. The compound has “a lot of activity” in MCL, according to Smith.

MCL is one of the most difficult-to -treat subtypes of non-Hodgkin lymphoma. Between 2% and 7% of all patients with non-Hodgkin lymphoma have MCL. The disease is often diag-

Sonali M. Smith, MD

nosed at stage IV and is most common in men age 60 years and over. Because this older patient population is more likely to have comorbidities, they are not candidates for more intensive treatments, even though cytotoxic chemotherapy regimens—including rituximab and the chemotherapy regimen CHOP— appear to be effective in achieving a response, and even complete remission in many cases. Additionally, many patients relapse after receiving front-line treatments. TTN Key Research Hess G, Smith SM, Berkenblit A, Coiffier B. Temsirolimus in mantle cell lymphoma and other non-Hodgkin lymphoma subtypes. Semin Oncol.

2009; 36(suppl 3):S37-S45.

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Targeted Therapies: Hematologic Malignancies

Bruton’s Tyrosine Kinase Inhibitor PCI-32765: Durable Responses in Refractory CLL

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pdated results from a phase Ib/II clinical trial in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) showed that the new Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 could be an important approach for these patients.

BTK is a cytoplasmic tyrosine kinase important for B-lymphocyte development, signaling, and differentiation; it is a central mediator of B-cell receptor signaling, essential for normal B-cell development. PCI32765 is an oral, irreversible inhibitor of BTK that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. The initial phase Ib/II data showed the therapy to be highly active and tolerable for CLL patients. These original data were presented at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting.

Both previously untreated and relapsed

or refractory patients who had at least two prior therapies were treated with the tyrosine kinase inhibitor until disease progression. Two doses, 420 mg and 840 mg, were tested. Sixty-one patients with relapsed or refractory CLL were enrolled in the trial. Patients in the 420-mg cohort had a median of three prior therapies. The median number of prior therapies was five for the 840-mg cohort. The trial results were presented at the American Society of Hematology (ASH) Annual Meeting in December 2011.

In the 420-mg cohort, the objective response (OR) was 70% with a 10.2-month median follow-up. The OR was 44% in the 840-mg group with a 6.5 month median follow-up. Another 19% and 35% of patients in the 420-mg and 840-mg cohorts, respectively, had a nodal partial response with residual lymphocytosis. ORR, according to the trial authors, appears to be independent of

molecular risk features. Most (82%) patients were still being treated on the trial, while only 8% had progressive disease at the time of data presentation. The six-month progression-free survival was 92% in the 420mg cohort and 90% in the 840-mg cohort.

The therapy was well tolerated. Two patients discontinued therapy, and six had their dosage lowered. Approximately 21% of patients had a grade 3 adverse event potentially related to the investigational therapy. Most patients experienced a transient high lymphocyte count during the first two months of treatment and resolved over time.

Data at the ASH meeting on PCI-32765 also showed a high rate of OR in patients with relapsed or refractory mantle cell lymphoma (MCL) in a phase II trial. Phase III trials in MCL patients are being planned. Interim data from phase IB/II trials of patients

with treatment-naïve chronic lymphocytic leukemia (CLL) and combination therapy of PCI-32765 and atumumab in patients with chronic lymphocytic leukemia will be presented at the upcoming ASCO Annual Meeting in June 2012.

PCI-32765 is being jointly developed by Janssen Biotech, Inc., owned by Johnson & Johnson, and Pharmacyclics Inc. The two companies have a 50/50 profit/loss agreement and will share development and commercialization activities. TTN Key Research O’Brien S, Burger JA, Blum KA, et al. The Bruton’s Tyrosine Kinase (BTK) Inhibitor PCI-32765 induces durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Follow-up of a phase Ib/II study. Presented at the ASH Annual Meeting; December 10-13, 2011; San Diego, CA. Blood. 2011;118(21): abstr 983.

Obinutuzumab Compares Favorably With Rituximab in NHL Trial

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reatment with obinutuzumab (GA101) showed higher response rates compared to rituximab in patients with relapsed or refractory nonHodgkin lymphoma (NHL) in a phase II randomized trial. Patients in the trial had a previous complete response (CR) or unconfirmed complete response (CRu) to a rituximab-containing regimen. Both obinutuzumab and rituximab antibody therapies target the CD20 protein expressed on cancerous B-cells. Obinutuzumab is designed to bind CD20, a major lymphoma biomarker on the surface of B-cells selectively and with higher affinity. The drug is a novel glyco-engineered anti-CD20 monoclonal antibody that causes cell death of cancerous B-cells that express CD20 by activating the patient’s immune cells to attack the cancer cells or by inducing apoptosis of the cancerous cells.

Rituximab (Rituxan, Roche), a chimeric antibody against CD20, is approved as a first-line treatment for CD20-positive B-cell NHL in combination with chemotherapy and as a maintenance monotherapy following the rituximab plus chemotherapy combination treatment for patients who achieve a response. Rituximab and other therapies have improved survival rates in patients with NHL. Still, relapse of the dis-

ease and resistance to treatments remains a major hurdle.

Although obinutuzumab has shown activity against lymphoma in single-arm studies, the current GAUSS trial is the first comparing the therapy to an approved NHL treatment. The results of the GAUSS international trial were reported by Laurie H. Sehn, MD, MPH, a medical oncologist at the British Columbia Cancer Agency and clinical associate professor at the University of British Columbia, in Vancouver, BC, Canada, at the American Society of Hematology (ASH) Annual Meeting in December 2011.

“This is the first head-to-head trial of GA101 against rituximab in patients with relapsed, indolent NHL,” said Sehn. “GA101 demonstrated promising efficacy with a trend towards higher response rates, without appreciable differences in safety,” she added. The study was not powered to show superiority of obinutuzumab over rituximab. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety outcomes in patients receiving both treatments.

A total of 175 patients (149 follicular [FL] and 26 nonfollicular indolent NHL) were randomized to receive four weekly infusions of either obinutuzumab or ritux-

imab. Patients had received an average of two prior lines of therapy—all containing rituximab. Patients without evidence of progression following induction therapy received ongoing treatment with GA101 or rituximab every two months for up to two years at the same dose. The groups were balanced, although at baseline patients receiving obinutuzumab had a larger volume of disease.

The primary efficacy analysis was conducted in the FL population (n=149) at the end of the induction phase. The ORR was 44.6% in the obinutuzumab arm compared with 33.3% in the rituximab arm; there were 11.3% more responses in the experimental agent arm. A complete remission (CR) or unconfirmed complete remission (CRu) was seen in 12.2% versus 5.3% of patients in the obinutuzumab and rituximab arms, respectively. The best overall response in the FL population was CR/CRu for 35.1% of the obinutuzumab group and 18.7% of the rituximab group.

While there were more infusion-related reactions with obinutuzumab (74% vs 51%), both agents were well tolerated. Infusionrelated reactions are common with antibody treatments and were generally mild and did not result in significant differences in treatment discontinuations, according

Laurie H. Sehn, MD, MPH

to Sehn. Grade 3 infusion-related reactions were 11% and 6% in the obinutuzumab and rituximab arms, respectively.

“Based on these data, we believe that phase III trials to truly test the efficacy of this agent are warranted, and they are now under way,” she said. A large phase III study testing obinutuzumab in combination with chemotherapy compared to rituximab with chemotherapy in patients with advanced indolent NHL is ongoing.

Another phase III trial is testing the drug in combination with CHOP chemotherapy in patients with large B-cell lymphoma whose cancer cells express CD20. Obinutuzumab is also being investigated in patients with treatment-naïve chronic lymphocytic leukemia. TTN Key Research Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing GA101 (obinutuzumab) with rituximab in patients with relapsed CD20 indolent B-cell non-Hodgkin lymphoma: preliminary analysis of the GAUSS study. Presented at the ASH Annual Meeting; December 10-13, 2011; San Diego, CA. Blood.

2011;118(21): abstr 269.

Targeted Therapy News•06.12

14

News Targeted Therapies: Hematologic Malignancies

Nilotinib Beats Imatinib for CML in Two Phase III Trials

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ata presented at the American Society of Hematology (ASH) Annual Meeting in December 2011 showed that nilotinib (Tasigna) continues to exhibit better molecular response levels in patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) compared with imatinib mesylate (Gleevec). Imatinib, approved in 2001 for CML, is considered the established standard of care; nilotinib was approved in 2011.

The ENEST (Evaluating Nilotinib Efficacy and Safety in clinical Trials) research program aims to assess the efficacy of nilotinib, a next-generation tyrosine kinase inhibitor (TKI) in patients with CML who have developed resistance to or are unable to tolerate imatinib. Three-year follow-up data from the ENESTnd confirmed the superiority of nilotinib over imatinib and acceptable tolerability for patients newly diagnosed with Ph+CML. The second result from this program presented at ASH showed that switching patients with Ph+CML from imatinib to nilotinib led to faster and better molecular responses. This ENESTcmr trial aimed to test whether switching patients from imatinib to nilotinib would be more efficacious for CML patients on long-term imatinib therapy. The ENEST program is funded by Novartis Pharmaceuticals, the manufacturer of both medications.

The Philadelphia chromosome is a fusion of the abl protein with bcr, leading to a constitutive activation of the abl tyrosine kinase, the hallmark of CML. Imatinib selectively binds and inhibits

ENESTnd Study Design

the activity of the mutated abl protein.

Nilotinib also blocks bcr-abl activity— based on in vitro studies, nilotinib has a greater binding potency for bcr-abl compared with imatinib and has activity against many of the imatinib-resistant bcr-abl mutations. The other nextgeneration bcr-abl inhibitor is dasatinib (Sprycel, Bristol-Myers Squibb), also approved for resistant and relapsed CML after imatinib treatment.

Recent studies have demonstrated that about 40% of very highly selected Ph+ CML patients treated with imatinib achieved durable CMR and may be able to cease therapy without disease recurrence. However, most patients with CML do not achieve CMR on imatinib, even with long-term therapy, mostly due to resistance to the TKI. The ENESTcmr trial enrolled 207 patients who had been treated with imatinib for at least two years. The primary endpoint was confirmed CMR (undetectable levels of bcr-abl by 12 mo). Of the intention-to-treat group still in the study at 12 months, 14.9% of patients on nilotinib and 6.1% of patients on imatinib achieved a confirmed CMR (P = .04).

The results showed 23% (n = 24) of patients who received nilotinib at 400 mg twice daily had undetectable levels of the bcr-abl protein in a blood test after 12 months. This level was higher than the 11% of patients (n = 11) taking imatinib once daily (P = .02). Adverse events were higher in the nilotinib group, but consistent with previous studies: 29% of nilotinib-treated patients compared with 2% of imatinib-treated patients

experienced grade 3 or 4 events. The authors of the study concluded that the deeper molecular responses with nilotinib could increase the eligibility of patients to enroll in tyrosine kinase discontinuation studies. A discontinuation study is currently ongoing.

The ENESTnd trial studied the effectiveness of nilotinib at two different dose levels compared with imatinib in patients with newly diagnosed Ph+ CML in chronic phase. The study randomized 846 patients to receive nilotinib 300 mg twice daily (n = 282), nilotinib 400 mg twice daily (n = 281), or imatinib 400 mg once daily (n = 283). The three-year follow-up results showed that fewer patients taking nilotinib experienced disease progression to accelerated phase

Stratified by Sokal risk score

Year 3

Nilotinib 300 mg BID (n = 282)

Patients diagnosed with Ph-positive CP-CML within 6 months

Nilotinib 400 mg BID (n = 281)

(N = 846) Nilotinib 400 mg QD (n = 283)

Targeted Therapy News•06.12

5-year follow-up

or blast crisis, whether in the 300-mg arm (n =2) or the 400-mg arm (n = 3) compared with the group taking imatinib (n =12). Among patients taking nilotinib 400 mg twice daily, 97% were alive at the three-year mark (8 patient deaths) compared with 94% of patients on imatinib (17 patient deaths). Nilotinib was superior to imatinib in all major efficacy endpoints, including CMR and major molecular response.

Nilotinib was also associated with fewer CML-related deaths. The study found that five patients taking nilotinib 300 mg twice daily and four patients taking nilotinib 400 mg twice daily died of CML-related issues in the follow-up period compared with 14 patients in the imatinib arm. Overall, 28% of patients taking nilotinib 400 mg twice daily achieved the deepest levels of response compared with 15% of patients taking imatinib (P = .0003). TTN

Key Research Hughes TP, Lipton JH, Leber BL, et al. Complete molecular response (CMR) rate with nilotinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) without CMR after ≥2 years on imatinib: preliminary results from the randomized ENESTcmr trial of nilotinib 400 mg twice daily (BID) vs imatinib. Presented at the ASH Annual Meeting; December 10-13, 2011; San Diego, CA. Blood. 2011;118(21): abstr 606.

Saglio G, LeCoutre PD, Pasquini R, et al. Nilotinib versus imatinib in patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 36-month (mo) follow-up.

Presented at the ASH Annual Meeting; December 10-13, 2011; San Diego, CA. Blood. 2011;118(21): abstr 452.

B:9” T:8.25” S:6.75”

Cabozantinib (XL184) phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases CabOzantinib MET Inhibition CRPC Efficacy Trials 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

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

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/TT 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

B:11.125”

PRIMARY ENDPOINT

S:9.75”

COMET-2

T:10.875”

COMET-1

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.

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

Mechanism of action

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 AUC 0-∞ (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.

KAPLAN-MEIER SURVIVAL CURVES OF PATIENTS TREATED WITH EITHER ZYTIGA® + PREDNISONE OR PLACEBO + PREDNISONE (INTERIM ANALYSIS) 100

P < 0.0001; HR = 0.646; 95% CI: 0.543, 0.768

% Survival

80

ZYTIGA®: 14.8 months (median) (95% CI: 14.1, 15.4)

60 Placebo: 10.9 months (median) (95% CI: 10.2, 12.0)

40 20 0 0

3

6

9

12

15

18

21

68 30

2 3

0 0

Time to Death (Months) ZYTIGA® 797 Placebo 398

736 355

657 306

520 210

282 105

The median duration of treatment with ZYTIGA® was 8 months.

Proven survival benefit At the interim analysis of the phase 3 study,*† ZYTIGA® in combination with prednisone showed a statistically significant improvement in overall survival compared with placebo plus prednisone and resulted in a 35% reduction in the risk of death (hazard ratio [HR] = 0.646; P < 0.0001; 95% confidence interval [CI]: 0.543, 0.768; median survival: 14.8 months vs 10.9 months, respectively) In an updated survival analysis,‡ results were consistent with those from the interim analysis (HR = 0.74; 95% CI: 0.638, 0.859; median survival: 15.8 months vs 11.2 months)

*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 3/12 08Z12066B

study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398).

Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival. †552 events. ‡775 events.

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.

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®.

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

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

www.zytiga.com

News

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Targeted Therapies: Prostate Cancer

Zytiga Study Unblinded After Interim Analysis

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ue to the positive results found in an interim review, researchers unblinded a phase III study of abiraterone acetate (Zytiga) plus prednisone ahead of schedule. The drug combination is being tested in asymptomatic or mildly symptomatic men with metastatic castration-resistant prostate cancer (CRPC) who have not received chemotherapy.

The Independent Data Monitoring Committee (IDMC) unanimously recommended unblinding the study (COUAA-302) early after a planned interim analysis found clinical benefit in radiographic progression-free survival and overall survival, the primary endpoints of the study, according to Janssen Research & Development.

In addition, the committee found a favorable safety profile among men in the treatment arm. The committee not only recommended unblinding the study, but also that patients on placebo be offered treatment with abiraterone, the company said.

The international, multicenter, double-blind study included 1088 patients who were randomized to receive abiraterone 1000 mg once a day with prednisone 5 mg administered twice daily or placebo plus the steroid.

A company official indicated that the IDMC analysis helps advance explorations of the drug. “The COU-AA-302 study has been a key priority for us as we expand our understanding of the utility of Zytiga in metastatic prostate cancer,” William N. Hait, MD, PhD, global head of Janssen R&D, said in a press release.

The company did not provide more details of the results because it plans to submit them for publication in a peerreviewed journal.

In April 2011, the FDA approved abiraterone in combination with prednisone to treat men with metastatic CRPC who have received prior chemotherapy containing docetaxel. Later this year, Janssen plans to seek an expanded indication in men with CRPC

Sipuleucel-T Stimulates Response in Localized Setting, Study Finds

By Ben Leach

Illustration courtesy Ben Mills/Wikimedia Commons

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he neoadjuvant administration of sipuleucel-T (Provenge) may stimulate an immune response in patients with localized prostate cancer without adversely affecting their surgeries, according to study results presented at the 2012 Genitourinary Cancers Symposium. The study explored the possibility of using the vaccine earlier in the treatment timeline than its current approved indication for patients with asymptomatic or minimally symptomatic metastatic castrationresistant prostate cancer.

In a phase II trial, 42 patients with localized prostate cancer who were slated for radical prostatectomy were given sipuleucel-T in three infusions administered 6 to 7 weeks prior to their surgeries. Prostate cell specimens were collected prior to and following treatment with sipuleucel-T. Patients were

Leonard G. Gomeela, MD

followed for 72 weeks, and also randomly assigned to receive a booster treatment with the vaccine or no further treatment.

who have not received chemotherapy.

Abiraterone, which inhibits the CYP17 enzyme, is a first-in-class agent targeting testosterone, according to the National Cancer Institute. It blocks androgen production at three sources—the testes, the adrenal glands, and the tumor itself, the company said. TTN

Molecular structure of abiraterone

At the time of the presentation in February, immunohistochemistry analysis had been completed on 19 patients.

“Significant increases (>2‑fold) in CD3positive and CD4-positive T-cell populations were observed at the tumor rim, where benign and malignant glands interface, compared with the pretreatment biopsy,” researchers said in their abstract. Surgical impact was measured by operative complications, procedure time, and estimated blood loss.

In a companion abstract, investigators reported a “robust immune system activation,” including antigen-presenting cells and memory and activated mature B cells.

Although the results are preliminary, the study suggests more work should be done to explore the potential benefits in patients who have an earlier-stage prostate cancer, according to Leonard G. Gomella, MD, Bernard W. Godwin Jr. Professor of Prostate Cancer, chairman, Department of Urology, and director, Clinical Affairs, Kimmel Cancer Center Thomas Jefferson University, Philadelphia, Pennsylvania. Gomella served as chair of the conference program committee at the American Society of Clinical Oncology symposium.

“This is very exciting because if immunotherapies work, they tend to work when there’s a minimal amount of disease,” Gomella said.

He also said the study found tumor

markers through which the impact of the treatment could be evaluated.

“One of the challenges that we have when we look at all immunotherapy, and particularly when we look at the sipuleucel-T immunotherapies, is that we don’t have a specific marker for response,” Gomella said. “This is very encouraging and very positive news that this study was able to show that there were specific markers of an immune response in the prostate.”

He noted that the study is among early-phase investigations into stimulating the immune cells in the preprostatecomy setting, but that major clinical trials are “a long way off.”

Investigators said in their abstract that “work is ongoing to more fully characterize the immune response within the prostate tumor tissue and in the peripheral blood.” TTN

References Fong L, Weinberg VK, Corman JM, et al. Immune responses in prostate tumor tissue following neoadjuvant sipuleucel-T in patients with localized prostate cancer. J Clin Oncol. 2012;30:(suppl 5). Abstr 181.

Sheikh NA, Wesley JD, Perdue N, et al. Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized prostate cancer. J Clin Oncol. 2012;30:(suppl 5). Abstr 178.

Targeted Therapy News•06.12

20

News Targeted Therapies: Renal Cell Carcinoma

Approval of Axitinib Adds Another Therapy Option for Metastatic RCC

Brian I. Rini, MD

A

xitinib (Inlyta, Pfizer) is the seventh drug approved for the treatment of advanced renal cell carcinoma (RCC) since 2005. The small-molecule tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptors (VEGFR-1, 2, 3), platelet-derived growth factor receptor (PDGFR), and cKIT was approved by the FDA in January of this year as a second-line treatment.

Axitinib joins three other multi-tyrosine kinase inhibitors, two mTOR inhibitors, and an antiangiogenic therapy as available treatments for metastatic RCC. “We went from almost no therapies to many promising therapies. Now, patients with metastatic disease are living more than twice as long as they did before—two years on average. It’s harder to measure quality of life and how much better they feel, but they feel better being alive than not, and that’s the ultimate test,” said Brian Rini, MD, associate professor of Medicine at Case Western Reserve University and a practicing oncologist at the Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio. Rini was the principal investigator of the pivotal phase III AXIS trial that led to the approval of axitinib in RCC. Rini presented AXIS trial secondary results at the American Society of Clinical Oncology (ASCO) 2012 Genitourinary Cancers Symposium. The original trial results were presented at the annual 2011 ASCO conference. The 723 patients on the trial who had failed an initial systemic therapy (either sunitinib, bevacizumab plus interferon-alpha, temsirolimus, or cytokines) for treatment of their metastatic clear-cell RCC were randomized to either 5 mg of axitinib or 400 mg of sorafenib (Nexavar, Bayer)—both administered twice a day (BID). The majority of patients (54%) had

Targeted Therapy News•06.12

received sunitinib as their initial therapy.

Treatment was discontinued in 14 of 359 patients receiving axitinib and in 29 of 355 patients receiving sorafenib.

Patients in the axitinib arm began with a 5-mg dose; those who tolerated this dose could be titrated up to a 10-mg dose, depending on tolerability. The outcome and frequency of adverse events were similar in both patients whose axitinib dose was titrated and those who received a constant dose: Both subgroups showed superior responses compared with sorafenib. Progression-free survival (PFS), the primary outcome, favored the axitinib arm, which had a median PFS of 6.7 months compared with 4.7 months for the sorafenib arm (hazard ratio [HR] = 0.665; P < .0001).

Prior treatment did not affect outcomes; both patients previously treated with sunitinib and cytokine therapy had a robust response to axitinib. The objective response rates were 19.4% for patients taking axitinib compared with 9.4% for those on sunitinib (P = .0001).

The AXIS trial was the first trial for kidney cancer to compare two kidney cancer drugs. “I started working with this drug eight years ago, so it’s been a long road,” Rini said. “Thousands, if not tens of thousands, of people must come together to make trials like this happen, not to mention the patients,” he said. “This is the fun part, when we get to the end and get results like this. It’s gratifying for all the hard work people have put in along the way.”

Rini was also involved in the phase III trial of bevacizumab combined with standardof-care interferon-alfa that resulted in approval of the combination by the FDA in 2009 for metastatic RCC. Because earlier-stage trials showed intrapatient variability on the ability to achieve

therapeutic levels with the standard 5-mg BID dose, a dose-titration strategy was applied to normalize plasma levels of axitinib exposure. In the phase III study, criteria for dose titration included no toxicity greater than grade 2 for two weeks or more, a blood pressure of <150/90 mmHg, and no antihypertensive medication. Investigators had the discretion to titrate axitinib to 7 mg, and then to 10 mg, depending on patient reaction to the drug. A total of 25% of patients experienced dosage reductions or progression, and one-third did not need any dosage changes. Thirty-seven percent received escalating doses of ixitinib—17% to 7 mg and 20% to 10 mg.

The phase IIII secondary analysis presented by Rini showed a roughly equivalent PFS in the titrated group compared with the nontitrated group of axitinibtreated patients. Both subgroups had a superior PFS compared with patients treated with sorafenib. Adverse events were consistent among the titrated and nontitrated patients.

“One would expect this,” Rini said. “Both groups had similar blood levels of the drug,” No difference in PFS was observed in the axitinib-treated groups who had a prior response to sunitinib, but PFS improved in sorafenib-treated patients with a prior response to sunitinib. “This is a small subset of patients,” he said. A further subanalysis of patients from the AXIS trial who had initially received cytokine therapy will be presented at the upcoming 2012 ASCO meeting in June.

Axitinib is currently being tested in the front-line metastatic RCC setting. The fully-accrued trial is testing axitinib given at a 5-mg dose twice daily compared with sorafenib at 400 mg twice daily, the same dose as in the second-line study. After four weeks, axitinib-treated patients are segregated to either a dose-titration or a steady 5-mg dose subgroup. Results of the trial are expected in 2013. Data from the phase II first-line trial of axitinib will be presented at the 2012 ASCO annual meeting by Rini.

RCC researchers are getting more comfortable with axitinib titration, according to Daniel C. Cho, MD, of the Beth Israel Deaconess Medical Center in Boston, Massachusetts. Cho believes that this titration approach should also be applied to other therapies. He noted that sorafenib is too toxic at higher doses, but that the newer TKIs may be more amenable to dose titration.

Despite the progress in new treatments, the field has a long way to go, Rini said.

New therapies have extended patients’ lives, but resistance is a major issue. The researcher is determined to continue to develop unique approaches and new drugs for RCC. Thankfully, new potential treatments are in the pipeline, with some already in phase III trials.

A phase III IMPACT global trial is testing a therapeutic vaccine, IMA901, in combination with sunitinib compared to sunitinib alone in treatment-naïve metastatic RCC patients. IMA901 is a combination of multiple tumor-associated peptides. The vaccine is being developed by immatics biotechnologies GmbH. The primary endpoint of the trial is overall survival. Phase II data had shown

“PFS was roughly equivalent in the titrated and nontitrated groups of axitinib-treated patients, and both groups had superior PFS versus sorafenib in this second-line setting.”

–Brian I. Rini, MD both promising immune response and survival in patients with advanced RCC. Another trial, at the Cleveland Clinic, is a sunitinib-dosing study. The phase II pilot study started last year to test whether giving sunitinib for six months, and then giving the patients a break from the drug for two months, may be more efficacious than continuous drug therapy. The rationale is that the two-month break may provide a better quality of life for patients. The long-term on-off schedule may be more sustainable compared to ongoing therapy that results in intolerable side effects that result in discontinuation of treatment. TTN Key Research Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931-1939.

News

21

Targeted Therapies: Skin Cancer

New Laboratory Melanoma Research Supports Ongoing Clinical Trials

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Courtesy Genentech BioOncology, member of the Roche Group

wo new treatments for metastatic melanoma were approved in 2011— the first in more than a decade. Ipilimumab (Yervoy, Bristol-Myers Squibb), an immunotherapy, showed overall survival improvement, leading the FDA to approve the therapy for both treatmentnaïve and previously treated patients in March of that year. Five months later, vemurafenib (Zelboraf, Genentech), a targeted BRAF inhibitor, was approved for use in metastatic melanoma tumors that have the BRAFV600E mutation—about 40% of all patients with meatstatic melanoma. Even before the formal approval of the BRAF inhibitor, the two companies that manufacture ipilimumab and vemurafenib, Bristol-Myers Squibb and Genentech, respectively, entered into a collaboration to formally test the safety and efficacy of the combination therapy in patients with the BRAF mutation. The phase I/II, 50-person, dose-escalation trial formally started in November 2011.

At the 2012 American Association of Cancer Research annual meeting held at the end of March, melanoma researchers from the MD Anderson Cancer Center in Houston, Texas, presented formal evidence supporting the combination trial.1 Patrick Hwu, MD, head of MD Anderson’s Department of Melanoma Medical Oncology, presented data showing that adding a BRAF inhibitor to immunotherapy can reverse the immunosuppressive tumor microenvironment induced by the BRAF mutation.

Additionally, the researchers found that a BRAF inhibitor increased the im-

mune response to a tumor in a mouse tumor model. The study provided evidence that the BRAF inhibitor targeted therapy does not prohibit the immune function of patients with metastatic melanoma. This is an important result, as evidence exists that kinase-targeted treatments can have detrimental off-target effects on the cells of the immune system. Vemurafenib may not because of its specificity and minimal

Patrick Hwu, MD

off-target effects, according to Gregory Lizée, PhD, of the same department, who was also a part of the study. Both human data and mouse models led to the conclusion that the combination of a BRAF inhibitor with immunotherapy may act in a synergistic way.

Another recent study addresses mechanisms of resistance to BRAF inhibitor treatment in patients with metastatic melanoma.2 Roger Lo, MD, PhD, and colleagues at the Johnsson Comprehensive Cancer Center at the University of California in Los Angeles have discovered

how tumor cells are able to stop responding to treatment with vemurafenib. The team sequenced the protein-coding parts of the genome of tumors from patients treated with the drug. “Patient biopsy-oriented translational research is absolutely key to overcoming targeted drug resistance,” Lo stressed.

The research team found the tumors to have higher copy numbers of the BRAF gene, meaning the tumor is producing extra BRAF protein, rendering inhibition by the drug ineffective. About 20% of patients (a total of 20 were sampled) who developed resistance had this amplification of the BRAF gene. Using cell lines, the researchers also found that the combination of a BRAF and MEK inhibitor could overcome the amplification-driven resistance. This combination treatment is currently in a phase I/II clinical trial for advanced melanoma. “[In an earlier study], we initially found no evidence of secondary mutations in the BRAF gene,” said Lo.3 “This shifted the pharmaceutical community away from further drug development for alternative BRAF inhibitors that might circumvent mutated BRAFV600 harboring secondary mutations. The surprise is we have recently come full circle to find that alterations in BRAF—beyond the mutation that activates this oncogene—are important.” These BRAF mutations include truncations in the gene4 and the newly described BRAF amplification.

Researchers have discovered resistance mechanisms that account for somewhere between 60% and 70% of resistance cases;

the other relapsed patients develop resistance by as yet unknown means. The next steps for Lo and his team will be to study each individual patient and find out what happens during relapse at the molecular level. This research will facilitate nextgeneration clinical trials and new therapies that can be combined for a more robust response. It could also result in ways to avoid needing to overcome resistance.

“The goal is to understand all possible mechanisms and deduce the common denominator molecules that can be targeted, together with mutant BRAF, in combinatorial approaches,” Lo said. Already, the combination of a BRAF inhibitor with a MEK inhibitor is expected to be a “powerful two-hit,” increasing efficacy and reducing side effects, Lo said. TTN

References 1. Hong DS, Vence L, Falchook G, et al.

BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency.

Clin Cancer Res. 2012;18:2326-2335.

2. Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies (V600E) B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun. 2012;3:724.

3. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature.

2010;16;468(7326):973-977.

4. Poulikakos PI, Persaud Y, Janakiraman M, et al.

RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature.

2011;480(7377):387-390.

First-Ever Drug Approved for Advanced Form of Most Common Skin Cancer

B

asal cell carcinoma (BCC) makes up about 80% of all skin cancers and affects up to 2 million Americans every year. This most common form of cancer is curable if the lesion is within a confined area and rarely progresses to a more advanced form. Still, until the approval of vismodegib (Erivedge, Roche) this past January, there were few options for patients who had progressed to the metastatic form of the disease.

Vismodegib is not only the first treatment approved for advanced BCC (as

well as for adults with advanced BCC that cannot be treated with radiation or surgery), but the first inhibitor of the Hedgehog signaling pathway to gain authorization from the FDA. The decision, based on the pivotal phase II ERIVANCE study, came after an expedited six-month review. Vismodegib showed a 43% objective response rate for locally advanced BCC and a 30% response rate for metastatic BCC. The median duration of response was 7.6 months.

Vismodegib is an oral medication that

selectively inhibits the smoothened receptor (SMO) in the Hedgehog pathway.

Abnormal signaling through the Hedgehog pathway is the major underlying molecular driver of BCC. Genentech, a

part of the Roche Group, discovered the molecule and collaborated with Curis, Inc on preclinical studies. TTN

Targeted Therapy News•06.12

22

Feature

ASCO: A Focus on Personalized Medicine

By Anna Azvolinsky, PhD vice on individual new therapies.

This new feature is part of a set of premeeting seminars that start one day before the official meeting kick-off. Notably, six of the seven drugs discussed are targeted treatments. Two of these treatments, axitinib and vismodegib, were approved by the FDA in 2012. Drugs to be discussed include:

• Vemurafenib (Zelboraf, Genentech), an oral, small-molecule BRAF inhibitor for patients with metastatic melanoma whose tumors harbor a BRAFV600E mutation.

Patricia LoRusso, DO

T

he year 2011 marked a milestone of sorts for new drug approvals by the FDA. Thirty-five new medicines were approved—the second highest number of approvals in the last decade. Seven were oncology drugs, including the first one approved for Hodgkin lymphoma in 30 years.

With the influx of these new drugs, awareness and education for oncologists are paramount, and this year’s annual meeting of the American Society of Clinical Oncology (ASCO) will include educational seminars on these latest clinical advances. Leading researchers involved in the development of the oncology drugs will provide practical ad-

• Crizotinib (Xalkori, Pfizer), an oral, small-molecule, dual inhibitor of the c-MET and ALK receptor tyrosine kinases for advanced non-small cell lung cancer (NSCLC) that expresses the EML4-ALK fusion gene.

• Brentuximab vedotin (Adcetris, Seattle Genetics), for intravenous infusion, an anti-CD30 antibody for the treatment of CD30-positive relapsed Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma.

• Abiraterone acetate (Zytiga, Janssen), an oral inhibitor of the cytochrome P450 17A1 protein (CYP17A1) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in men who have received prior chemotherapy.

• Axitinib (Inlyta, Pfizer), an oral smallmolecule inhibitor of multiple tyrosine kinases including cKIT, VEGFR 1-3, and PDGFR, for treatment of relapsed advanced renal cell carcinoma (RCC).

• Vismodegib (Erivedge, Genentech), an oral inhibitor of the Hedgehog pathway for the treatment of advanced basal cell carcinoma (BCC). Uninhibited signaling of the Hedgehog pathway is the molecular driver of BCC. Another pre-meeting session will focus specifically on targeted therapy approaches. Patricia LoRusso, DO, of the Karmanos Cancer Institute, Detroit, Michigan, in the session “Where Did We Come From, Where Do We Go From Here?” will give a bird’s-eye view of targeted therapies, discussing past and present development and how to approach the next phase based on what targeted therapies have taught us thus far.

Because many of the new targeted therapies are oral medications that patients take at home, the ways in which patients are educated about their treatments and monitored have fundamentally evolved. The management of side effects of targeted therapies will be discussed in a session by an oncology nurse, Peg Esper, MSN, MSA, RN, ANPBC, AOCN, from the University of Michi-

gan School of Nursing, Ann Arbor.

“Targeted therapies for such tumors as metastatic melanoma, prostate cancer, and renal cell cancer will most likely be presented at the meeting,” said LoRusso. “There is also a lot of activity ongoing with other novel targets, such as agents targeting the PI3 kinase pathway and various isoforms of the PIK3CA mutation. Hopefully some of this data will be mature enough and presented as well.”

According to LoRusso, the face of melanoma has changed completely because of targeted and biologic treatments: “There has been a huge impact.”

Phase III results of the effectiveness of vemurafenib for melanoma were presented at last year’s ASCO plenary session. This compound has had a major impact on the BRAF-mutated subset of melanoma. Results of new targeted treatments and their combinations will likely be a highlight of this year’s meeting as well.

LoRusso sees combination therapies as the future of targeted therapies. “In metastatic disease, where we are going for one major target because there is one major driver mutation—such as with basal cell cancers, ALK-mutated lung cancer, or BRAF-mutated melanoma, for example—the majority of these patients will eventually go on to progress despite continued therapy,” said

Targeted Therapy Presentations to Watch for at ASCO • Metastatic melanoma: Results of the phase III METRIC clinical trial of trametinib, a MEK inhibitor tested in a global, randomized trial of patients with metastatic melanoma, the results of the phase III BREAK-3 trial of dabrafenib, a BRAF kinase inhibitor; also, an update on a phase I/II trial of dabrafenib combined with trametinib in treatment-naïve patients.

• Non-small cell lung cancer: Results of the pivotal phase III LUX-Lung 3 trial of afatinib in treatment-naïve patients with metastatic NSCLC with EGFR mutations. The trial compares the efficacy of afatinib, an irreversible ErbB family inhibitor, to pemetrexed/cisplatin. Mutations in EGFR, also known as ErbB1, are found in approximately 12% of Caucasians and as many as 40% of Asian patients with NSCLC.

• RCC: Results of the global, randomized, phase III TIVO-1 clinical trial testing the efficacy of tivozanib, a receptor tyrosine kinase inhibitor, against sorafenib, the current standard of care, as a first-line treatment for advanced RCC.

• Acute myeloid leukemia and acute lymphoblastic leukemia: Six-month follow-up data from the pivotal PACE trial of ponatinib, a pan-BCR-ABL inhibitor, in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are resistant or intolerant to the currently approved BCR-ABL inhibitors dasatinib and nilotinib, or who have the T315I mutation. Positive preliminary data were presented at the American Society of Hematology (ASH) meeting in December 2011.

• Liver cancer, RCC, prostate cancer, and thyroid cancer: Four oral presentations of studies with cabozantinib (XL184) are expected during ASCO. Cabozantinib is a small-molecule inhibitor of the tyrosine kinases c-Met and VEGFR2. The four presentations will be: • Clinical data of a phase II randomized, discontinuation trial in hepatocellular carcinoma • Efficacy of cabozantinib in patients with metastatic, refractory RCC • Phase II nonrandomized, expansion cohort results in chemotherapy-pretreated mCRPC • Full results of the pivotal phase III EXAM trial in medullary thyroid cancer patients

Targeted Therapy News • 06.12

• Immunotherapy for melanoma, RCC, and lung cancer: Several abstracts will be presented on phase I and phase II clinical trials of MDX-1106/ BMS-936558, an antiPD1 immunotherapy that is seen as the next generation of immunotherapy after ipilimumab. Anti-PD1 is being developed by Bristol-Myers Squibb. Results are expected from the large expansion cohort data of the phase I/II solid tumor trial and potentially from the phase II RCC trial.

Feature LoRusso. “Based on this evidence, combination targeted therapies is the way to go forward.”

Many monotherapies have not resulted in robust responses, or at least not in long-term responses, according to LoRusso. “We are in the process of being challenged to re-think how we give these targeted therapies, especially if combination data demonstrate better efficacy over monotherapy.” LoRusso also pointed out that because of the high potential cost of combining therapies, combinations will have to show robust efficacy in order to be widely utilized.

Science is what is driving the combination therapies. Hypothesis-driven clinical trials based on robust laboratory research results is now much more prevalent, said LoRusso. The challenge will be to not only further develop new therapies, but to find better ways to measure progress and genomic evolution of a tumor through the course of disease and treatment.

Serial biopsies are at times necessary and ultimately can benefit a patient by providing accurate information that influences further treatment. However, these biopsies can be invasive and come with many adverse effects. “We realize that the information biopsies provide is important for treatment decisions and assessment of disease. They are important but associated with toxicities,” LoRusso said. New technologies such as assaying for circulating tumor cells or circulating DNA are in development as potential ways to access the cancer information less invasively—a topic to be discussed at the ASCO 2012 meeting.

Identifying patients who will benefit

most from a medication is also important, both for patient outcomes and to minimize cost of care, two major ongoing issues in oncology. “We need to focus on what is best for the patient,” said LoRusso.

Rising Cost (continued from cover)

prehensive Cancer Center and professor of Oncology at Johns Hopkins Medical School in Baltimore, Maryland. Smith discussed the rising cost of cancer therapies, the burden of cost, and the costbenefit analysis of end-of-life care, and will also speak about these issues at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in a session titled, “Costs of Cancer Care: Affordability, Access, and Policy.”

few months at most. As a result, as new therapies become available in clinical practice, questions about costs versus benefits are increasingly emerging.

Among the often difficult questions being asked: Are the survival gains worth the burden on the healthcare system and individual patients? How do we pay for new drugs, diagnostics, and technologies—and who should pay?

Like it or not, economics are driving treatment choices for patients in the real world. Even when a drug is covered by insurance, many patients are not able to afford even the copay. Thus, despite advances in innovation and care, cost is hindering use of new therapies.

To gain perspective on these issues, Targeted Therapy News spoke with Thomas J. Smith, MD, director of Palliative Medicine at The Sidney Kimmel Com-

Provocative NCI Questions To Be Addressed A key theme at this year’s ASCO meeting will be sessions that aim to address some of the provocative questions that were assembled by the National Cancer Institute (NCI) in 2011. The goal of the questions is to identify and address the most complex cancer care and research problems. The ASCO sessions will be a forum for the oncology community to discuss the problems and think of innovative, “outside-the-box” ways to use laboratory, clinical, and population studies to begin to offer answers. Many educational sessions at ASCO will highlight these questions.

One of the proposed questions, “Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene?” highlights the ability of targeted therapies to inhibit a specific driver mutation within a tumor.

The question also brings to light our relatively meager understanding of why inhibition of oncogenic drivers leads to cancer cell death for some tumor types but not others. Many broad and tumor type-specific sessions will address this question. Some of these sessions include “Biologic Principles of Targeted Combination Therapy,” “Developing a Targeted Therapy: Issues in the Age of Personalized Therapy,” and “New Options, New Questions: How to Select and Sequence Therapies for Metastatic Melanoma.” TTN

TTN: How can oncologists stay informed about the best decisions on care alongside their patients in the context of new high-cost targeted therapies?

Smith: It is complicated. I think the first question we have to ask ourselves as oncologists is, “Does it work?” Is there a clear-cut improvement in overall survival or disease-free survival, or quality of life that makes it better than other treatments? If the answer to this first question is yes, then the

23

ASCO: Targeted Therapy Educational Sessions Treating patients with targeted therapies requires a new approach to diagnosis (using molecular biomarkers), monitoring of patients, management of new types of adverse events, and cost decisions due to high prices of these medications. We have witnessed a range of successes in the advancement of targeted therapy research and clinical trials, and approvals for different types of cancers. For example, lung cancer, breast cancer, and melanoma are now at the forefront of personalized medicine and targeted therapy options. The following ASCO 2012 educational meeting sessions will highlight the latest research developments in targeted treatments and new ways clinicians need to be thinking about this type of approach to cancer care.

Several sessions specifically highlight personalized medicine for different tumor types: – “The Cost of Lung Cancer Care: Screening, Personalized Medicine, and Palliative Care” (Friday, June 1) – “Personalized Medicine in Lung Cancer in 2012” (Saturday, June 2) – “New Options, New Questions: How to Select and Sequence Therapies for Metastatic Melanoma” (Saturday, June 2) – “‘Personalized’ Oncology for Colorectal Cancer: Ready for Prime Time or Stop the Train” (Tuesday, June 5) – “Mechanisms of Resistance to Targeted Anticancer Agents” (Saturday, June 2) – “Biologic Principles of Targeted Combination Therapy” (Sunday, June 3) • Many TKIs are approved for a range of cancers, including imatinib and dasatinib for CML, gefitinib for breast and lung cancers, erlotinib for lung and pancreatic cancers, and sunitinib for RCC. “Laboratory and Clinical Insights into Resistance to Tyrosine Kinase Inhibitors” (Sunday, June 3) will address a key issue in the use of TKIs. • A novel view on targeted therapies will be discussed on Monday, June 4, in the session “Targeting Critical Molecular Aberrations Early in the Course of Solid Tumors: Is It About Time?” Targeted therapies are now predominantly utilized in the advanced cancer and metastatic setting, but this session will discuss moving these agents into the adjuvant setting, and potentially even to earlier-stage settings.

• A “Meet the Professor” session on Monday, June 4, “Bringing Personalized Cancer Therapy into Routine Use,” will focus on the practical aspect of personalized care for clinicians.

Like it or not, economics are driving treatment choices for patients in the real world. next question is, “How much does it cost and to whom?” And these are really difficult questions because sometimes the cost can be extraordinary to society as a whole but very little to the patient. The patient may only have an annual $1000 copay for a $120,000 new melanoma treatment, for example. In other cases, they may need to pay up to 40% of the cost of treatment. Oncologists need to discuss costs directly with their patients. I have learned to ask my patients, “What is your insurance coverage?” and “How much is this going to cost you?” before having the patient

receive a $120,000 bill they cannot pay.

For example, aromatase inhibitors for breast cancer cost $450 a month even though there are three of them on the market and all of them are essentially interchangeable. This gets to an issue of compliance. Some patients simply cannot afford the 20% copay.

TTN: The cost of the end-of-life care is very high for cancer patients. How do oncologists reconcile these costs (continued on next page)

Targeted Therapy News • 06.12

24

Feature

with providing the best treatment for their patients, while also recognizing whether the quality of life may be more important for a patient with advanced-stage cancer?

Smith: Many of us were trained to treat the disease and as long as there is something that can be done, to keep treating as long as it does not make the patient deathly ill. This has worked for our patients for the most part. Sometimes, I think the deathly ill part gets neglected a little bit because we tend to ask less about our patients’ quality of life than we should.

TTN: What are some of the ways that oncologists can curb costs while providing good care for patients at the end of life?

Smith: There are a couple of strategies for oncologists that make good sense.

One is to get people into a care system that keeps them out of the hospital near the end of life. The best way to do this is hospice. ASCO and many of us who are practicing oncologists are now recommending that when patients have about three to six months left to live, they should visit a hospice for information. This does a few things. It makes it

“ASCO and many of us who are practicing oncologists are now recommending that when patients have about three to six months left to live, they should visit a hospice for information.”

—Thomas J. Smith, MD

TTN: What role does palliative care play?

Smith: Palliative care was always designed to improve patients’ symptoms and coping, to lessen depression, and to lessen caregiver burden. It is only an interesting sidebar that it results in cost savings. The cost savings are substantial. It could be anywhere from 20% to 50% of the cost in the last month or six months of life that can be reduced. This type of care allows patients to get out of the hospital, where most people don’t want to be.

TTN: How does this affect our current healthcare spending as a whole?

Smith: There are really imperative reasons to have this cost discussion. First, our cancer care system is simply not sustainable. Even though it is only 5% of the national budget, in the insured population it is 15% to 20%, a substantial amount. The cost per person per year in the US is $8100. It is $4500 in Canada for exactly the same amount of health benefit. The cost of insurance for a family of four has gone from $6000 in the year 2000 to over $15,000 in the year 2012. Insurance premiums went up 8% to 9% last year, and that is simply not sustainable either. There were close to a million, if not more, medical bankruptcies last year alone. So we need to do something. The question is, “What can we do that will cause as little harm as possible?”

Targeted Therapy News • 06.12

real for the patient and the family that this is where things are headed and it is time to plan. It introduces the hospice team as the best way to take care of people at the end of life—which all professional societies agree on, every single one. It introduces the hospice care team as part of the regular oncology care plan. Integrating the hospice early is now part of best practices for most oncologists. It makes the transition easier, so that when a patient has tried a third-line chemotherapy in lung cancer or colorectal cancer without success, the oncologist can say, “Now is the time for you to switch to the hospice care,” with the nurses and social workers that the patient has already met.

TTN: ASCO released palliative care guidance in March of this year. How do you see this being implemented?

Smith: Palliative care should be a part of the care of anyone with a serious illness. The uptake should not be slow.

All of us who are practicing oncologists work with hospice providers. I like to use the analogy of we know the radiation therapist and our surgeons very well. We know their phone numbers and their fax numbers probably by heart. For the hospice providers, it tends to be a love-hate relationship.

It shouldn’t be that way. It should be part of the normal process of care. I

think oncologists like me should be calling the hospice providers and saying, “We actually work a lot together.

Let’s figure out what we can both do to improve the care our patients get.”

Hospice providers like to see patients when they have at least a month to live rather than a day left to live. It is a terrible process of care when we simply avoid having this conversation until the patient is bed-bound, in renal failure, and has an infection and two days left to live. In this situation, hospice is just scurrying around and doesn’t even have a chance to speak to the patient, and is left to pick up the pieces for bereavement and grief counseling. Patients in hospice care and with palliative care tend to live longer rather than shorter.

Oncologists should speak to the hospice providers to understand how they can do better. We should ask them how our statistics compare to the national average in terms of referral time. As oncologists, we need to be having realistic conversations about how many treatment types a patient can go through before we run out of options. Saying that there is a limit to treatments and there will be a time when treatment will only do more harm than good is necessary.

This conversation needs to happen early and be reinforced throughout treatment.

TTN: Who are the other players that need to be involved in these cost decisions on a policy level?

Smith: This is a big point. I don’t think that cost control should fall to the individual oncologist. I think one of the worst things would be that no one at the insurance or government or societal level wants to make these decisions, so it is all a burden on the individual oncologist. I don’t think individual oncologists should be the only ones having difficult conversations with patients because no one else wants to do it. But, as oncologists, we need to be prepared to ask our patients about cost.

TTN: The US highly values new scientific innovation. The FDA last year approved 35 new, innovative drugs. Most of these approvals were the first global approvals. How do we reconcile the need and benefit of new innovations in spite of cost?

Smith: I think it is fascinating that the average cost of a new therapy has gone up by hundreds of percentage points while the improvement in overall survival or disease-free survival has stayed at about 1%. I would like to see data showing that [the cost increases are] due to the increased cost of clinical trials, but it seems hard to imagine. I think companies are doing what we would like them to be doing from a business perspective. They are valuing their drugs at what they think the market will bear. It is great for the company, but it is impossible to sustain.

There may be instances where targeted therapies or testing will actually save money. A good example is the Oncotype DX 21 [21 gene assay] in breast cancer, which we use routinely. The data are quite convincing that this allows us to spare chemotherapy in many situations and simply treat patients with a hormonal agent. To me, there is not an obvious correlation between a high price and the fact that a therapy is targeted.

Many of these drugs are in the metastatic setting at the end of life. We as a society need to step up and say, “How much of this can we actually afford?”

As an individual oncologist, I can’t fix the cost of targeted therapies. What I can fix as a regular oncologist is the high cost of end-of-life care, much of which is not desired by the patient. I can fix this part by having an open and honest conversation with patients and their families about the reality of the situation. Keeping patients out of the hospital in the last one or two months of life would save billions of dollars for insurance companies and Medicare, and it is what many patients want. This cost savings will allow us to better afford many of these innovative and exciting therapies, all of which I want to keep using.

TTN: What is the current level of change and awareness on a government and policy level?

Smith: Change is already happen-

TTN: Are we going in the right direction and having this discussion?

Smith: I think that it is fascinating to

ing. Insurance companies are making decisions about what they cover and don’t cover. Medicare makes decisions by basically not making decisions on whether Medicare will pay for an FDAapproved indication. But we do need to be having more adult conversations about what we can and cannot pay for.

This extends beyond cancer to ventricular assist devices, $100,000 pulmonary hypertension treatment, and the expensive rheumatologic drugs. We cannot continue to spend the way we have been spending.

see what is being proposed on the federal level. A lot of the plans being proposed will actually turn over the benefit determination to insurance companies.

It will not be Medicare making the decision, but it will contract with an insurance company that will determine what is covered. Somehow, that is thought to be better at this point. Medicare is already divided into regions. Coverage is determined by someone, whether a bureaucrat or at a large company. I think things will get worse before they get better. TTN

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Stage 2

Metastatic NSCLC Patients

Determine PI3K Pathway Activation

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Enrollment

Group 1: Squamous NSCLC pretreated with 1 prior platinum-based chemotherapy line for advanced disease

Group 2: Non-Squamous NSCLC pretreated with 1 or 2 prior antineoplastic therapies for advanced disease

BKM120

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End of Treatment due to toxicity  Continue tumor assessments  Progression-Free Survival and Survival OR End of Treatment due to progression  Progression-Free Survival and Survival Up to 180 patients will be enrolled Biomarker prescreening can take place before formal eligibility Study population comprises 1 prior treatment for squamous histology and 1-2 prior treatments for non-squamous histology

• Progression-Free Survival

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BKM120 is an investigational compound. Efficacy and safety have not been established.

There is no guarantee that BKM120 will become commercially available.

© 2012 Novartis

Printed in USA

5/12

ONC-1040998

26

Feature

A New Look at Survival Data for Sipuleucel-T

By Anita T. Shaffer

Leonard G. Gomella, MD

A

further analysis of clinical trial data for sipuleucel-T (Provenge, Dendreon) suggests that the therapeutic prostate cancer vaccine may have delivered a greater overall survival (OS) benefit than previously described in the study that paved the way for its approval nearly two years ago, according to a leading researcher.

In fact, the analysis indicated that the survival benefit may be significantly higher than the 4.1-month advantage reported in the IMPACT study when the experiences of patients in the control arm who crossed over to a cryopreserved form of the vaccine are considered, said Leonard G. Gomella, MD, chairman of the Department of Urology and director of Clinical Affairs at the Kimmel Cancer Center, Thomas Jefferson University, in Philadelphia, Pennsylvania.

Gomella discussed his hypothesis at the 5th Annual Interdisciplinary Prostate Cancer Congress (IPCC) March 31 in New York City, for which he served as a program director. The research was presented at the 2012 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology (ASCO) in February and at the 2011 ASCO Annual Meeting.

Gomella’s comments come amid continuing controversy over sipuleucel-T, including a recent commentary in the Journal of the National Cancer Institute that maintained that previously unpublished data cast doubt on the vaccine’s survival benefit partly because of factors involving patients in the placebo arm.

The FDA approved Provenge on April 29, 2010, for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant, hormone-refractory prostate cancer, based on clinical trial

Targeted Therapy News•06.12

data demonstrating that patients who took the vaccine experienced a median OS of 25.8 months versus 21.7 months for those who received placebo.

Sipuleucel-T is custom manufactured for each patient from antigen-presenting cells (APCs) that are harvested from the patient through the process of leukapheresis, then cultured to activate immunogenicity and infused into the patient. The treatment course consists of three intravenous infusions.

In his analysis, Gomella looked more closely at participants in the control arms of three randomized, double-blind sipuleucel-T studies. Of 249 people in the control arms, 216 participants who experienced disease progression had the option of receiving APC8015F, an autologous immunotherapy with the same potency as sipuleucel-T, which was made for each patient and cryopreserved at the time the placebo was prepared.

much more robust response of about 10 to 12 months.”

In an interview, Gomella added, “From my viewpoint, the benefit of sipuleucelT has been understated because many of the patients who received the frozen product who were on the control arm actually enjoyed a longer survival, decreasing the difference between the control arm and the treatment arm.

“In fact, if you look at our analysis of the patients who received a frozen product on the control arm and those who did not receive it, there was a significant survival advantage to those patients who did receive the frozen product,” said Gomella.

“It made the difference between the control arm and the actual treatment arm much closer. And if you take out those patients who did not receive the frozen product on the control arm, that survival difference actually approaches 10 to 11 months.”

bo was prepared by culturing one-third of the leukapheresis collection without PA2024 at 2 degrees to 8 degrees C. The remaining cells collected from patients in the placebo arm were cryopreserved.

Such procedures not only made the placebo “a biologically significant different intervention that could have had distinct clinical properties,” but also might have placed older patients at a disadvantage when it came to replacing cells lost in leukapheresis, according to the article

by Huber et al. “Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival ‘benefit’” of sipuleucel-T, the authors said.

In his IPCC presentation, Gomella said that researchers are debating the impact of extracting immune cells, but that a study pending publication indicates the “number of immune cells you pull out of the body with leukapheresis is clinically insignificant.”

Meanwhile, Dendreon Corporation, the Seattle, Washington, company that developed sipuleucel-T, is continuing to investigate the vaccine for patients with earlier-stage disease. TTN

Control Arm Flow Diagram APC8015F Infusions

Control Infusions

Randomization to control group

249 control subjects in 3 mCRPC studies

216 with confirmed disease progression*

155 received APC8015F 61 did not receive APC8015F

*10 control subjects did not have confirmed disease progression and were treated with APC8015F Median time from randomization to first APC8015F infusion was 5.2 months (range, 1.8-33.1) Median time from disease progression to first APC8015F infusion was 2.2 months (range, 0.5-14.6)

For the 155 patients from the control arm who received APC8015F, the median OS was 23.6 months from randomization and 20.0 months following disease progression, which compared favorably with the median OS in the sipuleucel-T arms of 25.4 months from randomization and 20.7 months after progression.

In contrast, the 61 participants from the control arm who experienced disease progression but did not cross over to APC8015F had a median OS of 12.7 months from randomization and 9.8 months following disease progression.

“The survival difference was dramatically different,” Gomella said during his IPCC presentation. “So in a way, the sipuleucel-T trials shot themselves in the foot because the frozen product was included.

If you exclude the frozen product, you actually get a much more dramatic and a

Gomella’s analysis, however, stands in sharp contrast to the contentions of Huber et al, who argue that previously unpublished trial data show worse OS in older versus younger patients in the placebo groups, and that the difference may enhance the sipuleucel-T survival advantage.

Patients on placebo who were younger than age 65 experienced an unexpected 11-month median survival advantage when compared with those over age 65 (28.2 mo vs 17.2 mo, respectively), the authors said.

All of the 512 patients in the IMPACT study were scheduled for three leukapheresis procedures followed by infusions with either sipuleucel-T or placebo. While the antigen-presenting cells of patients in the sipuleucel-T arm were incubated at 37 degrees C with immuneactivating proteins, including the recombinant fusion protein PA2024, the place-

Key Research Gomella LG, Nabhan C, Whitmore JB, et al. Postprogression treatment with APC8015F may have prolonged survival of subjects in the control arm of sipuleucel-T phase III studies. Poster presented at: 2011 ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Abstract 4534.

Huber ML, Haynes L, Parker C, et al. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer [published online ahead of print January 9, 2012]. J Natl Inst.

2012;104(4):273-279.

Kantoff PW, Higano CS, Shore ND, et al. SipuleucelT immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.

Nabhan C, Gomella LG, DeVries T, et al. An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study. J Clin Oncol. 2012;30(suppl 5;abstr 144).

Feature

27

Breast Cancer (continued from cover)

Courtesy Genentech BioOncology, member of the Roche Group

The genetic research is identifying new subpopulations of breast cancer to allow for better treatment options— some of the new subtypes could benefit from existing targeted agents and chemotherapy. This new breast cancer subtype clustering based on genetic and transcription data is also identifying new molecular drivers.

Translational research is using the new genetic data to develop drugs from a range of many newly identified targets. Advances in both basic research and translational research are producing a plethora of new targets, according to Leyland-Jones. “The number of targets is shooting up, but fortunately we are getting the drugs to handle those targets,” he said.

Although identification of driver mutations such as HER2 overexpression in breast tumors has allowed for tailored therapies, many aggressive tumor types have no distinguishing genetic characteristics on which to base treatments.

Research in this field is very active. A recent study published in the journal Nature characterized over 2000 breast tumors. The study revealed new breast cancer subgroups based on both genomic and transcription analyses.1 The authors of the study identified three new deletion mutations that correlated with already known breast cancer subtypes. Researchers can now take advantage of this knowledge to identify patients with these mutations and test specific drugs that target specific mutations. These types of genomic breast tumor studies will lead to more precise diagnoses and tailored treatments that target the specific molecular defects of a patient’s tumor.

Mapping the genetic landscape of a tumor allows for identification of biomarkers, which can be used to predict response to treatment or better predict patients with high-risk disease or re-

Members of the human epidermal growth factor receptor family.

currence. For example, a research team at the Dana-Farber Cancer Institute in Boston, Massachusetts, has identified a marker of DNA damage in patients with triple-negative breast cancer that may be able to predict whether a patient has the potential to respond to platinumbased chemotherapy agents such as carboplatin and cisplatin.2 Currently, triple-negative breast cancer does not have any targeted therapy options because the subtype is actually a heterogeneous group of tumor types

that is characterized by what they lack (no expression of estrogen or progesterone receptor and no HER2 overexpression) rather than distinct and targetable genetic aberrations. Platinum-based chemotherapy is widely used as a treatment, but it exposes the patient to toxicity and does not help all patients.

Identifying patients who would benefit would save many patients from the toxic effects of systemic therapies that will not be efficacious—and lower unnecessary costs of treatment.

“It is becoming clear that breast cancer has 50 to 80 targetable drivers. This is a time of massive knowledge change in the entire field.”

—Brian Leyland-Jones, MD, PhD

HER2 Targeting: Advancements Beyond Trastuzumab Approximately 20% of breast cancers produce too much HER2. These HER2positive breast cancers are typically more aggressive compared with other types of breast cancer and are fastgrowing. “When amplified, the expression of HER2 goes way beyond its normal dynamic range—there is a wide range of normal HER2 expression—so that you get pathologic overexpression.

When overexpressed to this extent, it plays a dominant role in proliferation and motility and resistance to hormonal control,” said Dennis Slamon, MD, PhD, director of Clinical/Translational Research, director of the Revlon/UCLA Women’s Cancer Research Program, and chief of the Division of Hematology/Oncology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

The HER2 gene was discovered in the late 1970s and cloned in 1985 by scientists at Genentech. That same year, scientists at the National Institutes of Health discovered that the gene is frequently present in multiple copies in human breast tumors. Trastuzumab (Herceptin, Genentech) was created at Genentech in 1990. The antibody specif-

(continued on page 30)

Targeted Therapy News • 06.12

30

Feature

Breast Cancer (continued from 27)

“When amplified, the expression of HER2 goes way beyond its normal dynamic range—there is a wide range of normal HER2 expression—so that you get pathologic overexpression.”

ically binds to the extracellular domain of the HER2 receptor. The drug was approved for metastatic breast cancer that overexpresses the HER2 protein in 1998—either as a monotherapy for patients who have received at least one chemotherapy treatment or as a first-line therapy in combination with paclitaxel. Phase III trials showed the antibody reduced rates of recurrence by about 50%. Since then, it has become one of the most common therapeutic agents used in the treatment of breast cancer. Trastuzumab was subsequently approved as an adjuvant treatment for HER2-overexpressing, early-stage breast cancer.

—Dennis Slamon, MD, PhD

HER2 Signaling Basics HER2 is a receptor tyrosine kinase that is part of a signaling network that controls important cellular processes such as cell survival, proliferations, angiogenesis, invasion, and metastasis.

HER2 belongs to the human epidermal growth factor family of receptors, along with HER1 or EGFR, HER3, and HER4. The basic signaling mechanism for this family involves dimerization— the coming together of two of the same receptors (homodimerization) or two different receptors (heterodimerization) within the plasma membrane.

Heterodimers of HER2 and HER3 have been shown to be more potent compared with homodimers in activation of downstream targets. Activation results in intracellular signaling through an important pathway also frequently mutated in cancer: the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway.

“HER2-HER3 dimerization is a particularly important aspect of HER2 signaling, as these dimers potently signal to the PI3K survival pathway and are the main mechanism driving HER2-positive cancers,” said Carlos L. Arteaga, MD,

director of the Breast Cancer Research Program at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Arteaga’s research focuses on the role of signaling by oncogenes in the progression of breast tumor cells and molecular therapies in breast cancer.

Next-Generation HER2 Therapies in Development Although it was a great advance that led to improvement in survival of patients with an aggressive form of breast cancer, trastuzumab is not a “magic bullet.”

Significant problems of resistance to the therapy and relapse require next-generation solutions, despite the availability of trastuzumab and lapatinib (Tykerb, GlaxoSmithKline), another inhibitor of the HER2 pathway.

One of the mechanisms of resistance to trastuzumab may be an incomplete blockade of HER2 signaling. Trastuzumab blocks ligand-independent signaling, but not ligand-dependent signaling that results in HER2-HER3 dimerization. The monoclonal antibody pertuzumab, also developed by Genentech, may overcome this form of resistance. Pertuzumab binds to a different region of the HER2

extracellular domain and can block ligand-dependent HER2 dimerization.

As a single agent, trastuzumab is more effective than pertuzumab in inhibiting HER2-dependent growth in vitro and in vivo, according to Slamon, who had played a major role in the development of trastuzumab.

“But when you hit the receptor twice, it appears you have even better activity. We had preclinical data from our lab from several years ago that demonstrated this. So, it appears that two assaults on the receptor gives you synergistic activity,” Slamon explained.

Pertuzumab is currently being studied in patients with early and advanced HER2-positive breast cancer and advanced HER2-positive gastric cancer.

Pertuzumab has limited activity as a single agent, but the synergistic effect of trastuzumab plus pertuzumab that was demonstrated in preclinical studies has been confirmed in phase II trials in patients who had disease progression after trastuzumab monotherapy.

The phase II NeoSphere (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) trial

HER2-Positive Studies To Be Featured at ASCO 2012 Annual Meeting • One of the four abstracts selected to be presented during the plenary session of the meeting: Results of the EMILIA phase III study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in patients with HER2-positive locally advanced or metastatic breast cancer who have previously been treated with trastuzumab and a taxane.

• Results of the phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3K or PTEN altered HER2-positive metastatic breast cancer, at a clinical science symposium oral session.

• Results of the SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER-positive/HER2-negative metastatic breast cancer, at a clinical science symposium oral session.

• A 13-gene signature to predict rapid development of brain metastases in patients with HER2-positive advanced breast cancer, at an oral session.

• The National Surgical Adjuvant Breast And Bowel Project (NSABP) protocol, evaluation of lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer, at an oral session.

Targeted Therapy News • 06.12

showed higher pathologic complete response (pCR) rates in newly diagnosed patients with HER2-positive breast cancer treated with a triple combination of pertuzumab, trastuzumab, and chemotherapy.3 The trial demonstrated that chemotherapy may not be necessary, as pertuzumab plus trastuzumab without chemotherapy also produced higher pCR rates. These results suggest that if it were possible to predict which patients would respond to the dual HER2-targeted combination, it may be possible to treat patients effectively without chemotherapy.

Subsequently, the phase III CLEOPATRA (CLinical Evaluation Of Pertuzumab and TRAstuzumab) trial compared the triple combination of pertuzumab, trastuzumab, and docetaxel chemotherapy to trastuzumab and docetaxel alone in 808 patients with HER2-positive metastatic breast cancer who had not been previously treated.4 Patients who received the triple combination had a 38% reduction in the risk of their disease worsening. The median progression-free survival (PFS) was 18.5 months for the triple combination compared with 12.4 months for trastuzumab plus chemotherapy (P < .0001)— an increase of 6.1 months. The overall survival data were still immature when the trial data were presented but favored the triple combination. The objective response was 80.2% in the triple-therapy group compared with 69.3% in the control group.

Leyland-Jones called the survival impact demonstrated in the study “practice-changing.” Arteaga believes that the results are due to a comprehensive blockade of HER2 signaling. “Frankly, I think these results were expected and, as strongly suggested by the mechanistic and preclinical data, the results could almost have been written before the trial,” he added.

The CLEOPATRA trial results were published in The New England Journal of Medicine in January. The combination has

Feature been submitted for approval in both the US and in Europe for previously untreated, HER2-positive, metastatic breast cancer. The decision from the Food and Drug Administration (FDA) is expected June 8, 2012, based on a priority review.

The pertuzumab, trastuzumab, and chemotherapy combination is also being investigated in a phase III trial as adjuvant therapy in nearly 4000 patients with HER2-positive breast cancer.

In addition to trastuzumab and pertuzumab, other agents such as HER2 dimerization inhibitors are in development. “Overall, these represent an important class of agents as they disrupt a central mechanism of signaling by the HER2 receptor,” said Arteaga. These therapies include the monoclonal antibody MM-21 (SAR256212; sanofi-aventis and Merrimack Pharmaceuticals), which disrupts HER3-ligand-induced HER2-HER3 dimerization. MM-121 is under clinical development in a variety of settings, including in combination with cetuximab and irinotecan in colorectal,

Another approach is the combination of trastuzumab plus lapatinib used in the phase III NeoALTTO trial in women with HER2-positive primary breast cancer.5 This trial demonstrated that the combination of trastuzumab plus lapatinib is more efficacious in achieving pCR compared with lapatinib alone.

A Novel Approach to Combining a HER2-Targeted Drug With Chemotherapy Another promising agent for HER2positive disease is T-DM1 (trastuzumab emtansine, Genentech). This novel therapeutic is an antibody drug conjugate that combines trastuzumab with the chemotherapy agent DM1 through a linker designed to stabilize the antibody-chemotherapy combination. The goal is for the T-DM1 to specifically reach its HER2 target without significant off-target effects, as occur with the administration of chemotherapy.

Results of a phase II trial, presented at the San Antonio Breast Cancer Sympo-

2012. Patients in the trial were previously treated with trastuzumab and chemotherapy. Roche and Genentech will submit applications for approval of T-DM1 to both the FDA and the European Medicines Agency (EMA) this year.

Another ongoing three-arm, phase III study is the MARIANNE trial comparing T-DM1 with and without pertuzumab to trastuzumab plus a taxane chemotherapy in 1000 patients with HER2-positive, previously untreated metastatic breast cancer. The primary endpoint of the trial is PFS.

Other Pathway Targets Many additional targets are under development for breast cancer therapies, including poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors may have efficacy in BRCA-associated cancer.

In a phase III trial published in January 2011, the PARP inhibitor iniparib (BiParSciences/sanofi-aventis) did not meet the primary dual endpoints of overall survival (OS) and PFS in metastatic

31

cer; and Src in trastuzumab resistance.

The use of large-scale siRNA screens to identify and validate targets is also under way. Translational research has recently facilitated research to overcome endocrine therapy resistance, overcoming HER2-targeted therapy resistance, and classification and prognosis in triple-negative breast cancer.

Over the next five years, therapy will be increasingly based on genome sequencing, said Leyland-Jones. As the cost of sequencing keeps dropping, genetic analysis of a patient’s tumor could become routine, with results available as quickly as two weeks.

While the approach to treatment of breast cancer continues to rapidly evolve, and our understanding of the drivers of the disease increase, there is still a long way to go. Many more academic studies are needed on the genetics of breast cancer—particularly on understanding the many types of diseases within the current category of triplenegative breast cancer. TTN

“HER2-HER3 dimerization is a particularly important aspect of HER2 signaling, as these dimers potently signal to the PI3K survival pathway and are the main mechanism driving HER2-positive cancers.”

—Carlos L. Arteaga, MD

head and neck, non-small cell lung, and triple-negative breast cancers.

Another agent is a fully human antiHER3 monoclonal antibody, U3-1287/ AMG-888 (Daiichi Sankyo Co Ltd, U3 Pharma, and Amgen), which is currently being studied in a phase Ib/II trial in combination with trastuzumab and paclitaxel in patients with newly diagnosed HER2-positive metastatic breast cancer.

Additionally, Arteaga highlighted data on a novel HER3 antibody developed

by Novartis that has shown the ability to block both ligand-dependent and ligand-independent formation of HER2HER3 dimers. “The preclinical data suggested this monoclonal antibody could be mechanistically superior to the other two HER3 antibodies, but it has not been tested in patients yet,” he said.

Other dual HER2-blockade approaches include trastuzumab in combination with a PI3K inhibitor. “The ‘dual’ approach targets different molecules or nodes in the HER2 pathway, the HER2 receptor, and PI3K immediately downstream,” said Arteaga.

sium (SABCS), in December 2011, compared the combination of trastuzumab plus docetaxel with T-DM1 in HER2positive metastatic breast cancer as a first-line therapy. T-DMI significantly improved PFS (median PFS for trastuzumab/docetaxel was 9.2 mo vs 14.2 mo for T-DM1; HR = 0.594; P = .0353) compared with the trastuzumab/docetaxel combination. Toxicity was significantly less with T-DM1, presumably because the chemotherapy was delivered specifically to HER2-expressing tumors.

T-DM1 has since shown efficacy in a phase III trial. Roche, Genentech’s parent company, announced at the end of March that the phase III EMILIA trial in 991 patients met one of its primary endpoints: T-DM1 showed a significant improvement in PFS. The overall data for the trial are still immature. The trial compared T-DM1 therapy to a combination of capecitabine and lapatinib. The full trial results will be presented as a late-breaking abstract at the plenary session of the upcoming American Society of Clinical Oncology (ASCO) Annual Meeting to be held in June

triple-negative breast cancer. However, a prespecified subgroup analysis suggested improvements in OS and PFS in the second- and third-line settings.

Researchers are continuing to investigate potential uses for iniparib and to discover which patients will most likely respond to PARP inhibitors.

Iniparib is considered a relatively weak PARP inhibitor, said LeylandJones. Other PARP inhibitors under development include rucaparib (Clovis), for BRCA-positive, post-neoadjuvant, triple-negative breast cancer; olaparib (AstraZeneca), for BRCA-positive breast cancer; and veliparib (ABT-888; Abbott), for BRCA-positive, triple-negative breast cancer.

Advances in basic research are leading to a greater understanding of the tumor microenvironment, noted Leyland-Jones. New therapeutic targets as a result of these advances include metabolic pathways (serine, glycine synthesis); JAK2 in triple-negative and potentially other breast cancers; androgen receptors in HER2-positive breast can-

References 1. Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups [published online ahead of print April 18, 2012]. Nature. 2012. doi:10.1038/nature10983.

2. Birkbak N, Wang ZC, Kim J-Y, et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discovery.

2012. doi: 10.1158/2159-8290.CD-11-020.

3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial [published online ahead of print December 6, 2011]. Lancet Oncol. 2012;13:25-32.

4. Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer [published online ahead of print December 7, 2012]. N Engl J Med. 2012;366:109-119.

5. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial [published online ahead of print 17 January 17, 2012]. Lancet. 2012;379:633640. doi:10.1016/S0140-6736(11)61847-3.

Targeted Therapy News • 06.12

Jakafi™ (JAK-ah-fye)—First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*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 trademark of Incyte Corporation. © 2012, Incyte Corporation. All rights reserved. RUX-1008U 05/12

• 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

-100

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

80

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/explore

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. November 2011. 2. Data on file.

Incyte Corporation.

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

JAK targeted to make a difference

1INC007 JK0 BS 12P_Layout 1 11/16/11 9:16 AM Page 1

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Grade 4 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.

A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Issued: November 2011 RUX-1040

Research Profile

35

Leonard M. Neckers, PhD

Leonard M. Neckers, PhD

Leonard M. Neckers, PhD, is chief of the Tumor Cell Biology Section, Urologic Oncology Branch of the National Cancer Institute, Rockville, Maryland. His lab has been studying the role of the molecular chaperone Hsp90 in signal transduction and the translational development of Hsp90-targeted anticancer agents for two decades. Research conducted in his laboratory uncovered the importance of Hsp90 in the growth and survival of cancer cells and led to the first clinical trials of Hsp90 inhibitors. Targeted Therapy News spoke with him about the role of his work in cancer research.

TTN: What role does Hsp90 play in normal cells?

Molecular chaperones help nascent polypeptides fold correctly and multimeric protein complexes assemble productively, while minimizing the danger of aggregation in the protein-rich intracellular environment. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that participates in stabilizing and activating more than 200 proteins—referred to as Hsp90 “clients”—many of which are essential for constitutive cell signaling and adaptive responses to stress.

To accomplish this task, Hsp90, the chaperone Hsp70, and additional proteins termed co-chaperones form the dynamic complex known as the Hsp90 chaperone machine.

TTN: How is Hsp90 implicated in the development of cancer?

Cancer cells use the Hsp90 chaperone machinery to protect an array of mutated and overexpressed oncoproteins from misfolding and degradation.

Hsp90 is recognized as a crucial facilitator of oncogene addiction and cancer cell survival.

TTN: How has the role of Hsp90 been exploited in cancer research and drug development?

Like the prototypic Hsp90 inhibitor geldanamycin (which was identified in 1994), Hsp90 inhibitors currently under clinical evaluation interact with Hsp90’s N domain ATP-binding pocket, prevent ATP binding, and stop the chaperone cycle, leading to client protein degradation.

Hsp90 inhibitors have proven to be very useful as probes of Hsp90 function in both normal and cancer cells.

Progress has been made in the clinical evaluation of targeting Hsp90 in cancer. Patient selection based on tumor molecular characterization indicating

heightened dependence on Hsp90 and sensitivity to Hsp90 inhibition is proving fruitful, as exemplified by RECIST responses in a recent clinical trial involving patients whose non-small cell lung cancers expressed EML4-ALK fusion protein, and in a trial involving HER2positive breast cancer patients.

Another strategy that has shown promising results is the combination of Hsp90 and proteasome inhibitors to treat multiple myeloma. The first Hsp90 inhibitor, 17-AAG (tanespimycin), entered clinical trials in 1999. In 2004, a second Hsp90 inhibitor, 17-DMAG (al-

cancer. Studies are now in progress to confirm the link between tumor Hsp90 expression and tumor grade.

TTN: What is the future of research with regard to our understanding of Hsp90 or the development of Hsp90-targeted cancer therapy?

Although many Hsp90 clients are oncogenes, and many of the compensatory mechanisms used by tumors to overcome other molecularly targeted and cytotoxic therapies are vulnerable to Hsp90 inhibition, it is now apparent that Hsp90 is also a key regulator of host

Hsp90 is recognized as a crucial facilitator of oncogene addiction and cancer cell survival.

—Leonard M. Neckers, PhD

vespimycin), entered a first-in-human study. Owing to extensive efforts in rational drug design and discovery, 13 additional Hsp90 inhibitors are currently undergoing clinical evaluation in cancer patients. Ten of these agents have entered the clinic in the past three years.

TTN: Can Hsp90 be used as a biomarker or prognostic indicator in cancer?

Numerous published studies have reported elevated Hsp90 expression to be a characteristic of cancer cells in vivo.

Further, a recent study reported a significant inverse correlation between prolonged survival and tumor Hsp90 level in patients with non-small cell lung

cell biology at the systems level. These systemic effects can either enhance or antagonize the antitumor activity of Hsp90 inhibitors in cancer patients.

Studies of the impact of targeted therapy in oncology trials have tended to focus on the predicted effects of the drug on the tumor without consideration of the impact of therapy on the host, and the evaluation of Hsp90 inhibitors is no exception. As we move forward in developing these agents, it will be critically important to consider the impact of Hsp90 inhibitors on the patient as well as on the tumor, in order to identify the most fruitful indications for Hsp90 inhibitor therapy in oncology. TTN

Targeted Therapy News•06.12

Targeted Therapy

36

Trials in Progress

The Trials in Progress section is intended to stimulate discussion about ongoing clinical trials and to promote collaboration across the oncology community. Each issue, Targeted Therapy News will present summaries of ongoing research in a broad range of cancer types.

Breast Cancer

Hematologic Cancer

Endocrine Therapy With or Without Anti-VEGF Therapy for Advanced Breast Cancer

Lenalidomide and Dexamethasone With or Without Bortezomib in Multiple Myeloma

This phase III study will examine the use of tamoxifen or letrozole alone or combined with bevacizumab in women with hormone receptor-positive stage III or IV breast cancer. Participants will be randomized to receive either tamoxifen citrate or letrozole once daily on days 1 to 21 or tamoxifen or letrozole once daily on days 1 to 21 plus bevacizumab intravenously (IV) on day 1. In both arms, treatment is repeated every 21 days in the absence of disease progression or unacceptable toxicity. The primary outcome measures include progression-free survival, the rate of adverse events (especially stroke, proteinuria, thrombosis, and hypertension in patients treated with tamoxifen), and toxicity. The target recruitment for the study is 502 patients.

Sponsor: Cancer and Leukemia Group B ClinicalTrials.gov Identifier:NCT00601900

Lung Cancer Sunitinib Maintenance Therapy in Advanced Lung Cancer This phase III study is comparing sunitinib with placebo as maintenance therapy in patients with stage IIIB or IV non-small cell lung cancer who have stable or responding disease after prior treatment with 4 courses of platinum-based chemotherapy. Participants are stratified according to ECOG performance status, disease stage, prior treatment with bevacizumab, and gender. After the completion of treatment, patients will be followed every 3 months for 1 year, every 6 months for 1 year, and periodically for 3 years. The primary outcome measure is progression-free survival. Secondary outcome measures include grade and type of toxicity, response rate, and overall survival. The study has a target recruitment of 244 patients.

Sponsor: Cancer and Leukemia Group B ClinicalTrials.gov Identifier: NCT00693992

This phase III study will determine the efficacy of lenalidomide and low-dose dexamethasone with or without bortezomib for induction in patients with previously untreated multiple myeloma. Patients are stratified according to the International Staging System and intent to undergo transplantation at relapse.

The primary outcome measure is progression-free survival. Secondary outcome measures include response rates, overall survival, and the correlation of genetic polymorphisms with biology and prognosis.

In both arms, patients who intend to undergo transplantation at relapse undergo peripheral blood stem cell collection, preferably after course two. The study has an estimated enrollment of 440 patients.

Sponsor: Southwest Oncology Group ClinicalTrials.gov Identifier: NCT00644228

Rituximab and Combination Chemotherapy for Diffuse Large B-Cell Non-Hodgkin Lymphoma This phase III study will compare R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in patients with previously untreated, histologically confirmed de novo diffuse large B-cell non-Hodgkin lymphoma. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for up to 3 years. The primary outcome measure is event-free survival 5 years after completion of study treatment. Secondary outcome measures include R-CHOP and dose-adjusted-EPOCH-R molecular predictors of outcome as measured by cDNA microarray 5 years after completion of study treatment. A total of 478 patients will be recruited for the study.

Sponsor: Cancer and Leukemia Group B ClinicalTrials.gov Identifier: NCT00118209

Head and Neck Cancer Renal Cancer Sunitinib or Placebo for Patients at High Risk of Recurrent Renal Cell Cancer This phase III study is comparing sunitinib with placebo as adjuvant treatment in patients at high risk of recurrent kidney cancer per modified University of California Los Angeles Integrated Staging System (UISS) criteria after surgery. Subjects are Eastern Cooperative Oncology Group (ECOG) grade 0 to 2 and have predominant clear cell histology. In addition, they have not undergone prior anti-cancer treatment but have had their kidney tumor removed with no evidence of macroscopic disease following surgery.

Approximately 720 patients will be randomized to sunitinib 50 mg PO or placebo on a 4/2 schedule: 4 weeks on, 2 weeks off for 1 year or until disease recurrence or occurrence of a secondary malignancy, significant toxicity, or withdrawal of consent. The primary outcome measure is disease-free survival.

Investigators will also determine overall survival, safety, tolerability, and patient-reported outcomes.

Sponsor: Pfizer ClinicalTrials.gov Identifier: NCT00375674

Axitinib (AG-013736) for the Treatment of Metastatic Renal Cell Cancer The phase III study is designed to determine whether axitinib is superior to sorafenib in delaying tumor progression in patients with metastatic renal cell cancer. Participants are required to have histologically documented metastatic renal cell cancer with a component of clear cell histology and evidence of measurable disease. They cannot have received prior systemic first-line therapy or must have progressive disease per Response Evaluation Criteria In Solid Tumors (RECIST) - version 1.0 after one prior systemic first-line regimen for metastatic disease containing sunitinib, cytokine(s), or both. Subjects will be randomized to axitinib at a starting dose of 5 mg bid with continuous dosing or sorafenib at a dose of 400 mg bid with continuous dosing. The primary outcome measure is progression-free survival. Secondary outcome measures include overall survival, response rate, safety and tolerability, duration of response, and kidney-specific symptoms and health status.

Sponsor: Pfizer ClinicalTrials.gov Identifier: NCT00920816

Targeted Therapy News•06.12

Efficacy of Reolysin with Paclitaxel and Carboplatin in Platinum-Refractory Head and Neck Cancer This phase III study is comparing intravenous administration of Reolysin (Reovirus Serotype 3 Dearing) combined with paclitaxel and carboplatin or chemotherapy treatment alone in patients with metastatic or recurrent squamous cell carcinoma of the head and neck who have progressed on or after prior platinum-based chemotherapy. Reolysin is an unmodified oncolytic reovirus that selectively replicates in Ras-activated cancer cells while not causing any significant human illness in its wild form. The primary outcome measure is overall survival. Patients will be evaluated clinically after each treatment course and radiologically every 6 weeks during and after treatment. The safety of the paclitaxel and carboplatin with intravenous blinded placebo or intravenous blinded Reolysin will also be assessed. The study aims to recruit 280 patients.

Sponsor: Oncolytics Biotech ClinicalTrials.gov Identifier: NCT01166542

Prostate Cancer Oral MDV3100 in Chemotherapy-Naïve Patients with Metastatic Prostate Cancer This phase III study will test the efficacy and safety of the novel androgen signaling inhibitor MDV3100 in chemotherapy-naïve patients who have progressive metastatic prostate cancer despite androgen deprivation therapy (ADT) as defined by rising prostate specific antigen levels or progressive soft tissue or bony disease. Study participants are asymptomatic or mildly symptomatic from prostate cancer. The primary outcome measures are overall survival and progression-free survival. Secondary outcome measures are time to first skeletal-related event and time to initiation of cytotoxic chemotherapy. An estimated 1680 men will participate in the study, which has a targeted primary completion date of September 2014.

Sponsor: Medivation, Inc ClinicalTrials.gov Identifier: NCT01212991

At diagnosis of metastatic colorectal cancer (mCRC)

Are you getting the full picture?

Name: Age: Cancer: Specialty: Biomarker Status:

George 58 mCRC Storyteller

Not an actual patient.

At diagnosis of mCRC, testing a patient’s tumors for biomarkers can help determine predictive and/or prognostic information1 Colorectal cancer is the 3rd leading cause of cancer death in men and women in the U.S.2 Understanding the patient’s biomarker profile helps define the characteristics of the patient’s disease and their overall prognosis.1 Knowing a patient’s biomarker status at diagnosis may help guide clinical decisions.3,4 Understanding the biomarker pathways involved in mCRC tumorigenesis can help inform appropriate treatment planning.3,5,6

KRAS and BRAF signaling are involved with colorectal tumorigenesis and tumor progression3 The KRAS gene may be mutated or wild-type. When KRAS is mutated, it is permanently switched on, whereas wild-type KRAS protein is activated when the EGFR is stimulated.3,5 Increased BRAF signaling may occur due to mutations in the BRAF gene.5 BRAF mutations are limited to those tumors that do not have KRAS exon 2 mutations.7

Testing of biomarkers at diagnosis of mCRC is important for treatment planning3,7*

T e s T

T o

p l a n

EGFR = epidermal growth factor receptor. *In a CLIA-certified laboratory.

References: 1. Tejpar S, Bertagnolli M, Bosman F, et al. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15:390-404. 2. American Cancer Society. Cancer Facts & Figures: 2011. http://www.cancer.org/acs/groups/content/@epidemiologysurveillance/ documents/document/acspc-029771.pdf. Accessed March 1, 2012. 3. Monzon FA, Ogino S, Hammond EH, et al. The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. Arch Pathol Lab Med. 2009;133(10):1600-1606. 4. Grossman AH, Samowitz WS. Epidermal growth factor receptor pathway mutations and colorectal cancer therapy.

Arch Pathol Lab Med. 2011;135:1278-1282. 5. Krasinskas AM. EGFR signaling in colorectal carcinoma. Pathol Res Int. 2011;2011:1-6. http://www.hindawi.com/journals/pri/2011/932932/cta.

Accessed January 6, 2012. 6. Linardou H, Briasoulis E, Dahabreh IJ, et al. All about KRAS for clinical oncology practice: gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer. Cancer Treat Rev. 2011;37(3):221-233. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.

NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Accessed March 15, 2012.

©2012 Bristol-Myers Squibb. All rights reserved. 693US12AB00111 04/12 Printed in USA.

Targeted Therapy

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Evidence-Based Oncology

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004

Breakthroughs in Targeted Therapies Not Applicable If Not Cost-Effective

By Marie Rosenthal, MS

B

efore the oncology treatment paradigm can move from a one-sizefits-all model to true personalized medicine, the medical establishment must find a cost-effective way to identify biomarkers that determine which therapies patients should receive.

That is the message in a recent report by two Colorado researchers who performed a cost-effectiveness analysis of targeted therapies for lung cancer, using the biomarker ALK and the targeted therapy crizotinib (Xalkori, Pfizer) to build their model.

In the analysis, published recently in the British Journal of Cancer, the researchers found that costs rose considerably as more people were tested who didn’t have the biological abnormality being sought. However, when the researchers controlled costs by applying methods to target patients for screening who were more likely to test positive, they missed a significant proportion of the patients who could have benefited from targeted therapy.1 D. Ross Camidge, MD, PhD, who performed the analysis with Adam J. Atherly, PhD, said that cost-effectiveness of screening has to be considered when determining the costs of treatment with targeted therapy, and that the high costs of a “test-everyone” approach may not be feasible in today’s healthcare environment.

“The big advances in lung cancer (and many other cancers) have come from not giving one drug to everyone, but developing tests to find out in advance who will get maximal benefit from the drug. If you don’t, the average benefit is very poor.

However, the cost of testing now has to be factored into the calculations of determining the cost-effectiveness of any drug used in this way. Bringing down the cost per positive is essential,” explained Camidge, who was involved in early research for the development of crizotinib and helped to develop one of the assays used to test for the ALK gene alteration.

“Assuming you only treat those who come up positive on a test, your costeffectiveness goes down as you screen more people who don’t have the abnormality you are looking for. It increases the up-front costs of finding those positives,” Camidge said. “For a $1000 test, if the

Targeted Therapy News • 06.12

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy.

1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

D. Ross Camidge, MD, PhD

group you screen has a 50% hit rate, you have to add $2000 to the costs of treating every patient. If it is 1%, you have to add $100,000 up front as the money you spend to find even one patient who is positive.

“For me, the message is to the wider community of doctors, insurers, healthcare providers, and patients. Breakthroughs will not be feasibly applicable unless we make the cost-effectiveness realistic.”

In the initial modeling, the researchers explored a range of costs, assuming that costs would vary over time. They found that, if all patients with advanced non– small cell lung cancer were screened for ALK, and the assay cost around $1400, screening would be $106,707 per qualityadjusted life-year (QALY) before any drugrelated costs were considered. If the population could be narrowed to only those more likely to test positive, the QALY cost would fall to $4756. However, physicians would miss more than half the patients who would benefit from treatment.

“When you start to think like this, the cost-effectiveness of these breakthroughs becomes a real problem,” Camidge said. “We can either enrich the population being screened by other means but run the risk of missing some people, or bring down the cost of finding each positive patient, such as by reducing the cost of the individual test or multiplexing the tests so you get more positives (even if in different markers) per dollar spent.” TTN Reference 1. Atherly AJ, Camidge DR. The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. Br J Cancer. 2012; 106(6):1100-1106. doi:10.1038/bjc.2012.60.

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% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy

AVASTIN® (bevacizumab) was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).

[See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

• Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

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

The data below reflect exposure to Avastin in 3795 patients with CRC, non‑squamous NSCLC, MBC, 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).] Data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, an indication for which Avastin is not approved. The population was aged 18‑88 years (median 59), 43.2% male and 85.3% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.

In Study 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).]

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab) Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

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).]

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

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.

In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%).

In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 5, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%.

Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 7). [See Warnings and Precautions (5.8).]

Congestive Heart Failure 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 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test)was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84 or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

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

Arm 2 IFL ++ Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

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).

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) 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%

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.

55% 55% 19%

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

Adverse events were encoded using MedDRA, Version 10.1.

a

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 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 );

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

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).

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).]

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.

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 Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/ carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/ carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions.

[See Nonclinical Toxicology (13.3).]

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

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.

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

01/12 AVA0000765901 10127309 Initial U.S.Approval: February 2004 Code Revision Date: December 2011 Avastin® is a registered trademark of Genentech, Inc. ©2012 Genentech, Inc.

To confront a common threat across approved indications...

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Because anti-angiogenesis matters Avastin is designed to directly inhibit the VEGF ligand to specifically inhibit angiogenesis1*

VEGF=vascular endothelial growth factor. *The mechanism of action of Avastin has been elucidated primarily in preclinical models.

Its clinical significance is unknown.

Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. 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.

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Most common adverse events

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

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother In mRCC, 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%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events 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 were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,† the incidences of Avastinrelated adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

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, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Avastin is not approved for use in combination with irinotecan.

†

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Reference: 1. Avastin Prescribing Information.

Genentech, Inc. December 2011.

©2012 Genentech USA, Inc. All rights reserved. AVA0000488401 Printed in USA. (01/12)

www.avastin.com