The International Journal of Targeted Therapies in Cancer February 2013 by Intellisphere, LLC

dvanced In prostate advancedcancer prostate cancer

REAT TREAT FIRST FIRST LINELINE WITH WITH PROVENGE PROVENGE TO TO PROVENGE

Activate Activate Resting T cell

Resting T cell

T-cell activation

PROVENGEPROVENGEactivated T cells activated T cells

PROVENGE

T-cell activation

Amplify Amplify Activated T cell Activated T cell attacks prostate attacks cancer prostate cancer

Attack Attack Prostate cancer cell Prostate cancer cell cell Prostate cancer cell Prostate cancer

XTEND EXTEND SURVIVAL SURVIVAL

1,2 1,2 OVERALLOVERALL SURVIVAL SURVIVAL BENEFITBENEFIT OF PROVENGE OF PROVENGE 100

100 100

100

PROVENGE (n=341)

Control* (n=171)

PROVENGE (n=341)

Control (n=171)

50 21.7

Survival (%)

75 Survival (%)

Survival (%)

PROVENGE (n=341)

25.8

months 25.8

months

22.5%

25.8

RISK REDUCTION

months 25.8

22.5%

RISK REDUCTION

months

21.7

months 21.7 months 21.7 21.7 21.7 months months

months21.7 months21.7 months months 25 25

HR=0.775 HR=0.775

(95% 0.614, 0.979) (95% 0.614, 0.979) (95% CI:CI: 0.614, 0.979) (95% CI:CI: 0.614, 0.979) P=0.032 P=0.032 P=0.032 P=0.032

0 0

012

12 0 24

0 60 36 24 12 244848 24 3660 01236 36

72 48 4872

60 60

72 72

Time From Randomization Time From (Months) Randomization (Months)

*64% of patients in the*64% control of patients group, following in the control progression, group, following crossed over progression, to a nonrandomized, crossed over open-label to a nonrandomized, open-label protocol to receive anprotocol investigational to receive autologous an investigational immunotherapy autologous madeimmunotherapy from cryopreserved madecells. from cryopreserved cells. Data originally publishedData in The originally New England published Journal in The ofNew Medicine: England Kantoff Journal PW,ofHigano Medicine: CS, Kantoff Shore ND, PW,etHigano al; for the CS,IMPACT Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T Study Investigators. immunotherapy Sipuleucel-T for castration-resistant immunotherapyprostate for castration-resistant cancer. N Engl Jprostate Med. 2010;363:411-422. cancer. N Engl J Med. 2010;363:411-422.

2 2 1 1 1 1 > years

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® (sipuleucel-T) INDICATION: PROVENGE INDICATION: PROVENGEis®an (sipuleucel-T) autologous iscellular an autologous immunotherapy cellular immunotherapy indicated for the indicated treatmentfor of the treatmen asymptomatic or asymptomatic minimally symptomatic or minimally metastatic symptomatic castrate metastatic resistantcastrate (hormone resistant refractory) (hormone prostate refractory) cancer. prostate cancer. IMPORTANT SAFETY IMPORTANT INFORMATION: SAFETYPROVENGE INFORMATION: is intended PROVENGE solelyisforintended autologous solely useforand autologous is not routinely use andtested is notfor routinely tested transmissible infectious transmissible diseases. infectious In controlled diseases. clinical In controlled trials, serious clinical adverse trials,events seriousreported adverseinevents the PROVENGE reported ingroup the PROVENGE g included acute infusion included reactions acute infusion (occurring reactions within 1(occurring day of infusion) within 1and daycerebrovascular of infusion) andevents. cerebrovascular Severe (Grade events. 3) acute Severe (Grade 3) a infusion reactionsinfusion were reported reactions in 3.5% were reported of patients in in 3.5% the of PROVENGE patients ingroup. the PROVENGE Reactions group. included Reactions chills, fever, included fatigue, chills, fever, fat asthenia, dyspnea, asthenia, hypoxia,dyspnea, bronchospasm, hypoxia,dizziness, bronchospasm, headache, dizziness, hypertension, headache, muscle hypertension, ache, nausea, muscle andache, vomiting. nausea, and vomiti No Grade 4 or 5 acute No Grade infusion 4 orreactions 5 acute infusion were reported reactions in patients were reported in the PROVENGE in patients in group. the PROVENGE group. The most commonThe adverse most events common (incidence adverse ≥15%) events (incidence reported in≥15%) the PROVENGE reported group in the PROVENGE were chills, fatigue, group were fever, chills, backfatigue, pain, fever, back p nausea, joint ache,nausea, and headache. joint ache, and headache. For more information For more on PROVENGE, information please on PROVENGE, see Brief please see Brief Summary of Prescribing Summary Information of Prescribing on adjacent Information pages.on adjacent pages.

www.PROVENGE.com 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.)

Table 1 Incidence of Adverse Events Occurring in â&#x2030;Ľ5% 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 (%)

Grade 3-5 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)

*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.3.2012. National Comprehensive Cancer Network Web site. www.nccn.org. Accessed April 26, 2012.

The International

Targeted

Journal of Targeted Therapies

Healthcare Communications p r e sid e n t

in Cancer

™

February 2013

Contents

Peter Ciszewski pciszewski@targetedHC.com

North American Edition www.TargetedHC.com

e dit o r i a l & p r o d u cti o n Editor Devera Pine dpine@onclive.com Vice President, Oncology and Managed Markets Lyn Beamesderfer lbeamesderfer@onclive.com Senior Editors Anita T. Shaffer Jason M. Broderick Beth Fand Incollingo

Associate Editor Ben Leach Web Editor Silas Inman Assistant Web Editor Andrew Roth Art Director Leighanne Tillman

s a l e s & m a r k e ti n g Vice President, Sales & Marketing Lisa Greene lgreene@targetedHC.com

Director of Sales Scott Harwood sharwood@targetedHC.com

digit a l m e di a Vice President, Digital Media Jung Kim

Director, Digital Content Sean Johnson

Featured Article

Clinical Articles

28 Companion Diagnostics and Multiplex Testing Evolve Along With Targeted Therapies

Peer Reviewed

Clinical Trial Profile 34 Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia (The EPIC Trial)

Departments 5

From the Editor

Controller Jonathan Fisher, CPA

Director of Circulation John Burke jburke@mdng.com

Assistant Controller Leah Babitz, CPA

c o r p o r at e Chairman/ Chief Executive Officer Mike Hennessy

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 Vice President/

11 Targeted Therapy Clinical Trials in Progress 16 Conference Highlights: ASH 2012

Ponatinib 12-Month Data Demonstrate Robust Response in TreatmentResistant CML and Ph+ ALL Pomalidomide Siginficantly Improved Outcomes in Multiple Myeloma; Gains FDA Approval

MLN9708 May Be Alternative to Bortezomib in Multiple Myeloma

ISSN 2168-2119 (print) ISSN 2168-2127 (online) The content contained in this publication is for general information purposes only. The reader is encouraged to confirm the information presented with other sources. The International Journal of Targeted Therapies in Cancer 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. The International Journal of Targeted Therapies in Cancer reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. The International Journal of Targeted Therapies in Cancer 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 The International Journal of Targeted Therapies in Cancer.

February 2013

Wen Wee Ma, MBBS Nab-paclitaxel, when added to gemcitabine, has demonstrated improvements in survival in patients with metastatic pancreatic cancer. Given favorable survival data and toxicity profile, the nab-paclitaxelplus-gemcitabine regimen will be a welcome addition to the armamentarium for treating pancreatic cancer. Future research will focus on investigating the role of this regimen in patients with resected, borderline resectable, and locally advanced disease. 42

Clinical Indications for ZivAflibercept in Colorectal Cancer

Ibrutinib Performance in CLL Patients Hailed

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

Nab-Paclitaxel Plus Gemcitabine in Pancreatic Cancer

c o l o r e ct a l c a n c e r

Alex A. Adjei, MD, PhD

o p e r a ti o n s Director of Operations Thomas J. Kanzler

p a n c r e a tic c a n c e r

Studies Investigate Panobinostat in Combination With Proteasome Inhibitors for Relapsed/Refractory Multiple Myeloma Novel JAK2 Inhibitor Shows Promise as Myelofibrosis Therapy Quizartinib Produces Remissions in Some Patients With Resistant AML Frontline Brentuximab Shows Promise in Two Lymphoma Trials

Sigurdis Haraldsdottir, MD, and Tanios Bekaii-Saab, MD Ziv-aflibercept is a soluble fusion protein that is approved by the FDA, in combination with FOLFIRI, for the treatment of patients with metastatic colorectal cancer (mCRC) who have previously progressed on an oxaliplatin-based regimen. Following its approval, it remains unclear where to incorporate its use. Biomarkers are needed to help determine who would best benefit from zivaflibercept, and may facilitate further its placement in the continuum of care for patients. 46 New Targets in Advanced Colorectal Cancer: Moving Beyond EGFR and VEGF Safi Shahda, MD, and Ramesh K. Ramanathan, MD The treatment of metastatic colorectal cancer (mCRC) has evolved over the last 20 years, with the addition of targeted agents improving the outlook for overall survival. More recently, two new agents targeting the VEGF pathway were approved for mCRC, and advances in molecular biology using high-throughput techniques and genome sequencing have led to the identification of numerous aberrations and mutations in key genetic pathways. Clinicians are challenged to identify key oncogenic events so that patients can be treated with the appropriate targeted therapies. This review highlights some of the new, lesser-known targets that are undergoing evaluation, with a focus in mCRC.

Interested in contributing?

If you’d like to submit an article outline or abstract for consideration in an upcoming issue, please e-mail Devera Pine at dpine@onclive.com. The International Journal of Targeted Therapies in Cancer

From the Editor Alex A. Adjei, MD, PhD e dit o r i a l b o a r d p h y sici a n e dit o r - i n - chi e f Alex A. Adjei, MD, PhD Professor and Chair, Department of Medicine Katherine Anne Gioia Chair in Cancer Medicine Senior Vice President, Clinical Research Roswell Park Cancer Institute Buffalo, NY

Colleagues,

a ss o ci a t e e dit o r s

Welcome to the first issue of The International Journal of Targeted Therapies in Cancer for 2013. Starting with this issue, we plan to publish the journal on a bimonthly basis. In case you did not have a chance to review our inaugural issue in June 2012, this is a peer-reviewed journal that was initially published quarterly and that is aimed at nonacademic oncologists. This issue of the journal focuses mainly on new systemic therapies for gastrointestinal malignancies. The pivotal studies of aflibercept for advanced colorectal cancer are discussed, as are novel targets in colorectal cancer. Also discussed is the exciting phase III study of nab-paclitaxel in combination with gemcitabine for the frontline therapy of pancreatic cancer. Finally, this issue brings you a special section that highlights the major scientific breakthroughs covered at last December’s American Society of Hematology (ASH) meeting that have the potential to positively affect your daily practice. Please write to us with your suggestions and constructive criticism. Our aim is to ensure that the journal serves your education and information needs as you strive to provide the highest level of care for your patients.

— Alex A. Adjei, MD, PhD p h y sici a n Edit o r - i n - C hi e f

Roger B. Cohen, MD Professor of Medicine Associate Director of Clinical Research Abramson Cancer Center University of Pennsylvania Philadelphia, PA Grace Dy, MD Assistant Professor Department of Medicine Roswell Park Cancer Institute Buffalo, NY

Edward Chu, MD Chief, Division of Hematology-Oncology University of Pittsburgh School of Medicine Deputy Director, University of Pittsburgh Cancer Institute Pittsburgh, PA Robert L. Coleman, MD, FACOG, FACS Professor of Gynecologic Oncology Vice Chair, Clinical Research, Department of Gynecologic Oncology The University of Texas MD Anderson Cancer Center Houston, TX Jorge Eduardo Cortes, MD Chair, CML Section, Department of Leukemia Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX Ramaswamy Govindan, MD Professor Department of Medicine Oncology Division Washington University School of Medicine St. Louis, MO Axel Grothey, MD Professor of Oncology Consultant, Medical Oncology Mayo Clinic Rochester, MN Jonathan L. Kaufman, MD Assistant Professor Associate Director Fellowship Program Department of Hematology and Medical Oncology Winship Cancer Institute Emory University Atlanta, GA

Wen Wee Ma, MBBS Assistant Professor Phase I and GI Oncology Department of Medicine Roswell Park Cancer Institute Buffalo, NY Igor Puzanov, MD, MSCI, FACP Associate Professor of Medicine Associate Director of Phase I Drug Development Clinical Director, Renal Cancer Melanoma/ Renal Cancer Program Division of Hematology-Oncology Vanderbilt University Medical Center Nashville, TN

Sagar Lonial, MD Professor, Emory School of Medicine Vice Chair of Clinical Affairs, Department of Hematology and Medical Oncology Director, Translational Research, B-cell Malignancy Program Emory University School of Medicine Atlanta, GA Joyce A. O’Shaughnessy, MD Co-Director, Breast Cancer Research Baylor Charles A. Sammons Cancer Center/Texas Oncology US Oncology Dallas, TX Roberto Pili, MD Professor of Oncology Chief, Genitourinary Section Leader, Genitourinary Program, Department of Medicine Roswell Park Cancer Institute Buffalo, NY Antoni Ribas, MD, PhD Associate Professor, HematologyOncology and Surgical Oncology Assistant Director for Clinical Programs, UCLA Human Gene Medicine Program Director, JCCC Cell and Gene Therapy Core Facility David Geffen School of Medicine University of California, Los Angeles Los Angeles, CA Hope Rugo, MD Clinical Professor, Department of Medicine (Hematology/Oncology) Director, Breast Oncology Clinical Trials Program University of California, San Francisco San Francisco, CA Oliver Sartor, MD Piltz Professor of Cancer Research Departments of Medicine and Urology Tulane University School of Medicine New Orleans, LA

To reach Dr. Adjei and/or the journal’s editorial staff, please e-mail: dpine@onclive.com.

TargetedHC.com

February 2013

INDICATIONS s DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy s DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy IMPORTANT SAFETY INFORMATION BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution s The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 – Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose – Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy s Acute infusion-related reactions including, but not limited to, ﬂushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate – Serious and sometimes life-threatening or fatal allergic/anaphylactoidlike infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use

– The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions s Severe myelosuppression may occur s DOXIL® dosage should be reduced in patients with impaired hepatic function s Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS s Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ADDITIONAL SAFETY INFORMATION s Cardiac function should be carefully monitored – Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy – For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the beneﬁt of therapy must be weighed against the risk of myocardial injury – In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (deﬁned as absolute decrease ≥15% over baseline or a ≥5% decrease below institutional lower limit of normal) s Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® – In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL®

DOXIL Is Now Available. ®

We Are COMMITTED

long-term to ensuring a reliable supply of DOXIL®.

Prescribe With CONFIDENCE.

– In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE – Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage – Sepsis occurring during neutropenia has resulted in discontinuation of treatment and, in rare cases, death s DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow s Hand-foot syndrome (HFS) may occur during therapy with DOXIL® – Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required – HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier s The reaction was mild in most patients, resolving in 1 to 2 weeks s The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy s DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation s DOXIL® can cause fetal harm when used during pregnancy s Because of the potential for serious adverse reactions in nursing infants, discontinue nursing during treatment with DOXIL® s Recall reaction has occurred with DOXIL® administration after radiotherapy

Janssen Products, LP Distributed by: Janssen Products, LP, Horsham, Pennsylvania 19044-3607 © Janssen Products, LP 2012 10/12 KO8D121011

s DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl s In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) ≥20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%) – In addition, 19% vs 52.3% reported alopecia (all grades) – Grade 3/4 hematologic ARs reported in ≥5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%) s In patients with multiple myeloma, the most common all-grade ARs ≥20% (DOXIL® plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) – In addition, 19% vs <1% reported HFS VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information on the following pages.

K08D121023

The brand you’ve long relied on remains an important therapeutic option for you and your patients.

DOXIL®

(doxorubicin HCl liposome injection) for intravenous infusion BRIEF SUMMARY. Please see Full Prescribing Information. WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION 1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500-550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXIL should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings and Precautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis [see Full Prescribing Information]. INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. Multiple Myeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy. CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should be carefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below. Table 1: Number of Patients With Advanced Breast Cancer DOXIL (n=250) Patients who Developed Cardiotoxicity 10 (LVEF Defined) Cardiotoxicity (With Signs & Symptoms of CHF) 0 Cardiotoxicity (no Signs & Symptoms of CHF) 10 Patients With Signs and Symptoms of CHF Only 2

DOXIL® (doxorubicin HCl liposome injection) In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of ≥ 15% over baseline or a ≥ 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes lifethreatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusionrelated events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Full Prescribing Information]. Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions]. Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described in Dosage and Administration section [see Full Prescribing Information]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy. Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman. There are no adequate and wellcontrolled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs

DOXIL® (doxorubicin HCl liposome injection)

in the first few months following treatment with DOXIL, the prolonged halflife of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Full Prescribing Information]. Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [see Warnings and Precautions]. ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [see Warnings and Precautions] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma. Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma. Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Topotecan Patients Patients (n = 239) (n = 235) Neutropenia 19 (7.9%) 33 (14.0%) 500 - <1000/mm3 10 (4.2%) 146 (62.1%) <500/mm3 Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) <6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 3 (1.3%) 40 (17.0%) 10,000 - <50,000/mm3 <10,000/mm3 0 (0.0%) 40 (17.0%)

Table 3: Ovarian Cancer Randomized Study (continued) Non-Hematologic DOXIL (%) Topotecan (%) Adverse Reaction treated treated 10% or Greater (n = 239) (n =235) All Grades All Grades grades 3-4 grades 3-4

Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 3: Ovarian Cancer Randomized Study Non-Hematologic DOXIL (%) Adverse Reaction treated 10% or Greater (n = 239) All Grades grades 3-4 Body as a Whole Asthenia 40.2 7.1 Fever 21.3 0.8 Mucous Membrane 14.2 3.8 Disorder Back Pain 11.7 1.7 Infection 11.7 2.1 Headache 10.5 0.8 Digestive Nausea Stomatitis Vomiting Diarrhea Anorexia Dyspepsia

46.0 41.4 32.6 20.9 20.1 12.1

5.4 8.3 7.9 2.5 2.5 0.8

Topotecan (%) treated (n =235) All Grades grades 3-4 51.5 30.6 3.4

8.1 5.5 0

10.2 6.4 14.9

0.9 0.9 0

63.0 15.3 43.8 34.9 21.7 14.0

8.1 0.4 9.8 4.2 1.3 0

Nervous Dizziness

4.2

10.2

Respiratory Pharyngitis Dyspnea Cough increased

15.9 15.1 9.6

0 4.1 0

17.9 23.4 11.5

0.4 4.3 0

Skin and Appendages Hand-foot syndrome Rash Alopecia

50.6 28.5 19.2

23.8 4.2 N/A

0.9 12.3 52.3

0 0.4 N/A

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks. Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 4 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma. Table 4: Frequency of treatment emergent adverse reactions reported in ≥ 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. Adverse Reaction DOXIL + bortezomib Bortezomib (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0 Infections and infestations Herpes zoster 11 2 0 9 2 0 Herpes simplex 10 0 0 6 1 0 Investigations Weight decreased 12 0 0 4 0 0 Metabolism and Nutritional disorders Anorexia 19 2 0 14 <1 0 Nervous system disorders Peripheral Neuropathy* 42 7 <1 45 10 1 Neuralgia 17 3 0 20 4 1 Paresthesia/dysesthesia 13 <1 0 10 0 0

DOXIL® (doxorubicin HCl liposome injection) Table 4: Frequency of treatment emergent adverse reactions reported in ≥ 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. (continued) Adverse Reaction DOXIL + bortezomib Bortezomib (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Respiratory, thoracic and mediastinal disorders Cough 18 0 0 12 0 0 Skin and subcutaneous tissue disorders Rash** 22 1 0 18 1 0 Hand-foot syndrome 19 6 0 <1 0 0 *Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. 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. Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category D [see Warnings and Precautions].: DOXIL is embryotoxic at doses of 1 mg/kg/day in rats and is embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about one-eighth the 50 mg/m2 human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DOXIL, discontinue nursing during treatment with DOXIL. Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established. Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Hepatic Impairment: The pharmacokinetics of DOXIL has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Thus, DOXIL dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. Prior to DOXIL administration, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as SGOT, SGPT, alkaline phosphatase, and bilirubin [see Full Prescribing Information]. OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis. Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Manufactured for: Janssen Products, LP Horsham, PA 19044 © Janssen Products, LP 2010 Revised September 2012 TM

An ALZA STEALTH® Technology Product

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation. K08D121020

Targeted Therapy Clinical Trials

in progress

The Targeted Therapy Clinical Trials in Progress section is intended to stimulate discussion about ongoing clinical trials and to promote collaboration across the oncology community. Following are summaries of ongoing research in a broad range of cancer types.

Breast Cancer

Pertuzumab with trastuzumab/taxane combination for advanced breast cancer This phase III study will evaluate the safety and tolerability of pertuzumab (a HER2/neu receptor antagonist) combined with trastuzumab and a taxane as first-line treatment of metastatic or locally recurrent HER2-positive breast cancer. Subjects will receive pertuzumab 840 mg intravenously (IV) and trastuzumab 8 mg/kg IV plus a taxane on the first day of their first treatment cycle, followed by pertuzumab 420 mg IV and trastuzumab 6 mg/kg IV plus a taxane on the first day of each subsequent 3-week cycle. The study will enroll patients who are at least 18 years old with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 and left ventricular ejection fraction (LVEF) of at least 50%. The primary outcome measures are safety and tolerability. Secondary endpoints include progressionfree survival (PFS), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), duration of response, time to response, and quality of life (QoL). Sponsor: Hoffmann-La Roche ClinicalTrials.gov Identifier: NCT01572038

trial will assess the efficacy and safety of the comparator agents in two co-primary populations: all enrolled patients, and enrolled patients with KRAS wild-type status. Secondary endpoints include OS, PFS per investigator, best overall response, duration of response, overall safety by common terminology criteria for adverse events (CTCAE) grading at each specified visit, and LVEF every 3 to 6 months, as well as patient-reported outcomes of health-related quality of life, disease symptoms, and health status. The investigators will also examine KRAS mutation status in tissue samples and HER family genotypes from serum samples at baseline and PK trough concentrations. The target recruitment is about 800 patients. Sponsor: Pfizer ClinicalTrials.gov Identifier: NCT01360554

Renal Cancer

Pazopanib for metastatic renal cancer without disease after surgery

This phase III study will explore whether adding daily BKM120 (PI3 kinase inhibitor) to fulvestrant is effective and safe in patients with HR+, HER2-locally advanced or metastatic breast cancer refractory to aromatase inhibitor therapy. Individuals who have had more than one prior chemotherapy for locally advanced or metastatic disease or who have undergone prior treatment with PI3K inhibitors, AKT inhibitors, or fulvestrant will be excluded. The primary outcome measure is PFS. Secondary outcome measures include OS, ORR, CBR, and type, frequency, and severity of adverse events. The investigators hope to enroll 615 patients, with an estimated primary completion date of October 2016.

This phase III study will compare pazopanib to placebo in patients with stage IV renal cell cancer without apparent disease after metastasectomy. Study participants will be randomized to receive oral pazopanib or placebo daily on days 1-28, and treatment will be repeated every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. The primary outcome measure is disease-free survival. Secondary outcome measures include OS, toxicity, change in quality-adjusted time without symptoms or toxicity (Q-TWIST) between the two treatment arms, change in fatigue, and change in renal cancerrelated symptoms. Investigators aim to enroll about 180 patients, all of whom must have pathologically confirmed renal cell carcinoma with a clear cell component with pathologic confirmation of metastatic disease in the resected metastasectomy specimen. About 180 patients will be enrolled at a total of 65 study sites.

Sponsor: Novartis ClinicalTrials.gov Identifier: NCT01633060

Sponsor: National Cancer Institute ClinicalTrials.gov Identifier: NCT01575548

BKM120 added to fulvestrant for HR+, HER2metastatic breast cancer

Lung Cancer

Dacomitinib for advanced lung cancer This phase III study will compare dacomitinib (irreversible pan-HER tyrosine kinase inhibitor) versus erlotinib for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) following progression after or intolerance to at least one prior chemotherapy. The

TargetedHC.com

Timing of surgery for sunitinib-treated metastatic renal cancer This phase III study will compare immediate versus deferred nephrectomy in patients with resectable, synchronous, metastatic renal cell carcinoma treated with sunitinib. Study participants will be stratified according to World Health Organization (WHO) performance status (0 vs 1), number of metastatic sites (1 vs 2 or more), and

February 2013

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

• 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

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 (%)

50% Improvement Upper 50th Percentile

Placebo (n = 153)

In these charts, each bar represents an individual patient’s response.

Upper 50th Percentile

Jakafi (n = 145)

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, including abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. June 2012. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

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

JAK targeted to make a difference

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a registered trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011-2012 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: June 2012 RUX-1040a

Targeted Therapy Clinical Trials

in progress

institution. The primary outcome measure is overall PFS. Secondary outcome measures include OS, morbidity, overall response to treatment in the deferred nephrectomy arm, including the percentage of patients who become unresectable, and the effect of nephrectomy on early progression, in both arms. Researchers will also collect tumor tissue samples to assess possible differences in gene expression as well as blood samples to evaluate the potential impact of serum proteins on clinical outcome.

ECOG PS of 0-2 and failed to respond to or relapsed within 6 months of completing fludarabine or another purine analog alone or in combination regimen, OR who failed to respond to chemoimmunotherapy or relapsed within 24 months of completing therapy with a combination of chemotherapy plus an anti-CD20 monoclonal antibody.

Sponsor: European Organisation for Research and Treatment of Cancer Collaborators: Wales Cancer Trials Unit, Canadian Urologic Oncology Group, Arbeitsgemeinschaft Urologische Onlogie (AUO), Institute of Cancer Research, United Kingdom ClinicalTrials.gov Identifier: NCT01099423

Carfilzomib plus dexamethasone for relapsed multiple myeloma

H E M ATO L OGI C M A L IGNAN C IES

Rituximab with lenalidomide for untreated follicular lymphoma This phase III study will compare rituximab plus lenalidomide versus rituximab plus chemotherapy followed by rituximab in patients with previously untreated follicular lymphoma. Patients are eligible provided they are at least 18 years of age and have histologically confirmed follicular lymphoma grade 1, 2, or 3a, stage II-IV disease that is symptomatic and requires treatment, along with an ECOG PS of 0-2. Individuals who have had prior systemic treatment for lymphoma will be excluded. The primary endpoints are the complete response (complete response/ complete response unconfirmed rate, PFS, and safety. The target recruitment is 1000 patients. The aim of the study is to evaluate the effect of combined lenalidomide and rituximab with standard combination chemotherapy treatment. Sponsor: Celgene Corporation Collaborator: The Lymphoma Academic Research Organisation ClinicalTrials.gov Identifier: NCT01476787

Dinaciclib or ofatumumab for refractory chronic lymphocytic leukemia This phase III study will compare dinaciclib (a cyclindependent kinase [CDK] inhibitor specific for CDK 1, 2, 5, and 9) to ofatumumab in patients with chronic lymphocytic leukemia (CLL) with del 17p and the overall population of CLL patients who are refractory to either fludarabine treatment or chemoimmunotherapy. The primary outcome measure is PFS. The investigators aim to recruit about 466 patients for the trial. Patients will be considered eligible provided they have a confirmed diagnosis of CLL with an

TargetedHC.com

Sponsor: Merck ClinicalTrials.gov Identifier: NCT01580228

This phase III study will compare carfilzomib (a next-generation proteasome inhibitor) plus dexamethasone versus bortezomib plus dexamethasone in patients with multiple myeloma whose disease has relapsed after at least one but not more than three prior therapeutic regimens. Patients with stable disease or progressive disease as their best response to all prior therapies will be excluded. Subjects are allowed to have received prior carfilzomib or bortezomib as long as they had at least a partial response to such therapy and at least a 6-month treatment-free interval since receiving one of the two agents. Study participants may receive maintenance therapy with non-proteasome inhibitor drugs during this 6-month treatment-free interval. The primary outcome measure for the estimated 888-patient study is PFS. Sponsor: Onyx Pharmaceuticals ClinicalTrials.gov Identifier: NCT01568866 skin cancer

Dabrafenib plus trametinib for advanced cutaneous melanoma This phase III study will compare combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib to the BRAF inhibitor vemurafenib in patients with histologically confirmed cutaneous melanoma that is either stage IIIc (unresectable) or stage IV (metastatic) and BRAF V600E/K mutation positive. In order to be eligible, patients must also have measurable disease according to RECIST 1.1 and an ECOG PS of 0-1. Individuals with prior use of a BRAF or MEK inhibitor or prior systemic anticancer treatment in the advanced or metastatic setting will not be eligible, although prior systemic treatment in the adjuvant setting is permitted. The primary endpoint is OS. Secondary endpoints include PFS, ORR, and duration of response. The target recruitment is about 694 patients. Sponsor: GlaxoSmithKline ClinicalTrials.gov Identifier: NCT01597908

February 2013

Targeted Therapy Updates c o n f e r e n c e h i g h li g h ts

ASH 2012

December 8-11, 2012

Atlanta, Georgia

The 54th American Society of Hematology (ASH) Annual Meeting and Exposition was held December 8-11, 2012, in Atlanta, Georgia. The meeting provided practicing hematologists with information on nearly 30 of the most important areas of clinical progress, and the scientific program showcased the latest scientific advances in 17 key areas of hematology. Highlights of key presentations from the conference are presented on the following pages. Section contributors: Beth Fand Incollingo, Ben Leach, Devera Pine, and Anita T. Shaffer CML and Ph+ ALL

Ponatinib 12-Month Data Demonstrate Robust Response in TreatmentResistant CML and Ph+ ALL Twelve-month follow-up data from the phase II PACE trial, presented at the ASH meeting, demonstrated that ponatinib, an investigational oral tyrosine kinase inhibitor (TKI), can overcome a wide range of mutations that cause treatment resistance, including the T315I mutation, in all stages of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). “We have simply never had any treatment produce such high rates of durable response in such a heavily treated group of patients,” said Jorge Cortes, MD, lead author and professor of Medicine, deputy chair of the Department of Leukemia, and chief of the CML and AML Sections at The University of Texas MD Anderson Cancer Center in Houston. Following a priority review, the FDA approved ponatinib (Iclusig) on December 14, 2012, for treatment of adult patients Jorge Cortes, MD with chronic-, accelerated-, or blast-phase CML that is resistant or intolerant to prior TKI therapy, or for PH+ ALL that is resistant or intolerant to prior TKI therapy. The PACE trial enrolled 449 patients with CML or Ph+ ALL who had the T315I mutation and/or a history of resistance to dasatinib or nilotinib. Nearly all of the patients had been treated with multiple TKIs—90% with three such drugs and 60% with two. The patients were separated into six cohorts based on their disease resistance or genetic profile, and treated with ponatinib. The primary endpoint was major cytogenetic response within 12 months of treatment for those with chronic-phase CML, and major hematologic response within 6 months after treatment for those with advanced-phase CML or Ph+ALL. Results exceeded those criteria. 16

February 2013

Major cytogenetic response was observed in 56% of all patients with chronic-phase CML (70% of those with the T315I mutation and 51% of those with other mutations). Major hematologic response was observed in 57% of patients with acceleratedphase CML (50% of those with T315I and 58% of those with other reasons for resistance or intolerance) and 34% of those with blast-phase CML or Ph+ ALL (33% of those with the T315I mutation and 35% of resistant/intolerant patients). Complete cytogenetic response was achieved in 46% of patients with chronic-phase CML, with higher response rates observed in patients who were exposed to fewer prior TKIs and those with shorter disease duration. The portion of responders estimated to maintain their primary endpoint at 1 year was 91% in chronic-phase CML, 42% in accelerated-phase CML, and 35% in blast-phase CML or Ph+ ALL. Ponatinib was well tolerated in all cohorts. The most common adverse events were skin toxicity (including rash or dry skin), elevation of pancreatic enzymes and/or pancreatitis, and myelosuppression. At the time of analysis, 52% of patients remained on therapy. “This is a fantastic drug that offers an opportunity for patients who have failed everything else and don’t have anything more to receive,” Cortes said. “It gives us the most powerful tool we have for CML. The prospects for patients to be cured and have eradication of their disease are increasing greatly with drugs such as ponatinib.” Ongoing at MD Anderson are a study of ponatinib as initial therapy and a trial of the drug in comparison to imatinib, Cortes said. Studies to start soon will investigate ponatinib and chemotherapy in Ph+ ALL; ponatinib in patients who have failed just one prior therapy; and ponatinib for patients with acute myeloid leukemia, a strategy that showed promise in phase I trials. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. A pivotal phase II trial of ponatinib in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 12-month follow-up of the PACE trial. Presented at: 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 163.

The International Journal of Targeted Therapies in Cancer

Enrolling in

Investigating dacomitinib, an irreversible pan-HER inhibitor, versus erlotinib in secondor third-line therapy for advanced NSCLC1 Phase 3, randomized, double blind, multinational, multicenter study in NSCLC patients after at least one prior course of chemotherapy

Patients with locally advanced or metastatic NSCLC following progression after, or intolerance to, at least one prior course of chemotherapy N = 800

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

Dacomitinib 45 mg orally once daily 1:1 Erlotinib 150 mg orally once daily

Coprimary populations: all enrolled NSCLC patients and NSCLC patients confirmed for KRAS wild type

End Points Primary: Progression-free survival Secondary: Overall survival, objective response rate, duration of response, safety and tolerability, and patient-reported outcomes

For more information, please contact the Pfizer Oncology Clinical Trial Information Service at: 1-877-369-9753 in the United States and Canada (toll-free) +1-646-277-4066 outside the United States For more information, please visit www.pfizercancertrials.com or www.clinicaltrials.gov (NCT01360554) * Stratified by histology (adenocarcinoma vs non-adenocarcinoma), race (Asian vs non-Asian and Indian subcontinent), ECOG performance status score (0-to-1 vs 2), smoking status (never-smoker vs ever smoker). NSCLC = non-small cell lung cancer; ECOG = Eastern Cooperative Oncology Group. Reference: 1. Data on file. Pfizer Inc, New York, NY. This information is current as of October 2011.

Dacomitinib (PF-00299804) is an investigational compound

PFW 00029-B

ÂŠ 2012 Pfizer Inc.

Advanced NSCLC

Targeted Therapy Updates m u ltipl e m y e l o ma

Pomalidomide Siginficantly Improved Outcomes in Multiple Myeloma; Gains FDA Approval The combination of pomalidomide and a steroid significantly improved outcomes for patients with multiple myeloma (MM) who have exhausted other novel therapies, marking what researchers say is a notable advancement for a sizable proportion of those treated for the disease. In a phase III trial presented at the ASH meeting, pomalidomide given with low-dose dexamethasone nearly doubled median progression-free survival (PFS) to 15.7 weeks when compared with high-dose dexamethasone at a median PFS of 8.0 weeks (hazard ratio [HR] = 0.45; P < .001). Median overall survival (OS) had not yet been reached in the pomalidomide arm but is expected to be in about 11 to 12 months, said Meletios A. Dimopoulos, MD, lead author, and professor and chair of the Department of Clinical Therapeutics at Alexandra Hospital in Athens, Greece. The median OS was 34 weeks in the control arm (HR = 0.53; P <.001). Dimopoulos said in an interview that researchers are excited to have an option for patients who become resistant to lenalidomide (Revlimid) and bortezomib (Velcade), which often are combined with dexamethasone as frontline therapy in the United States. Although novel therapies have dramatically improved the median survival of the average patient with MM from no more than 3 years approximately a decade ago to more than 7 or 8 years today, patients ultimately relapse. Currently, patients who are resistant or refractory to the novel agents are often offered highdose dexamethasone as a palliative treatment because there are no alternatives, Dimopoulos said. “More and more patients with myeloma today are being treated with novel agents,” he said. “The majority of patients with

“More and more patients with myeloma today are being treated with novel agents. The majority of patients with myeloma will end up becoming refractory to bortezomib and lenalidomide, so this is a very large patient population.”

myeloma will end up becoming refractory to bortezomib and lenalidomide, so this is a very large patient population.” Patients who are refractory to current therapies experience PFS of no more than 5 months and OS of approximately 8 months, Dimopoulos said. “Clearly, there is a need to salvage patients who have acquired resistance. The goal is to be able to provide further treatment for patients with myeloma who have exhausted all available therapies.” Patients in the trial had been heavily pretreated, with a median of five prior therapies. In all, 455 patients were randomized 2:1 to receive pomalidomide plus low-dose dexamethasone (n = 302) versus high-dose dexamethasone (n = 153). In the experimental arm, each 28-day cycle consisted of pomalidomide 4 mg daily on days 1 to 21 plus dexamethasone on days 1, 8, 15, and 22 at 40 mg for participants age 75 years or younger, and 20 mg for those over age 75 years. In the control arm, patients received dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 at the same age-stratified dosages. The combination regimen was well tolerated. The frequency of grade 3/4 hematologic toxicities was higher in the pomalidomide arm compared with the control group for neutropenia (42% vs 15%, respectively) and febrile neutropenia (7% vs 0%, respectively), but lower for thrombocytopenia (21% vs 24%, respectively). Of those who discontinued therapy, progressive disease was the primary reason, with 35% of patients who had taken pomalidomide and 49% in the control group. In all, 25% of patients in the pomalidomide group and 38% in the control group died, primarily due to progressive disease and infections. In early February, the FDA granted accelerated approval to pomalidomide for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy. Celgene Corporation, which is developing the drug, has also applied to the European Medicines Agency for marketing authorization and anticipates a decision in the second half of 2013. Dimopoulos MA, Lacy MQ, Moreau P, et al. Pomalidomide in combination with lowdose dexamethasone: demonstrates a significant progression free survival and overall survival advantage, in relapsed/refractory MM: a phase III, multicenter, randomized, open-label study. Presented at: 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract LBA-6.

– M e l e ti o s A . D im o p o u l o s , M D

February 2013

The International Journal of Targeted Therapies in Cancer

Targeted Therapy Updates CLL/SLL

Ibrutinib Performance in CLL Patients Hailed The novel targeted agent ibrutinib has demonstrated dramatic activity in hard-to-treat patients with chronic lymphocytic leukemia (CLL) when used alone and in combination with rituximab, raising the prospect of a promising new therapy for elderly and frail patients who currently have few viable options. The findings of two studies of the drug were discussed at the ASH meeting. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is the most advanced in a new class of anticancer agents, and researchers were clearly excited about its potential. The drug is a welltolerated oral medication that produces “excellent responses,” without the need for the more intensive chemotherapy regimens that serve as first-line treatments for younger and fitter patients, said Claire E. Dearden, MD, consultant hematologist and head of the CLL Unit at The Royal Marsden NHS Foundation Trust in London, who served as moderator for a press briefing on the studies. “There’s a lot of excitement about the possibility of the landscape changing and leaning toward having chemotherapy-free treatments for patients with CLL that are as effective as giving them chemotherapy agents,” said Dearden. “It’s hugely exciting for us as clinicians, but also for the patient community.” The median age for diagnosis of CLL is 72 years, but such patients often are not able to tolerate the primary treatment regimen that includes the chemotherapy agents fludarabine and cyclophosphamide along with the humanized monoclonal antibody rituximab, researchers noted. Ibrutinib is an irreversible inhibitor of BTK, an enzyme that plays an essential role in B-cell receptor signaling and several other pathways, said John C. Byrd, MD, lead author of one of the studies and director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center–James Cancer Hospital and Solove Research Institute in Columbus. So far, he said, there is no indication that inhibiting BTK activates other cancer-causing pathways. Ibrutinib, formerly known as PCI-32765, was evaluated in a phase IB/II study in patients with CLL or small lymphocytic leukemia (SLL). The primary goal of the study was to determine the safety of the low and high doses, while secondary objectives included response rates and progression-free survival (PFS). Results were reported for 116 patients who were stratified into three cohorts: treatment-naïve ≥65 years (n = 31); relapsed/refractory (RR; n = 61), and high-risk RR (n = 24). Participants in the first two groups received dosages of either 420 mg daily or 840 mg daily, while those in the third group received the dosage of 420 mg daily. High risk was defined as progression of disease within 24 months of initiation of prior treatment or failure to respond to previous therapy. The overall response rates, which included partial and complete responses, were 68% in the treatment-naïve group at TargetedHC.com

20.3 months and 71% in the combined results for the two RR groups at follow-up, ranging from 14.7 months for the high-risk RR patients and 22.1 months for the RR group. Among previously untreated patients, there was a 96% estimated rate of both PFS and overall survival (OS) at 22 months. For patients in the RR groups, there was a 76% PFS rate and an 85% OS rate at 22 months. The majority of adverse events were grade 2 or lower, with diarrhea (54%), fatigue (29%), and upper respiratory tract infection (29%) most frequently reported. The incidence of hematologic toxicity grade 3 or higher was relatively infrequent, and there was no evidence of long-term safety concerns.

“There’s rarely something that comes along that you see helping patients so much.The quicker we get this across the finish line to patients, the better it’s going to be. This is a special therapy that all of us have seen really help patients.” – John C. Byrd, MD

“There’s rarely something that comes along that you see helping patients so much,” said Byrd. “The quicker we get this across the finish line to patients, the better it’s going to be. This is a special therapy that all of us have seen really help patients.” The drug is being developed under the FDA’s Fast Track program for patients with CLL/SLL who have relapsed or refractory disease after at least one prior therapy, according to Pharmacyclics, Inc, which is developing ibrutinib in collaboration with Janssen Biotech, Inc. In a second study, researchers sought to accelerate response to ibrutinib by pairing the drug with rituximab in 40 patients with CLL/SLL considered high risk, including those harboring the del 17p/TP53 mutation or del 11q, or those with fewer than 3 years remission after first-line chemo-immunotherapy. The median age was 65 years (range, 35-82 years), and nearly 28% had earlystage disease, while the remainder were stage III or IV. Participants received continuous daily ibrutinib at 420 mg daily in combination with weekly rituximab (375 mg/m2) for the first 4 weeks, and then monthly rituximab until cycle 6. Daily single-agent ibrutinib continued until progression. In all, 38 of 40 patients continued on therapy without disease progression. The overall response rate was 83%, with one patient exhibiting a complete response and the others achieving partial responses. In addition, three patients had a partial response with lymphoFebruary 2013

Targeted Therapy Updates cytosis, two participants did not exhibit any response, and results were too early to evaluate in two other patients. The most common adverse event was diarrhea, followed by bone pain/myalgias and fatigue. Jan A. Burger, MD, PhD, lead author and associate professor of Medicine in the Jan A. Burger, MD, PhD Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, said largerscale studies of the ibrutinib-rituximab combination are needed.

M u ltipl e M y e l o ma

MLN9708 May Be Alternative to Bortezomib in Multiple Myeloma MLN9708, an investigational proteasome inhibitor, demonstrated comparable efficacy and greater convenience and tolerability than a standard drug in its class, bortezomib, for patients with multiple myeloma (MM), investigators have found. Shaji K. Kumar, MD, of the Mayo Clinic in Minnesota, announced the findings at the ASH meeting. In a phase I/II study, MLN9708 was combined with the immunomodulatory agent lenalidomide and dexamethasone Shaji K. Kumar, MD and given to adult patients with previously untreated MM. Their response rates were consistent with those of MM patients who received, in previous trials, the combination of bortezomib, lenalidomide, and dexamethasone, a standard treatment for high-risk MM patients, Kumar said. While that standard is one of the most effective regimens for MM, bortezomib must be administered via injection and carries a risk of peripheral neuropathy, which can deter patient adherence to treatment, Kumar said. Thus, MLN9708, which is orally administered, may offer a more convenient and tolerable form of therapy that limits the risk of nerve damage, he said. In order to assess the efficacy, safety, and proper dose of MLN9708 in the target population, researchers enrolled 65 patients and treated them for up to a year in monthly cycles that each included three weekly doses of MLN9708, four weekly doses of dexamethasone, and 21 days of lenalidomide, followed by maintenance therapy with MLN9708 three times a month until disease progression or toxicity. Primary objectives in phase I included safety, maximum tolerated dose, and recommended phase II dose. In phase II, using a recommended dose of 4 mg, primary objectives included complete remission and very good partial response (VGPR), measured by a 90% or greater reduction in abnormal myeloma proteins in the blood. According to preliminary phase II results, investigators record20

February 2013

He also said that the rate of complete remissions might increase with more effective combination therapies. Byrd JC, Furman RR, Coutre S, et al. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: new and updated results of 116 patients in phase Ib/II study. Presented at: 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 189. Burger JA, Keating MJ, Wierda WG, et al. The BTK inhibitor ibrutinib (PCI-32765) in combination with rituximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients. Presented at: 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 187.

ed an overall response rate of 92% with the drug combination. Fifty-five percent of patients reached VGPR or better, including 23% who experienced complete remission. As the treatment cycles progressed, the rate and depth of response increased. Minor adverse events, such as fatigue, nausea, and rash, were noted in approximately 40% of patients. Thirty-two percent of patients reported neuropathy, in most cases grade 1. Serious adverse events were minimal and primarily consisted of decreased blood counts, nausea and vomiting, diarrhea, rash, and electrolyte disturbances. One patient died from pneumonia while on treatment, and seven patients discontinued treatment due to different side effects. “With the combination of MLN9708, lenalidomide, and dexamethasone, the improvements are convenience; that the combination appears to be less toxic; and that it appears to have at least the same efficacy as we would have expected,” Kumar said. “That will translate into patients being able to stay on it longer term, which might give more benefits than what we have seen with some other previous therapies. All of this must be confirmed in phase III studies before we consider it a standard of practice, but I have high hopes.” A phase III clinical trial of MLN9708 will test the same three-drug combination in the relapsed setting versus a pairing of lenalidomide and dexamethasone, Kumar said, and a separate phase III trial will test MLN9708 with lenalidomide and dexamethasone in newly diagnosed patients. Other combinations are being explored, he added, including that of MLN9708 with cyclophosphamide and dexamethasone. Also reported at the ASH meeting were the results of a phase I study of MLN9708 in patients with relapsed or refractory systemic light-chain amyloidosis. “Preliminary evidence of hematologic responses and early organ responses in this heavily pretreated population are encouraging,” said Karen Ferrante, MD, chief medical officer for the drug’s developer, Millennium Pharmaceuticals. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Presented at: 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 332. Merlini G, Sanchorawala V, Zonder JA, et al. MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis (AL): results of a phase 1 study. Presented at: 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 731.

The International Journal of Targeted Therapies in Cancer

NOW ENROLLING TWO PHASE IIISTUDIES STUDIES NOW ENROLLING TWO PHASE III NOW NOW ENROLLING ENROLLING TWO TWO PHASE PHASE III STUDIES III STUDIES

BELLE-2 and BELLE-3 BELLE-2 and BELLE-3 BELLE-2 BELLE-2 andand BELLE-3 BELLE-3 Two Phase III studies investigating the pan-PI3K

Two Phase IIIstudies studies investigating the pan-PI3K Two Two Phase Phase III III studies investigating investigating the the pan-PI3K pan-PI3K inhibitor, buparlisib (BKM120), plus fulvestrant in inhibitor, buparlisib (BKM120), plus fulvestrant in inhibitor, inhibitor, buparlisib buparlisib (BKM120), (BKM120), plus plus fulvestrant fulvestrant in in HR+/HER2– advanced breast cancer HR+/HER2– advanced breast cancer HR+/HER2– HR+/HER2– advanced advanced breast breast cancer cancer BELLE-2 and BELLE-3 1

BELLE-2 and BELLE-3 1 Postmenopausal 1 1 women with HR+/HER2– locally BELLE-2 BELLE-2 and advanced BELLE-3 and BELLE-3 Postmenopausal women with breast HR+/HER2– or metastatic cancer locally pretreated Postmenopausal Postmenopausal women women with HR+/HER2– withcancer HR+/HER2– locallylocally advanced oraromatase metastatic breast pretreated with inhibitor advanced or metastatic or inhibitor metastatic breastbreast cancer cancer pretreated pretreated withadvanced aromatase tumor tissue for analysis of PI3K with aromatase with Archival aromatase inhibitor inhibitor activation Archival pathway tumor tissue for analysis of PI3K Archival Archival tumor tumor tissuetissue for analysis for analysis of PI3K of PI3K pathway activation No more than one prior line of pathway pathway activation activation forline metastatic disease No morechemotherapy than one prior of No more No more than one than prior one line prioroflinedisease of chemotherapy for metastatic ECOGforPerformance Status ≤2 chemotherapy chemotherapy metastatic for metastatic disease disease ECOG Performance Status ≤2 1 ECOGECOG Performance Performance StatusStatus ≤2 ≤2 BELLE-3

Randomization Randomization Randomization Randomization Buparlisib + fulvestrant Placebo + fulvestrant Buparlisib + fulvestrant Placebo + fulvestrant Buparlisib Buparlisib + fulvestrant + fulvestrant Placebo Placebo + fulvestrant + fulvestrant

BELLE-3 1 Evidence of progression 1 1 BELLE-3 BELLE-3 onoforprogression after mTOR Evidence inhibitor-based Evidence Evidence of progression of progression on or after mTOR treatment on or on after or mTOR after inhibitor-basedmTOR inhibitor-based inhibitor-based treatment treatment treatment

Primary endpoint: Progression-free survival Primary endpoint: Progression-free survival Key secondary endpoint: Overall survival Primary Primary endpoint: endpoint: Progression-free Progression-free survival survival Key secondary endpoint: Overall survival KeyKey secondary secondary endpoint: endpoint: Overall Overall survival survival

Buparlisib (BKM120) is an investigational new drug. Efficacy and safety have not been established. There is no guarantee that buparlisib will become commercially available. 1 Buparlisib (BKM120) is an investigational new drug. Efficacy and safety have not been established. Additional inclusion/exclusion criteria apply. There is no guarantee that buparlisib will become commercially available. BuparlisibBuparlisib (BKM120) (BKM120) is an investigational isECOG, an investigational new drug. new Efficacy drug.Oncology and Efficacy safetyand have safety not been havehuman not established. been established. Abbreviations: Eastern Cooperative Group; HER2–, epidermal growth factor 1 There is no There guarantee is no guarantee that buparlisib that buparlisib will become will commercially become commercially available. available. Additional inclusion/exclusion apply. receptor-positive; receptor 2-negative;criteria HR+, hormone mTOR, mammalian target of rapamycin;

PI3K, phosphatidylinositol 3-kinase. 1 Additional Additional inclusion/exclusion inclusion/exclusion criteria apply. criteria apply. Abbreviations: ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; Abbreviations: Abbreviations: ECOG, Eastern ECOG,Cooperative Eastern Cooperative OncologyOncology Group; HER2–, Group;human HER2–, epidermal human epidermal growth factor growth factor PI3K, phosphatidylinositol 3-kinase. receptor 2-negative; receptor 2-negative; HR+, hormone HR+, hormone receptor-positive; receptor-positive; mTOR, mammalian mTOR, mammalian target of rapamycin; target of rapamycin; PI3K, phosphatidylinositol PI3K, phosphatidylinositol 3-kinase. 3-kinase.

Pioneering Research of PI3K inhibitors in Malignancies

Pioneering Research of PI3K inhibitors in Malignancies Pioneering Research Pioneering of PI3K inhibitors ResearchinofMalignancies PI3K inhibitors in Malignancies

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 Novartis Pharmaceuticals Novartis Pharmaceuticals Corporation Corporation East Hanover, East Hanover, NJ 07936NJ 07936

Novartis 2012

August 2012

August 2012 August 2012 August 2012

For more information www.clinicaltrials.gov (NCT01610284 and NCT01633060) For more information Novartis Oncology Clinical Trials Hotline: www.clinicaltrials.gov For more Forinformation more information 1-800-340-6843 (USA only) (NCT01610284 and NCT01633060) www.clinicaltrials.gov www.clinicaltrials.gov Or contactOncology your localClinical NovartisTrials representative Novartis Hotline: (NCT01610284 (NCT01610284 and NCT01633060) and NCT01633060) 1-800-340-6843 (USA only)Hotline: NovartisNovartis Oncology Oncology Clinical Trials Clinical Hotline: Trials Or contact your representative 1-800-340-6843 1-800-340-6843 (USA only) (USAlocal only)Novartis Novartis Pharma AG Or contact Or contact your local your Novartis local CH-4002, Novartis representative representative G-BKE-1047878 Basel, Switzerland G-BKE-1047878 G-BKE-1047878 G-BKE-1047878

Novartis Pharma AG CH-4002, Basel, Switzerland Novartis Pharma NovartisAG Pharma AG CH-4002,CH-4002, Basel, Switzerland Basel, Switzerland

Targeted Therapy Updates m u ltipl e m y e l o ma

Studies Investigate Panobinostat in Combination With Proteasome Inhibitors for Relapsed/Refractory Multiple Myeloma Two studies presented at the ASH meeting highlighted the possible use of panobinostat in combination with proteasome inhibitors for the treatment of relapsed or refractory multiple myeloma (MM). Panobinostat is an oral inhibitor of histone deacetylase (HDAC) enzymes, including those that may play a role in MM. When used as monotherapy, panobinostat achieved stable disease in patients with MM. However, it is thought that panobinostat produces a synergistic response in combination with proteasome inhibitors, via dual inhibition of the proteasome and aggresome pathways. The first study, the single-arm, nonrandomized, phase II PANORAMA 2 trial, enrolled a total of 55 patients. Most were heavily pretreated, with a median of four prior regimens. All patients had previously received bortezomib, dexamethasone, and at least one immunomodulatory drug. Treatment was divided into two phases: In phase 1, patients received eight 3-week cycles of oral panobinostat 20 mg and intravenous bortezomib 1.3 mg/m2 plus oral dexamethasone 20 mg. Patients who achieved stable disease or better proceeded to phase 2: 6-week cycles of treatment until disease progression.

m y e l o fib r o sis

Novel JAK2 Inhibitor Shows Promise as Myelofibrosis Therapy An investigational, selective JAK2 inhibitor known as SAR302503 reduced spleen size in patients with myelofibrosis, according to phase II data presented at the ASH meeting. Myelofibrosis, a condition in which scar tissue replaces healthy bone marrow, is thought to be caused by the deregulation of the JAK2 signaling pathway. In myelofibrosis, the bone marrow is unable to produce new blood cells, and the liver and spleen become responsible for producing them instead. As a result, the spleen often becomes enlarged in these patients. In this study, 31 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis were randomized 1:1:1 to receive either 300 mg (n = 10), 400 mg (n = 10), or 500 mg (n = 11) of SAR302503, taken orally once a day in consecutive 28-day cycles until disease progression or unacceptable tox22

February 2013

The primary endpoint was overall response rate (ORR; a partial response or better). The ORR was 35%, with one near complete response and 18 partial responses or better. Ten patients achieved a minimal response, and the clinical benefit rate was 53% (n = 29). The mediation duration of exposure was 4.6 months. A total of 33% of patients were on therapy for more than eight cycles. Common grade 3/4 adverse events, regardless of relationship to the study drug, were thrombocytopenia, fatigue, diarrhea, anemia, pneumonia, and neutropenia. The study authors concluded that the combination therapy is an important potential therapeutic option for relapsed/refractory MM, including patients whose disease is resistant to bortezomib, dexamethasone, and immunomodulatory therapy. A second study presented at the ASH meeting looked at the combination of panobinostat and carfilzomib, a proteasome inhibitor. The phase I/II trial is still enrolling patients and is designed to determine the maximum tolerated dose and to evaluate the safety and efficacy of the combination of the two drugs. Richardson PG, Alsina M, Weber D, et al. Panorama 2: panobinostat combined with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma. Presented at the 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 1852. Berdeja JG, Hart, Lamar R, et al. Phase I/II study of panobinostat and carfilzomib in patients (pts) with relapsed or refractory multiple myeloma (MM), interim phase I safety analysis. Presented at the 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 4048.

icity. The primary endpoint of the study was an absolute change in spleen volume at the end of cycle 3 as assessed by magnetic resonance imaging with independent central review. The mean (median) percentage reductions in spleen volume compared with baseline measurements at the end of cycle 3 were 30% (26%) in the 300-mg group, 33% (31%) in the 400-mg group, and 42% (38%) in the 500-mg group. By the end of cycle 3, a spleen reduction of at least 35% was seen in 30% of patients (3/10) in the 300-mg group, 50% (5/10) in the 400-mg group, and 64% (7/11) in the 500-mg group. The most common grade 3-4 hematologic adverse event was anemia, with rates across the 300-mg, 400-mg, and 500-mg dosages of 33%, 30%, and 55%, respectively. Rates of grade 3-4 thrombocytopenia were 20%, 0%, and 9%, respectively. The most common grade 3-4 nonhematologic adverse events were diarrhea (10%, 20%, 0%), nausea (10%, 10%, 0%), and vomiting (10%, 10%, 0%). â&#x20AC;&#x153;The results observed in our trial with SAR302503 are encouraging,â&#x20AC;? said Moshe Talpaz, MD, professor in the Department of Internal Medicine at the University of Michigan Medical School and lead investigator of the study, in a statement. â&#x20AC;&#x153;New treatment options are needed to fulfill existing treatment gaps for patients The International Journal of Targeted Therapies in Cancer

Targeted Therapy Updates with these debilitating blood disorders, and specifically targeting the JAK2 enzyme appears to offer a promising approach.” Following this study, the phase III JAKARTA trial enrolled 289 patients to test the efficacy of the 40-mg and 500-mg dosages of SAR302503. The results of the study are expected to be available in the second quarter of 2013, according to manufacturer sanofiaventis. The first JAK2 inhibitor to treat myelofibrosis, ruxolitinib (Jakafi), was approved by the FDA in November 2011.

a c u t e m y e l o id l e u k e mia

Quizartinib Produces Remissions in Some Patients With Resistant AML Quizartinib, a novel tyrosine kinase inhibitor, demonstrated a clinical benefit in patients with a particularly deadly form of acute myeloid leukemia (AML) in results of a phase II study presented during the ASH meeting. Quizartinib (AC220) is the only single-agent treatment that has been shown to benefit patients with FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) who have failed previous therapy, said Mark Levis, MD, PhD, lead author of the study and associate professor of Oncology, Pharmacology, and Medicine at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, Maryland. In 37% of the study’s 333 participants, the oral drug generated a long enough remission to allow a hematopoietic stem cell transplant, Levis said. Of the patients who received transplants, 18 appear to be cured. Levis added that, of patients who did not respond to their last AML therapy, 79% of those with FLT3-ITD and 48% of those without the mutation achieved a partial response or better with quizartinib. The FLT3-ITD mutation, present in 25% of patients with AML, causes leukemia cells to spread more aggressively, growing back immediately after standard chemotherapy, Levis said. Quizartinib is the first drug designed specifically as a FLT3 inhibitor, he said, and is 10% to 50% more potent in humans than any other agent that inhibits FLT3. In the study, the 333 patients were divided into two treatment cohorts. Cohort 1 consisted of patients age 60 years or older with the FLT3-ITD mutation who failed to achieve remission with standard chemotherapy, or who had recently relapsed for the first time. Cohort 2 consisted of patients age 18 years or older with the FLT3-ITD mutation who presented with relapsed or refractory AML, and who had been administered salvage chemotherapy after failing to respond to prior treatment, or who had relapsed after a stem cell transplant. Most patients in the study had the FLT3-ITD mutation, but a small number in TargetedHC.com

Talpaz M, Jamieson C, Gabrail NY, et al. A phase II randomized dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with intermediate-2 or high-risk primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or postessential thrombocythemia (ET) MF. Presented at the 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 2837.

each cohort lacked the mutation. The primary endpoint was the composite complete remission (CRc) rate of all patients, which includes complete remission (CR; no active disease), complete remission with incomplete platelet recovery (CRp; no active disease but abnormal platelet count), and complete remission with incomplete hematologic recovery (CRi; no active disease but abnormal red and white blood cell counts). In his presentation, Levis focused on Cohort 2. The prognosis for the 138 patients in that cohort was extremely poor, with survival measurable in weeks, Levis said. The patients, 100 with the mutation and 38 without, received continuous treatment with quizartinib at a fixed dose during 28-day cycles. Following one to three cycles, researchers observed a CRc rate of 46% (6% CR or CRp, and 40% CRi) in patients with the FLT3-ITD mutation, with a median duration of response of 12.1 weeks. In patients without the mutation, researchers observed a 32% CRc rate (6% CR or CRp, and 26% CRi) with a median duration of response of 7 weeks. Median overall survival (OS) for mutation-positive patients was 22.9 weeks versus 25.6 weeks for mutation-negative patients. Better outcomes were seen in patients who went on to receive stem cell transplant. Transplant patients with the FLT3ITD mutation had a median OS of 33.3 weeks versus 17.7 weeks for patients who did not undergo transplant. For transplant patients without the mutation, median OS was 20.8 weeks for those who did not receive a transplant; for those who did undergo transplant, median OS has not yet been reached. Adverse events observed in more than 20% of patients included QT prolongation (26%), which was managed by dosage reduction; nausea (38%); vomiting (26%); anemia (29%); fever (25%); diarrhea (20%); and fatigue (20%). The study’s results demonstrate that quizartinib can produce a high treatment response rate in a group of very-poor-prognosis AML patients with manageable toxicity, Levis said. “We plan to use these encouraging results to design and conduct additional randomized trials that will hopefully lead to the approval of quizartinib to make it accessible to those patients who previously had no hope for a cure.” Ideally, Levis said, quizartinib will be used in combination with existing therapies, and in patients with earlier-stage AML. “This is a drug that’s crying out to be used very early on, when February 2013

Targeted Therapy Updates

“We plan to use these encouraging results to design and conduct additional randomized trials that will hopefully lead to the approval of quizartinib to make it accessible to those patients who previously had no hope for a cure.” – M a r k L e v is , M D , P h D

HL/SALCL

Frontline Brentuximab Shows Promise in Two Lymphoma Trials Expanding the use of brentuximab vedotin (Adcetris) to treat patients with advanced Hodgkin lymphoma (HL) and systemic anaplastic large-cell lymphoma (sALCL) in earlier settings than currently indicated has resulted in high response rates in phase I studies, opening the door for pivotal clinical trials in frontline therapies. In separate trials, the complete remission (CR) rate among patients with HL who received brentuximab vedotin in combination with chemotherapy ranged from 92% to 95%, depending on the antineoplastic regimen used. Among patients with sALCL and other CD30-positive lymphomas, the CR was 88%. The findings were presented at the ASH meeting. As a result of the positive outcomes in these studies, phase III trials evaluating brentuximab vedotin in chemotherapy regimens are planned in both HL and sALCL, researchers indicated. Michelle A. Fanale, MD, the principal investigator on the

“I see a lot of potential for the current drug in terms of moving it up into the frontline setting and hopefully getting approvals to be given in conjunction with chemotherapy.” The goal is to prevent relapse, rather than treating patients after they relapse. – M i c h e ll e A . F a n al e , M D

February 2013

these patients come in at diagnosis, to prevent this relapse from occurring in the first place. I don’t think we’ll see resistance problems if we give it in a newly diagnosed setting.” If approved in AML, Levis added, quizartinib is likely to be tested in other cancer types. One is acute lymphoblastic leukemia, in which FLT3 is sometimes mutated or overexpressed. Since quizartinib also inhibits the expression of KIT mutations, it is likely to work in patients who have gastrointestinal stromal tumors, he said. Levis MJ, Perl AE, Dombret H, et al. Final results of a phase II open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. Presented at: 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 673.

sALCL trial and an associate professor at The University of Texas MD Anderson Cancer Center in Houston, said in an interview that brentuximab vedotin continues to demonstrate the dramatic outcomes in response rates that prompted the FDA to approve the drug in August 2011. Brentuximab vedotin is indicated for the treatment of patients with HL after the failure of autologous stem cell transplant or after the failure of at least two prior chemotherapy regimens in patients who are not transplant candidates. In addition, it is approved for patients with sALCL after the failure of at least one prior chemotherapy regimen. “I see a lot of potential for the current drug in terms of moving it up into the frontline setting and hopefully getting approvals to be given in conjunction with chemotherapy,” said Fanale, who has worked on the drug’s development since 2007. She said the goal is to prevent relapse, rather than treating patients after they relapse. At the same time, Fanale said she does not think clinicians should push brentuximab vedotin forward for their patients outside of the setting of a clinical trial, and noted that an extensive program to evaluate the drug is under way. Seattle Genetics, which markets brentuximab vedotin, is researching the compound in approximately 10 different hematologic malignancy types. Brentuximab vedotin is an antibody-drug conjugate (ADC), a new type of anticancer therapy. It is composed of a monoclonal antibody that targets the protein CD30—which is overexpressed in several hematologic malignancies, including HL and sALCL— and the microtubule chemotherapy agent monomethyl auristatin E (MMAE), joined by a protease-cleavable linker. Fanale said that brentuximab vedotin’s ADC technology has helped positively shift outcomes for high-risk HL and sALCL relapsed disease, and that there is a strong rationale for evaluating the drug earlier in the treatment timelines for both cancer types. The International Journal of Targeted Therapies in Cancer

Targeted Therapy Updates

Although a standard chemotherapy regimen is curative for most patients with advanced-stage HL, up to 30% will require salvage therapy. – S t e p h e n M . A n s e ll , M D , P h D

High Remission Rates in HL Study Although a standard chemotherapy regimen is curative for most patients with advanced-stage HL, up to 30% will require salvage therapy, said Stephen M. Ansell, MD, PhD, and colleagues, in an abstract presented at the ASH meeting. Ansell is a professor of Medicine at the Mayo Clinic in Rochester, Minnesota. The open-label multicenter study was designed to evaluate the safety of brentuximab vedotin when combined with either the standard chemotherapy of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) or a modified regimen without bleomycin (AVD). Participants received doses of 0.6, 0.9, or 1.2 mg/kg of brentuximab vedotin with standard doses of ABVD or 1.2 mg/kg brentuximab vedotin with AVD, on days 1 and 15 of each 28-day cycle for up to six cycles of therapy. In all, 51 patients were treated, including 25 who received one of the three dosages of ABVD and 26 who received brentuximab vedotin plus AVD. Data were available for 47 participants, after four people either withdrew their consent or were otherwise unavailable for follow-up. Overall, there was a 96% objective response rate. The CR rates were 95% in the ABVD group (21/22) and 92% in the AVD arm (23/25). However, 44% of patients in the ABVD arm (11/25) experienced pulmonary toxicity, interstitial lung disease, or pneumonitis, contributing to the deaths of two patients, according to the abstract. The bleomycin was discontinued. More than 10% of patients experienced ≥grade 3 adverse events (AEs). The most commonly observed AEs in the ABVD and AVD groups, respectively, were neutropenia (80% vs 65%), anemia (20% vs 12%), febrile neutropenia (20% vs 8%), and pulmonary toxicity (24% vs 0%). Ansell et al noted that the “very high CR rate compares favorably with historical controls,” and that a phase III trial evaluating brentuximab vedotin plus AVD versus ABVD alone is planned.

Benefit Achieved for sALCL Patients With sALCL, a subtype of non-Hodgkin lymphoma that expresses CD30, patients do not experience such broad benefits from standard therapy as do those with HL. Patients with low-risk factors have a 70% to 80% chance of being in remission for 5 years, but most patients have higher levels of risk factors, Fanale said. For that group, only about 15% to 20% will experience durable remissions. Comparatively few of the relapsed patients will go on to receive transplants because they continue to have refractory disease despite other therapies, Fanale said. TargetedHC.com

In a phase I, open-label, multicenter trial, Fanale and colleagues conducted a three-arm study in patients deemed at higher risk (including both ALK-negative ALCL patients and ALK-positive ALCL patients) with International Prognostic Index scores ≥2. Most patients had sALCL, but the group also included patients with other CD30-positive mature T- or NK-cell lymphomas, such as peripheral, angioimmunoblastic, adult, and enteropathy-associated T-cell lymphomas. Patients in Arm 1 received two cycles of brentuximab vedotin (1.8 mg/kg) followed by six cycles of standard-dose CHOP (cyclophosphamide/ doxorubicin/vincristine/prednisone) followed by eight cycles of maintenance brentuximab vedotin. Data for the 13 patients treated on Arm 1 was presented in October 2012 at the European Society for Medical Oncology conference in Vienna, Austria. Participants in Arms 2 and 3 received up to six cycles of brentuximab vedotin (1.8 mg/kg) in combination with standarddose CHP (cyclophosphamide/doxorubicin/prednisone) chemotherapy for six cycles. Those who responded received subsequent singleagent brentuximab vedotin therapy for an additional 10 cycles. Data were presented by Fanale et al at the ASH meeting for the 26 patients initially treated in Arms 2 and 3 of the trial. High levels of response were described with all of the patients achieving an objective response (100%), while 23 patients (88%) experienced CR. Perhaps most notable was that all seven patients with non-ALCL, CD30-positive T-cell lymphomas responded to treatment. As compared with patients with ALCL, these patients have more variable and lower levels of CD30 expression on the cell surface of their lymphomas. The toxicity profile was manageable among patients who received brentuximab vedotin plus CHP at a dose of 1.8 mg/kg, researchers concluded. Common adverse events included nausea (62%), fatigue (54%), diarrhea (58%), and neuropathy (62%). Most cases of peripheral sensory neuropathy were grade 1 or 2 (88%). The incidence of adverse events ≥grade 3 included febrile neutropenia (23%), nausea (8%), neutropenia (8%), and pulmonary embolism (8%). Six patients discontinued therapy due to adverse events. Peripheral neuropathy events were managed with dose delays (4 patients) and dose reductions (7 patients), and at the time of the last data cut, eight patients remained on active protocol treatment. Investigators concluded that the data support continued exploration of combining brentuximab vedotin and CHP in the frontline setting for this difficult-to-treat population. A phase III study comparing this combination regimen with standard CHOP is planned to begin enrollment shortly. Ansell SM, Connors JM, Park SI, t al. Frontline therapy with brentuximab vedotin combined with ABVD or AVD in patients with newly diagnosed advanced stage Hodgkin lymphoma. Presented at: 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 798. Fanale MA, Shustov AR, Forero-Torres A, et al. Brentuximab vedotin administered concurrently with multi-agent chemotherapy as frontline treatment of ALCL and other CD30-positive mature T cell and N cell lymphomas. Presented at: 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 60.

February 2013

www. Oncolytic Immunotherapy www.amgenoncology.com/#/our-science/oncolytic-immunotherapy

Oncolytic Immunotherapy

http://www.amgenoncology.com/#/our-science/oncolytic-immunotherapy

http://www.amgenoncology.com

Oncolytic Immunotherapy References: 1. Varghese S, Rabkin SD. Oncolytic herpes simplex virus vectors for cancer virotherapy. Cancer Gene Ther. 2002;9(12):967-978. 2. Dranoff G. GM-CSF-secreting melanoma vaccines. Oncogene. 2003;22(20):3188-3192. 3. Hawkins LK, Lemoine NR, Kim D. Oncolytic biotherapy: a novel therapeutic platform. Lancet Oncol. 2002;3(1):17-26. 4. Fukuhara H, Todo T. Oncolytic herpes simplex virus type 1 and host immune responses. Curr Cancer Drug Target. 2007;7(2):149-155.

.com Mapped!AR ÂŽ

Oncolytic Immunotherapy Platform Video Launch the mechanism of disease video online, or experience this video virtually through the OncLive AR mobile device app to learn more about Oncolytic Immunotherapy.

Oncolytic Immunotherapy Oncolytic immunotherapy utilizes a modified virus engineered to replicate selectively in tumor cells and to express an immunomodulatory cytokine such as GM-CSF.1, 2 The antitumor effect of the modified virus is based on two proposed modes of action. Oncolytic: Direct cytotoxic activity due to the replication of the virus and cell lysis of tumor cells.3 Immunotherapy: Tumor cell lysis leads to an indirect induction of a systemic, T-cell mediated, tumor-specific immune response, enhanced by GM-CSF and directed against other tumor cells expressing the same antigen profile.4

Additional Resouces for Download: Oncolytic Immunotherapy Slide Kit (PPT)

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Companion Diagnostics and Multiplex Testing Evolve Along With Targeted Therapies By Tracey Regan

A decade ago, the only diagnostic test for metastatic melanoma was a blood serum assay that measured levels of LDH, an enzyme associated with tissue damage. It was used primarily for prognostic purposes, and revealed little about the nature of the disease. “We had no way to distinguish one case of melanoma from another. There were no deep molecular insights. The amount of metastatic disease we found was predictive of survival—if the burden was high, there was a worse prognosis,” said Keith Flaherty, MD, director of Developmental Therapeutics at Massachusetts General Hospital and associate professor, Department of Medicine, Harvard Medical School. The therapeutic landscape for these cancer patients shifted dramatically in 2002, however, with the discovery

“All of the evidence suggests that if we understand the genetic alterations that lead to different subsets of disease, that will be key to success.” – G a rr e t H a m p t o n , Ph D

of the BRAF mutation, found in half of melanoma cases. Unlike mutations in NRAS, identified more than a decade earlier, which is present in about one-quarter of melanomas, the BRAF mutation was a druggable target that responded to vemurafenib (Zelboraf), a tyrosine kinase inhibitor developed shortly after its discovery. “It used to be that 80% of patients with metastatic melanoma were dead within a year. Now, with targeted therapies to treat BRAF, the one-year survival rate is 60%,” Flaherty said, noting that testing for the mutation is now standard, with results available in one to four weeks and the assurance of a high degree of accuracy. The evolution in melanoma treatment exemplifies not only recent trends in cancer research and therapy, but 28

February 2013

also in testing. When the FDA approved vemurafenib in 2011, the agency also approved a companion diagnostic, polymerase chain reaction (PCR)-based test. That same year, the FDA issued a draft guidance encouraging the development of therapies that are accompanied by a companion diagnostic to identify patients most likely to benefit from treatment, as well as patients likely to be at increased risk for a serious adverse reaction. “We spend a lot of time trying to understand the heterogeneity of the disease,” said Garret Hampton, PhD, senior director of Oncology Biomarker Development & Companion Diagnostics for Genentech, a subsidiary of Roche, which developed vemurafenib and its companion diagnostic. “All of the evidence suggests that if we understand the genetic alterations that lead to different subsets of Keith Flaherty, MD disease, that will be key to success.” In order to identify subgroups of patients most likely to respond to a given therapy, every drug in the pipeline has a biomarker strategy, said Walter Koch, PhD, vice president and head of Research for Roche Molecular Diagnostics. When feasible, Roche develops a biomarker-based diagnostic as it develops the therapy to ensure that the drug is as effective as possible, while also potenWalter Koch, PhD tially speeding up clinical trials. He called BRAF the “ideal case,” noting that preclinical data showed mutated cell lines responding more than those that were not mutated. “If we had not used the companion diagnostic, we would not have seen such a high response rate. The benefit of a companion diagnostic in this case is that it increases the risk-benefit ratio in favor of benefit and allows clinical trials to run much faster,” Hampton said. “Alternatively, we would have exposed patients to a drug that would not have been effective. It’s just as important to identify patients who do not respond as patients who do.” The International Journal of Targeted Therapies in Cancer

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Companion diagnostic tests are used when there is a scientific rationale to identify a subgroup of patients likely to respond, or not respond, to a specific treatment. Koch said the process begins “with a good hypothesis based on science, and we hope that the biomarker is predictive. Mutations can be very complex. There are also other questions. Does a biomarker inform how a cancer will progress—whether it’s indolent or progressive? And do you have an intervention?” The type of companion test developed varies according to the biomarkers identified. “We generally use a test that is suited to detect the genetic alteration of interest. For example, for mutations in oncogenes we use a molecular test; for protein overexpression, as with c-Met, we use immunohistochemistry,” Hampton said. In some cases, competing technologies are needed to clarify ambiguous results. “For example, immunohistochemistry can be relatively subjective, and in some cases expression of messenger RNA assessed quantitatively may prove more predictive,” Koch said. In evaluating melanoma, for example, Flaherty said that clinicians consider sequencing of the exons in which mutations are commonly found, as opposed to PCR-based methods, if they don’t find any mutations after initial testing. Adding a diagnostic to the drug approval process imposes logistical challenges. “Assays take a long time to make—from two to three years—and we have to coordinate timelines and seek approvals from different divisions of the FDA,” Hampton said. “When we bring the drug into the clinic for the first time, we’re investing in the development of the assay at the same time, and this increases the overall investment in drug development because we don’t yet know if the drug will be active.” Although companion diagnostics are for the most part one-mutation kits, there is a growing push to adopt multiplex testing, particularly for complex cancers such as lymphoma, for which there are many mutations. “Over the past 10 to 15 years, our understanding of the disease has changed dramatically. There are 80 different types of lymphoma as designated by the WHO, and the number of known biomarkers in lymphoma has expanded,” said Andrew Zelenetz, MD, PhD, chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center in New York City. Zelenetz cited mantle cell lymphoma, a rare, non-Hodgkin lymphoma, as a newly discovered subtype. “It was a new disease because we could make the diagnosis. Abnormal lymph nodes are an indicator, followed by a look under a microscope at cells, and then an immunohistochemical test,” he said. But he noted that the testing landscape is changing. “The tools we’re using to identify these mutations are rapidly evolving. With large-cell lymphoma, we know there are multiple mutations. We now test for one, two, or three things, TargetedHC.com

“There are 80 different types of lymphoma as designated by the WHO, and the number of known biomarkers in lymphoma has expanded” – A n dr e w Z e l e n e tz , M D , Ph D

but we’ll get to the point that we’re looking for 10 to 15 things. It is important to do sequencing of tumors,” he said. And while the FDA has yet to approve a multiplex sequencing test as a companion diagnostic, there are many strong arguments in favor of testing for several mutations at once, researchers and clinicians say. “The FDA is currently focused on single biomarker tests that are linked to a single treatment, and that can be a challenge. Increasingly, with non-small cell lung cancer [NSCLC], for example, the amount of tissue in a biopsy is small. Translocations such as ALK, for example, comprise a small percentage of NSCLC patients, and if we don’t find it, we need to do another test for a different biomarker,” Koch said. “If you’re testing for various markers, you can run out of tissue. Sequencing will give us more information from limited tissue.” “Multiplex testing for markers is where clinicians want us to be,” he added, noting, however, “the clinical development and path to regulatory approval are not at all clear, since traditionally in vitro diagnostic assays have been developed for a single biomarker at a time rather than as panels that represent the heterogeneity of a particular disease.” The FDA’s approval policy will likely evolve with the growing relevance of comprehensive testing able to measure many mutations in a single tumor sample, and the rapid increase in available targeted therapies, said Jeff Allen, PhD, executive director of Friends of Cancer Research, a think tank and advocacy organization based in Washington, DC. “Next-generation sequencing is increasing in use at a large scale, and within three to five years, better comprehensive testing is likely to be widespread at major medical centers,” he said. “The standard diagnostic approved in conjunction with a therapy is a one-mutation kit. But researchers and regulators alike are starting to acknowledge that needs to change. We have to work closely with health authorities to bring multiplex testing to patients as quickly as possible. The FDA is well aware of the emergence of these advanced technologies, and from what I have seen, very interested in being a part of their successful development.” He added, however, “I don’t think that this is a process that the FDA can necessarily drive on its own. It’s encouraging to see their willingness to discuss different aspects of developFebruary 2013

F e at u r e

Companion Diagnostics INFORM HER-2/neu FISH DNA Probe Assay (Ventana Medical Systems)

Fluorescence in situ hybridization (FISH) DNA probe to aid in stratifying patients who have had a priori invasive, localized breast carcinoma and who are lymph node-negative according to risk for recurrence or disease-related death.

PathVysion HER-2 DNA Probe Kit (Abbott Molecular)

FISH test to aid in the assessment of patients with breast cancer for whom trastuzumab (Herceptin) treatment is being considered.

PATHWAY HER-2/neu Rabbit Monoclonal Primary Antibody (Ventana Medical Systems)

Rabbit monoclonal antibody intended for laboratory use to aid in the assessment of patients with breast cancer for whom trastuzumab treatment is being considered.

Dako EGFR pharmDx (Dako North America)

Immunohistochemical (IHC) kit to aid in identifying patients with colorectal cancer eligible for treatment with cetuximab (Erbitux) or panitumumab (Vectibix).

Dako c-Kit pharmDx (Dako North America)

Qualitative IHC kit system used to identify gastrointestinal stromal tumor (GIST) in patients eligible for treatment with imatinib mesylate (Gleevec).

InSite HER-2/neu Kit (BioGenex Laboratories)

Mouse monoclonal antibody kit intended for in vitro use in IHC assays to semi-quantitatively localize by light microscopy the overexpression of HER-2/neu to aid in the assessment of patients with breast cancer for whom trastuzumab therapy is being considered.

SPoT-Light HER2 CISH Kit (Life Technologies)

Chromogenic in situ hybridization (CISH) and bright-field microscopy assay used to aid in the assessment of patients for whom trastuzumab treatment is being considered.

Bond Oracle HER2 IHC System (Leica Microsystems)

Semi-quantitative IHC assay to aid in the assessment of patients for whom trastuzumab treatment is being considered.

HER2 CISH pharmDx Kit (Dako Denmark)

2-color chromogenic in situ hybridization assay intended as an adjunct to the clinicopathologic information currently used to estimate prognosis in patients with stage II, node-positive breast cancer for whom trastuzumab treatment is being considered.

INFORM HER-2 Dual ISH DNA Probe Cocktail (Ventana Medical Systems)

2-color chromogenic in situ hybridization (ISH) probe indicated as an aid in the assessment of patients for whom trastuzumab treatment is being considered.

Vysis LSI ALK Break Apart Rearrangement Probe Kit (Abbott Molecular)

FISH probe intended to identify patients with non-small cell lung cancer (NSCLC) eligible for treatment with crizotinib (Xalkori).

cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems)

Real-time polymerase chain reaction (PCR) test intended as an aid in selecting patients with melanoma for treatment with vemurafenib (Zelboraf).

HercepTest (Dako Denmark)

Semi-quantitative immunocytochemical assay to determine HER2 protein overexpression in breast cancer tissue from patients with metastatic gastric or gastroesophageal junction adenocarcinoma. The test is indicated as an aid in the assessment of patients for whom trastuzumab treatment is being considered, and for patients with breast cancer for whom pertuzumab (Perjeta) treatment is being considered.

HER2 FISH pharmDx Kit (Dako Denmark)

Direct FISH assay to quantitatively determine HER2 gene amplification in breast cancer tissue specimens and formalin-fixed, paraffin-embedded specimens from patients with metastatic gastric or gastroesophageal junction adenocarcinoma. The test is indicated in the assessment of patients for whom trastuzumab treatment is being considered, and for patients with breast cancer for whom pertuzumab treatment is being considered.

therascreen KRAS RGQ PCR Kit (Qiagen Manchester Ltd.)

Real-time qualitative PCR assay to aid in the identification of colorectal cancer in patients eligible for treatment with cetuximab.

ment that a diagnostic company should consider, but it is up to the companies developing these new tools to bring them to the point of FDA approval for use in guiding treatment decisions—and I think we’ll see that in the not so distant future.” Allen also pointed to hopeful trends in the costs associated with testing, which can be expensive and timeintensive, particularly with single-mutation assays. “Not all clinics have advanced instrumentation, and so samples must be sent out to registered test sites,” he said “Over time, molecular testing is likely to become more ac30

February 2013

cessible. New technologies and instruments are reducing the costs associated with molecular analysis, as well as reducing the time it takes to get results. Cost and time are two factors that have likely been a barrier to widespread access to these types of tests.” Although the use of multiplex testing represents advances in diagnosis and cost, it presents challenges as well, clinicians and researchers say. It can, for example, reveal conditions for which there are no readily available therapies. “Some test platforms analyze 10 to 25 markers, and The International Journal of Targeted Therapies in Cancer

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the question is, will all 25 have a drug paired with them? There are no single drug candidates that can address them all,” said Allen. “Patients with overt metastatic disease undergo radiographic evaluation of their lungs, liver, and other internal organs, followed by surgery if the cancer is resectable, and PCR testing for three mutations: BRAF, NRAS, and c-Kit. Recently, some tests also include RF1, as inactivating NF1 mutations have been found in a distinct subset of melanomas that lack BRAF, NRAS, or c-Kit mutations and are felt to function as the primary oncogene in those cases. If we find BRAF, we’re done. With the other mutations, it’s about identifying patients for clinical trials,” Flaherty said. And given the heterogeneity of cancers, more information can make decisions over which therapies to apply even more complex. “As we jump into next-generation sequencing, we may find many mutations, but it’s not always clear which of these are the drivers of a particular cancer,” Hampton said. Zelenetz pointed to new resources such as The Cancer Genome Atlas, a federally backed effort among genetic researchers to systematically explore and catalog the entire spectrum of genomic changes involved in human cancer, as

“New technologies and instruments are reducing the costs associated with molecular analysis, as well as reducing the time it takes to get results. ” – J e ff A l l e n , Ph D

critical analytical tools. “We know the common (mutations) that are important to identify in one fell swoop,” he said. Additionally, the National Comprehensive Cancer Network recently established a compendium to identify the appropriate use of biomarkers to screen, diagnose, monitor, and provide predictive and prognostic information for the treatment of patients. Zelenetz, who chairs the NCCN’s guidelines panel for non-Hodgkin lymphoma, said that guidelines are updated frequently, as often as two to three times a year. Finally, with the proliferation in research, Zelenetz noted, many medical centers are developing tissue banks that will allow testing in the future as new diagnostics and therapies become available.

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February 2013

ENGINEERING THE NEXT G E N E R AT I O N O F ANTIBODY - DRUG C O N J U G AT E S

Leadership in antibody-drug conjugate development Antibody-drug conjugates (ADCs) use a conditionally stable linker to combine the specificity of monoclonal antibodies with the power of cytotoxic agents.1,2 This could allow drugs to be delivered directly to targeted cells and limit systemic toxicity.

Optimizing the parameters for clinical success Scientists at Seattle Genetics are focused on parameters critical to the effective performance of ADCs, including target antigen selection,3,4 linker stability5-7 and cytotoxic agents.4,7,8

Elements of an antibody-drug conjugate Linker

Antibody

Specific for a tumor-associated antigen that has restricted expression on normal cells.4,8

Cytotoxic agent

Attaches the cytotoxic agent to the antibody. Newer linker systems are designed to be stable in circulation and release the cytotoxic agent inside targeted cells.4,8,9

Designed to kill target cells when internalized and released.4,8

ADCs link precision and potency for greater activity A preclinical (in vivo) study demonstrated that the ADC is more active than the antibody alone (mAb) or the admixture (mAb + cytotoxic agent unlinked)10

The future of drug treatment in cancer Seattle Genetics is dedicated to improving the lives of people with cancer by developing innovative therapies for hematologic malignancies and solid tumors. For more information about Seattle Genetics and ADC technology, visit seattlegenetics.com.

Leadership in antibody-drug conjugate development www.seattlegenetics.com

REFERENCES: 1. Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21(1):5-13. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23(9):1137-1146. 3. Carter P, Smith L, Ryan M. Identification and validation of cell surface antigens for antibody targeting in oncology. Endocr Relat Cancer. 2004;11(4):659-687. 4. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3):154-169. 5. Alley SC, Benjamin DR, Jeffrey SC, et al. Contribution of linker stability to the activities of anticancer immunoconjugates. Bioconjug Chem. 2008;19(3):759-765. 6. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41(1):98-107. 7. Alley SC, Okeley NM, Senter PD. Antibody-drug conjugates: targeted drug delivery for cancer. Curr Opin Chem Biol. 2010;14(4):529-537. 8. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235-244. 9. Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the treatment of non–Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6): 2358-2364. 10. Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7):778-784. Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA US/BVP/2012/0113

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Clinical Trial Profile

A third-generation targeted therapy designed to combat native and refractory forms of chronic myeloid leukemia (CML) is being evaluated in an international phase III trial that will measure the drug’s effectiveness in treating patients with newly diagnosed disease. Ponatinib (Iclusig), was FDA-approved in December 2012 following an expedited review. Approval was based on earlier trials demonstrating high levels of response in heavily pretreated patients, including those with advanced CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), who had developed resistance to first- and second-generation inhibitors. Ponatinib is approved for the treatment of adult patients with chronic-phase, accelerated-phase, or blastphase CML that is resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy, or Ph+ALL that is resistant or intolerant to prior TKI therapy. It was approved with a Boxed Warning noting that arterial thrombosis and liver toxicity have occurred in patients treated with the drug. The phase III EPIC (Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia) trial now under way includes an interim analysis of efficacy, which will take place 12 months after half of the patients have been randomized. The final analysis will take place 12 months after full enrollment. Either analysis could support the accelerated approval. In the EPIC trial, the drug is being tested in a frontline setting against imatinib, the landmark first-generation TKI that has been in wide use for more than a decade. Both drugs block the signaling pathway of BCR-ABL,

“We want to get closer to 100% of patients, and if we find that fewer patients develop resistance, then that is a big advance.” – Jorge Cortes, MD

February 2013

an abnormal tyrosine kinase implicated in the deregulation and excessive production of white blood cells, while ponatinib was designed to overcome resistance in mutated versions of the protein, as well. It is the only therapy to date that is effective against the T315I mutation present in nearly a third of patients who participated in the drug’s phase II PACE trial, while maintaining activity against all other common mutations. Jorge Cortes, MD, deputy chair of the Department of Leukemia, Division of Cancer Medicine at MD Anderson Cancer Center, Houston, Texas, and a principal investigator for the trial, said that in its ability to “overcome all of the mutations that we know of today,” ponatinib had the potential to significantly expand the population of CML patients who might benefit from this treatment. “With this class of targeted therapies for CML, a significant proportion of patients are doing very well, but not everyone is doing as well as we’d like. Approximately 60% do well with Gleevec [imatinib], and with the secondgeneration therapies Sprycel [dasatinib] and Tasigna [nilotinib] we get to about 80%. But the 20% left is still a big number,” he said. “That’s what makes this study so important. We want to get closer to 100% of patients, and if we find that fewer patients develop resistance, then that is a big advance.” Cortes said that clinicians prescribing these therapies look for their patients to achieve a complete cytogenetic response (absence of Ph+ cells in bone marrow) at a minimum, and “ideally, even deeper responses, such as major molecular response or complete molecular response.” These are, respectively, significantly reduced and undetectable levels of BCR-ABL in bone marrow. By comparison, less than 20% of patients achieved a complete cytogenetic response with interferon, which was formerly the standard treatment for CML. Interferon is also associated with more toxicity. EPIC is a randomized, open-label trial that will divide more than 500 patients with newly diagnosed, untreated chronic-phase CML between two arms: 45-mg ponatinib orally once daily versus 400-mg imatinib orally once daily. The study, which began in June 2012, has an estiThe International Journal of Targeted Therapies in Cancer

Illustration courtesy of Ariad Pharmaceuticals/Business Wire

Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia (The EPIC Trial)

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Clinical Trial Profile

mated completion date of June 2021. Enrollment, at up to 175 investigational sites, will likely be completed by the end of this year. Eligibility is limited to patients who have been diagnosed within six months of their participation. “These are newly diagnosed patients in the chronic phase who in many cases have no symptoms,” Cortes said, adding, “More and more, we’re finding CML in patients with no symptoms through procedures like routine blood tests and elective operations that result in incidental diagnoses.” He called it a notable development, because “early does matter” in treating the disease, noting that “within the chronic phase, those with the lowest-risk features, such as smaller spleen and few basophils, have a better probability of a good, long-term outcome.” The primary endpoint of EPIC is major molecular response (MMR) at 12 months, defined as 0.1% or lower ratio of BCR-ABL to ABL transcripts on the International Scale. Key secondary endpoints include MMR at 5 years, molecular response (MR) at 3 months showing a reduction in the level of BCR-ABL transcripts to 10% or less, and complete cytogenetic response at 12 months. Participants will be assessed at 12 months through polymerase chain reaction (PCR). The study will also measure progression-free survival and overall survival in patients, who will be tracked for up to 8 years from the time the last patient is randomized. Cortes described MMR as a deeper level of response than complete cytogenetic response, representing an approximately 3-log reduction in the amount of disease present. “This is important because it is a surrogate marker of the probability of progression-free survival,” he said. In the phase II PACE trial, an international, single-arm trial of 449 patients with disease that was resistant or intolerant to prior TKI therapy, participants had failed at least one of the second-generation therapies or were Ph+ ALL. Results from the study, presented at the American Society of Hematology (ASH) annual conference in December, showed that 57% of patients with accelerated-phase CML, including 50% of patients with the T315I mutation, achieved a major hematologic response, the primary endpoint for patients with advanced disease. Thirty-four percent of patients with blast-phase CML or Ph+ ALL achieved a major hematologic response. Progression-free survival in patients with acceleratedphase CML was estimated to be 55% at 12 months (median, 18 months), while for patients with blast-phase CML or Ph+ ALL it was estimated to be 15% at 12 months (median, 3 months). Overall survival at 12 months in patients with accelerated-phase CML was estimated to be 84%, with the median not yet reached, while for blastphase CML or Ph+ ALL, it was estimated to be 33%, with a median overall survival of 7 months. TargetedHC.com

“The goal would be to use the drug in newly diagnosed patients and prevent mutations from ever occurring.” – Tim o t h y C l a c k s o n , P h D

Timothy Clackson, PhD, president of Research and Development and chief scientific officer for ARIAD Pharmaceuticals, said that data from the phase II trial pointed to a strong response in patients with less-advanced disease. He noted that 56% of participants with chronic-phase CML, including 70% of those with a T315I mutation, had achieved a major cytogenetic response, the primary endpoint for that group of patients. “We found that patients in the chronic phase had a higher response, and that the response was also higher in patients with the T315I mutation, who were younger in age and earlier on in therapy,” said Clackson, who called newly diagnosed patients “the holy grail” in terms of potential therapeutic impact. “The goal would be to use the drug in newly diagnosed patients and prevent mutations from ever occurring,” he said, referring to the EPIC trial. To date, the longest amount of time a patient has been taking ponatinib is 3.5 years, beginning in the drug’s phase I trial to establish dosing levels. “These patients are still responding to the drug, and so far there is no evidence of mutation.” Cortes said that the lack of resistance to ponatinib was “promising,” while adding, “We still need to see how this translates clinically.” In describing the drug’s development, Clackson called CML “the poster child for targeted therapy. The disease is caused by a protein [BCR-ABL] found in tumor cells that is absolutely linked to a specific cancer,” he said, noting that the oncogene is created when the ABL protein, a tyrosine kinase that plays a critical role in cell proliferation and survival, becomes deregulated by a translocation that occurs between the ABL and BCR genes, which are located on different chromosomes. “When the two exchange genetic material, it turns the ABL gene on permanently. It’s like putting a brick on the gas pedal, causing a proliferation of white blood cells and cell deformation,” Clackson said. Ponatinib was created through a computer-based structural design approach to function as a pan BCR-ABL inhibitor that can overcome a wide array of resistant forms of the disease, and potentially prevent resistance from occurring altogether. “The T315I mutation causes a bump in the binding site that prevents other drugs from binding, and so we February 2013

Clinical Trial Profile

F e at u r e

Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia (EPIC)

ta b l e .

C l i n ic a l T r i a l s . g o v I d e n t i f i e r : N C T 01 6 5 0 8 0 5

The purpose of this study is to compare the efficacy of ponatinib vs imatinib in patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase. Primary outcome measure: Secondary outcome measures:

Major molecular response (MMR) rate at 12 months after first dose MMR rate at 5 years after first dose Proportion of patients achieving a ratio of <10% BCR-ABL to ABL transcript levels at 3 months, as measured by the international scale (<10% BCR-ABL^IS) Complete cytogenetic response (CCyR) rate at 12 months after first dose Progression-free survival up to 8 years after the last patient’s first dose Overall survival up to 8 years after the last patient’s first dose

Study start date:

June 2012

Estimated study completion date:

June 2021

Estimated enrollment: Patients:

528 Adults 18 years or older

Selected inclusion Criteria: Chronic-phase CML within 6 months of diagnosis Presence of the BCR-ABL fusion as determined by evidence of the t(9;22) Philadelphia chromosome through cytogenetic assessment; variant translocations are only allowed provided they are assessable for cytogenetic response utilizing conventional cytogenetic techniques ECOG Performance Status of 0, 1, or 2 Adequate hepatic, renal, and pancreatic function Selected exclusion Criteria: Prior imatinib, dasatinib, or nilotinib therapy Prior systemic anticancer therapy for CML, experimental therapy, or radiation therapy with the exception of anagrelide or hydroxyurea Major surgery within 28 days prior to initiating therapy History of bleeding disorder unrelated to CML History of alcohol abuse Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL) Significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to: myocardial infarction, unstable angina and/ or congestive heart failure within 3 months prior to randomization or history of clinically significant atrial arrhythmia or any ventricular arrhythmia Uncontrolled hypertension (diastolic blood pressure >100 mm Hg; systolic >150 mm Hg)

designed a carbon-carbon triple bond that is long, thin, and linear, that is able to position itself in such a way that it avoids the bump and can still bind to the T315I mutant,” Clackson said. “Ponatinib’s profile suggests the possibility of preventing resistance mutations from occurring at all because it is designed to inhibit all mutations, and the mutant cells should still die in the presence of the drug.” The most common side effects reported in the phase II trial included rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. The most common hematologic treatment-emergent adverse events were thrombocytopenia, neutropenia, and anemia, which were primarily grades 3 or 4 in severity. Pancreatitis and pneumonia were the most common nonhematologic treatment-emergent serious adverse events (5% each), followed by abdominal pain (4%), myocardial infarction (3%), congestive heart failure (3%), atrial fibrillation (3%), and pyrexia (3%). The most common hematologic serious adverse events were anemia, febrile neutropenia, and thrombocytopenia (3% each). “The drug is very well tolerated, but like all drugs in the class, there are potential side effects. Some are minor, like dry skin and rash, but there are a few things of concern, such as pancreatitis and thrombosis. It’s not the frequency of these conditions, but the significance that catches our attention. Mostly, they are transient and reversible,” Cortes said. “But this does raise an interesting and very important point,” he added. “In clinical trials, the risk that patients and their doctors are willing to take is higher in difficult situations. Patients who are sicker are more willing to accept more risk because there is more at stake. And so when it comes to deciding on an initial therapy, choosing one of several drugs that are known to work well, we don’t want to accept too much risk. So we’ll monitor patients very closely, and if we achieve higher efficacy, it won’t be at a high cost in terms of side effects.” Like other drugs in the class, ponatinib would be prescribed as a lifelong drug. Cortes noted that there is research under way to determine whether there are cases in which patients can be deemed cured and stop treatment, “but for now, we don’t have those answers.” Ponatinib will also be tested in other cancers, including gastrointestinal stromal tumor, acute myeloid leukemia, and two specific forms of lung cancer.

Dosages:

Arm A:

Ponatinib tablet (45 mg) taken orally once daily

Arm B:

Imatinib tablet (400 mg) taken orally once daily

February 2013

The International Journal of Targeted Therapies in Cancer

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Nab-Paclitaxel Plus Gemcitabine in Pancreatic Cancer Wen Wee Ma, MBBS

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Until recently, there had been a lack of progress in pancreatic cancer therapy. Nab-paclitaxel is an albumin-bound formulation of paclitaxel that avoids the hypersensitivity reactions of the Cremophor formulation. When added to gemcitabine, the combination achieved an impressive response rate and survival improvements in a singlearm phase I/II pancreatic cancer trial. Recently, this was confirmed in the phase III MPACT trial, which demonstrated a statistically significant and clinically relevant survival improvement for nabpaclitaxel plus gemcitabine compared with gemcitabine alone in patients with metastatic pancreatic cancer. Toxicities related to the addition of nab-paclitaxel included febrile neutropenia, neutropenia, fatigue, and neuropathy, all of which were well tolerated and manageable with appropriate supportive care. Given favorable survival data and toxicity profile, the nab-paclitaxel-plus-gemcitabine regimen will be a welcome addition to the armamentarium for treating pancreatic cancer. Future research will focus on investigating the role of this regimen in patients with resected, borderline resectable, and locally advanced disease.

corresponding author W e n W e e M a , M BBS Assistant Professor, Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY; wenwee.ma@roswellpark.org

February 2013

Pancreatic cancer remains a highly fatal and difficultto-treat disease. In 2012, an estimated 43,290 patients were expected to be diagnosed with the disease in the United States, and approximately 37,390 will have died from the cancer.1 Almost all patients receive systemic chemotherapy, with the majority being treated for advanced incurable disease. Gemcitabine has been the main chemotherapeutic drug for treating pancreatic cancer since the 1990s, when the antimetabolite achieved superior overall survival (OS) and better quality of life versus fluorouracil in patients with advanced pancreatic cancer.2 Many gemcitabinecontaining combination regimens were evaluated thereafter, but most of them failed to achieve statistically significant survival improvements. Erlotinib, in combination with gemcitabine, was the second drug to receive regulatory approval in the United States for advanced pancreatic cancer.2 However, erlotinib plus gemcitabine achieved only marginal survival improvements in the National Cancer Institute of Canada Clinical Trials Group Study PA.3 (NCIC CTG PA.3). As a result, it is used, in general, in selected patients by the oncology community.3 A meta-analysis of 15 randomized trials evaluating gemcitabine-based cytotoxic combination regimens in 4465 patients showed that those with good performance were the ones most likely to benefit from combination treatment.4 As a result, use of gemcitabine-doublet cytotoxic regimens is recommended for patients with good organ reserves and functional status.5 In 2010, the PRODIGE 4/ACCORD 11 study demonstrated a major survival improvement using an intensive cytotoxic regimen, FOLFIRINOX, compared with gemcitabine alone in patients with metastatic disease.6 Shortly thereafter, in 2012, the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study team reported statistically significant and clinically relevant survival improvements using nab-paclitaxel (Abraxane) plus gemcitabine versus gemcitabine alone in a similar patient population.7 This article will review the development of nab-paclitaxel in the treatment of pancreatic cancer and the role of nab-paclitaxel plus gemcitabine in treating advanced pancreatic cancer in the era of FOLFIRINOX. The International Journal of Targeted Therapies in Cancer

Clinical Articles Peer Reviewed Pa n c r e at i c C a n c e r Clinical Pearls

Development of Nab-Paclitaxel in Pancreatic Cancer Paclitaxel was first identified in the extract of Pacific yew tree bark in 1971 and is now used to treat many cancers.8 The antimicrotubule drug is conventionally administered with polyoxyethylated castor oil solvent (Cremophor EL) due to its poor aqueous solubility.9,10 However, the Cremophor formulation has several challenges, including hypersensitivity reactions requiring premedication with antihistamines and steroids. In addition, the castor oil causes the formation of microscopic micelles that segregate and potentially limit the availability of free paclitaxel to tumor tissues with theoretical effects on antitumor efficacy, and may explain why the efficacy of paclitaxel did not improve proportionally at higher doses. Nab-paclitaxel is a solvent-free, 130-nm albumin-bound formulation of paclitaxel11 approved by the FDA for the treatment of breast and lung cancers.12 In addition to avoiding hypersensitivity reactions, patients receiving nab-paclitaxel had lower neutropenia risk and more rapid improvement of peripheral neuropathy compared with the Cremophor formulation. Also, a higher dose of paclitaxel could be administered using the nab-formulation partly due to a lower neutropenic risk at equivalent doses between nab-paclitaxel and Cre-paclitaxel. Previous pharmacokinetic (PK) modeling showed that paclitaxel-induced neutropenia was dependent on the time interval at which free paclitaxel concentration is above the threshold of 0.05 μM.13 A recent meta-analysis of various nano-formulations of paclitaxel using population PK modeling demonstrated that for equivalent dosing, the time of free paclitaxel concentration from nab-paclitaxel above the threshold was shorter than the Cremophor formulation, and thus the neutropenia risk was lower with nab-paclitaxel. Plans to develop nab-paclitaxel in pancreatic cancer were initiated, in part, following the observation of SPARC (secreted protein, acidic and rich in cysteine) overexpression in pancreatic cancer.15 SPARC was found to be epigenetically silenced in pancreatic cancer cells but frequently expressed in the adjacent stromal fibroblasts.16 The albumin moiety of the nab formulation was thought to play an important role in enhancing paclitaxel delivery to the pancreatic tumor, by binding to SPARC in the stroma, thus facilitating gp-60‒mediated endothelial transcytosis. A retrospective study found that patients with pancreatic cancer with high stromal SPARC expression had poorer survival than those with low expression.17 In a phase I/II study, gemcitabine 1000 mg/m2 was administered following nab-paclitaxel at 100, 125, and 150 mg/m2 weekly for 3 weeks on an every-4-week cycle.15 A total of 67 patients were enrolled, with 20, 44, and 3 patients in the respective dosage levels. The doseTargetedHC.com

• The recent MPACT trial demonstrated that nab-paclitaxel plus gemcitabine, compared with gemcitabine alone, achieved both statistically significant and clinically relevant survival improvements in patients with metastatic pancreatic cancer. • Toxicities related to the addition of nab-paclitaxel to gemcitabine included neutropenia, fatigue, and neuropathy. • Serum bilirubin level should be near normal in patients with pancreatic cancer receiving nab-paclitaxel, and biliary obstruction and infections should be managed proactively with stenting and antibiotics during therapy.

limiting toxicities were neutropenia and sepsis at the 150 mg/m2 dose level, and 125 mg/m2 was declared the maximum tolerated dose. The most common grade 3 or worse nab-paclitaxel-related hematologic toxicities were neutropenia (67%), leukopenia (44%), and thrombocytopenia (23%); nonhematologic toxicities were fatigue and sensory neuropathy (15%). For patients treated at the 125 mg/m2 -dosage level, the median OS was 12.2 months, 1-year survival was 48%, and the overall response rate (ORR) was 48%. For all treated patients, the median OS was 10.3 months and the ORR was 46%. Biomarker analysis suggested improved OS in patients with complete metabolic response on fluorodeoxyglucose positron emission tomography (FDG-PET) scan.18 CA19-9 decrease was correlated with tumor response, progression-free survival (PFS), and OS. Stromal SPARC expression was correlated with improved survival. The regimen was therefore tested in a phase III randomized trial. The results of the MPACT trial were presented at the 2013 Gastrointestinal Cancers Symposium in San Francisco in January.7 In the multicenter trial, 861 patients with metastatic pancreatic cancer were randomized to receive nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 weekly for 7 weeks followed by 1 week rest, then on days 1, 8, and 15 every 4 weeks thereafter. Patients with a Karnofsky performance score of 80 or better were eligible. Forty-three percent (43%) had head of pancreas lesions, and 84% and 39% had liver and lung metastases, respectively. The patients who received nab-paclitaxel/gemcitabine had superior clinical outcomes compared with those who received gemcitabine alone, with a median OS of 8.5 versus 6.7 months (hazard ratio [HR] = 0.72; P =.000015); 1-year survival of 35% versus 22% (P =.0002); 1-year PFS of 5.5% versus 3.7% (P =.000024); ORR by independent review was 23% versus 7% (HR = 3.19; P <.00000000011). The most common grade 3 or higher toxicities in the nab-paclitaxel arm were neutropenia (38% vs 27% in February 2013

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gemcitabine-alone arm), fatigue (17% vs 7%), and neuropathy (17% vs <1%). Febrile neutropenia was 3% versus 1%, respectively. Neuropathy was a major concern for the nab-paclitaxel arm; patients who developed grade 3 or higher neuropathy recovered to grade 1 or better within a median of 29 days once nab-paclitaxel was discontinued. Applications seeking regulatory approval for the use of nab-paclitaxel in pancreatic cancer are under way in the United States, Europe, and other markets.

nab-Paclitaxel in the Era of FOLFIRINOX To understand the contemporary role of nab-paclitaxel/ gemcitabine in pancreatic cancer treatment, one has to compare the MPACT data with those of the PRODIGE 4/ ACCORD 11 trial. In the latter, a total of 342 patients with metastatic pancreatic cancer were randomized to receive FOLFIRINOX or gemcitabine.6 FOLFIRINOX was administered every 2 weeks and consisted of fluorouracil 400 mg/m2 given as a bolus, followed by 2400 mg/m2 over 46 hours as a continuous infusion, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2. Gemcitabine was administered similar to the control arm of the MPACT trial. The median OS achieved in the FOLFIRINOX arm was 11.1 months versus 6.8 months in the gemcitabine arm (HR = 0.57; P <.001) and the ORR was 31.6% versus 9.4% (P <.01), respectively. The moderate survival improvement was accompanied by a significantly higher risk of toxicities such as febrile neutropenia (5.4% vs 1.2% in the FOLFIRINOX and gemcitabine arms, respectively), and grade 3 or higher neutropenia (45.7% vs 21%), thrombocytopenia (9.1% vs 3.6%), fatigue, diarrhea, vomiting, and peripheral neuropathy. Forty-two percent (42%) of patients in the FOLFIRINOX arm received granulocyte colony-stimulating factor (G-CSF) support compared with 5.3% in the gemcitabine group. A quality life-year analysis based on practice patterns in Canada found FOLFIRINOX to be more cost-effective than gemcitabine in patients with metastatic pancreatic cancer, even after taking G-CSF use into consideration.18 The median age of patients in the PRODIGE 4/ACCORD 11 trial was slightly younger than the MPACT trial (age 61 vs 63 years). In both studies, participants needed to have near-normal bilirubin levels, since both nabpaclitaxel and irinotecan are cleared by the liver, which might partly account for the lower proportion (approximately 40%) of patients with pancreatic head lesions in both studies compared with the typical pancreatic cancer patient population.19 Despite the positive result, FOLFIRINOX has to be used in carefully selected patients due to concerns about toxicities. As such, the nab-paclitaxel/gemcitabine regimen will be a welcome addition to the 40

February 2013

pancreatic cancer armamentarium, especially for patients who have a good performance status but are not candidates for FOLFIRINOX for medical or psychosocial reasons. Factors influencing the choice of regimen to initiate in the first-line metastatic setting include a patient’s physiological reserve, comorbidities, preferences, and impact of expected toxicities on a patient’s quality of life. Patients should have near-normal bilirubin to receive nab-paclitaxel or irinotecan, and biliary obstruction and infections should be managed proactively with stenting and antibiotics, especially in patients with a tumor in the head of the pancreas. In summary, these recent clinical trial results provide some measure of hope for the treatment of this devastating and difficult disease. Efforts are now under way or being planned to improve these regimens in metastatic disease by adding novel agents such as desulfated heparin (ODSH, ClinicalTrials.gov Identifier: NCT01461915), Hedgehog inhibitors (GDC-0449, NCT01088815; LDE225, NCT01485744), and erlotinib (NCT01010945). Future studies will also evaluate the role of these regimens in the adjuvant, neoadjuvant, and locally advanced settings.

RE F ERENCES 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. 2. Senderowicz AM, Johnson JR, Sridhara R, et al. Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas. Oncology (Williston Park). 2007;21(14):1696-706; discussion 1706-1709, 1712, 1715. 3. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960-1966. 4. Heinemann V, Boeck S, Hinke A, et al. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer. 2008;8(1):82. 5. Tempero MA, Arnoletti JP, Behrman SW, et al. Pancreatic Adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2012;10(6):703-713. 6. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. 7. Von Hoff DD, Ervin TJ, Arena FP, et al. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine vs. gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). Presented at: 2013 Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. J Clin Oncol. 2012;30(suppl 4; abstr LBA148). 8. Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med. 1995;332(15):1004-1014. 9. Rowinsky EK, Cazenave LA, Donehower RC. Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst. 1990;82(15):1247-1259. 10. Gradishar WJ. Albumin-bound nanoparticle paclitaxel. Clin Adv Hematol Oncol. 2005;3(5):348-349. 11. Gradishar WJ. Albumin-bound paclitaxel: a next-generation taxane. Expert Opin Pharmacother. 2006;7(8):1041-1053. 12. FDA approves ABRAXANE® for the first-line treatment of advanced non-small cell lung cancer [press release]. Celgene Corporation; October 12, 2012. Available at: http://ir.celgene.com/phoenix. zhtml?ID=1744792&c=111960&p=irol-newsArticle. Accessed January 29, 2013. 13. Gianni L, Kearns CM, Giani A, et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol. 1995;13(1):180-190.

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14. Ait-Oudhia S, Straubinger RM, Mager DE. Meta-analysis of nanoparticulate paclitaxel delivery system pharmacokinetics and model prediction of associated neutropenia. Pharm Res. 2012;29(10):2833-2844. 15. Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nabpaclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29(34):4548-4554. 16. Sato N, Fukushima N, Maehara N, et al. SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions. Oncogene. 2003;22(32):5021-5030. 17. Infante JR, Matsubayashi H, Sato N, et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol. 2007;25(3):319-325. 18. Attard CL, Brown S, Alloul K, Moore MJ. Cost-effectiveness of FOLFIRINOX for first-line treatment of metastatic pancreatic cancer. Presented at: 2013 Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. J Clin Oncol. 2012;30(suppl 4; abstr 199). 19. Joerger M, Huitema ADR, Huizing MT, et al. Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic–pharmacodynamic study. Br J Clin Pharmacol. 2007;64(5):622-633.

Author Disclosure Dr. Ma has no conflicts of interest to disclose.

Callfor Papers As targeted therapies for cancer emerge on the market at a recordbreaking pace, oncologists on the front lines of clinical practice are challenged to stay up to date on clinical trial evidence and on emerging strategies for successfully applying targeted therapies to patient care. The International Journal of Targeted Therapies in Cancer seeks to bridge this gap between bench science and bedside care on the use of targeted therapies in cancer. To that end, the editors are issuing a call for papers on topics that help community oncologists integrate information about targeted therapies into patient care.

In order to ensure that papers fit with the goals and scope of the journal, authors are encouraged to first contact the journal’s editors with either an outline or abstract of the proposed submission. Papers should aid oncology healthcare professionals in gaining a greater understanding of new therapies and diagnostics, and should focus on the application of these to clinical practice and optimal patient care. Topics of interest include, but are not limited to: • Molecular targets, pathways, and vaccines in development in cancer therapy • New and emerging targeted therapies and personalized medicine in oncology • Diagnostic and genetic testing in oncology • Management of adverse events in cancer targeted therapies

The journal editors will review all proposed outlines or abstracts and assign full papers according to those that best meet the journal’s goals. All assigned papers will undergo peer review. To submit an abstract or outline, or if you have questions or wish to speak to an editor, please email Devera Pine at dpine@onclive.com.

TargetedHC.com

February 2013

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Clinical Indications for Ziv-Aflibercept in Colorectal Cancer Sigurdis Haraldsdottir, MD, and Tanios Bekaii- Saab, MD

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Ziv-aflibercept is a soluble fusion protein that binds all isoforms of VEGF-A, VEGF-B, and PlGF, thereby leading to potent inhibition of angiogenesis and targeting potential mechanisms of resistance to VEGF therapy. Ziv-aflibercept was approved by the FDA in August 2012, in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) in patients with metastatic colorectal cancer (mCRC) who have previously progressed on an oxaliplatin-based regimen. The approval was based on the results of the VELOUR trial, a phase III, randomized, controlled study that showed a statistically significant 1.5 months improvement in overall survival when adding ziv-aflibercept versus placebo to FOLFIRI. Its safety profile includes both VEGF– and non-VEGF–specific toxicities, with the most common grade 3/4 toxicity being diarrhea. Following its approval, it remains unclear where to incorporate its use, given the recently published results of the TML trial that suggested a statistically significant overall survival benefit by continuing bevacizumab versus not continuing beyond progression. Biomarkers are needed to help determine who would best benefit from ziv-aflibercept, and may facilitate further its placement in the continuum of care in patients with mCRC.

Sigurdis Haraldsdottir, MD The Ohio State University Comprehensive Cancer Center, Columbus, OH

corresponding author Ta n i o s B e k a i i - S a a b , M D The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH; Tanios.Saab@osumc.edu

February 2013

Ziv-aflibercept is a soluble fusion protein that binds all isoforms of vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF). It is often referred to as a VEGF “trap” because it traps these growth factors and prevents them from binding to their receptors. It was recently FDA-approved for use with FOLFIRI in second-line colorectal cancer therapy after progression on an oxaliplatin-based regimen.

The Targeted (VEGF) Pathway Vascular endothelial growth factor is critical to angiogenesis1-3 and plays an important role in tumor growth and the development of metastasis. The VEGF family consists of VEGF-A through D, as well as PlGF. The biologic effects of the VEGF family are mediated via the receptor tyrosine kinases VEGFR1 to 3, which are expressed on the surface of vascular endothelial cells. VEGF-A, in particular, functions to activate endothelial cells and promotes their survival, and thus plays a crucial role in tumorigenesis. VEGFR2 is the most active receptor promoter of tumor angiogenesis.4 Tumors need vasculature to obtain oxygen and nutrients and remove waste products. They can use existing host vessels to some extent, but most tumors also induce new blood vessel formation, suggesting that neovascularization is required for their growth.5 Colorectal cancer (CRC) expresses high levels of VEGF-A,6 with hypoxia being an important inducer of VEGF production.7 VEGF is also derived from host cells, including tumor-associated stromal cells,8 platelets, and muscle cells.9 Higher levels of VEGF in CRC have been associated with poorer prognosis in some,10-12 but not in all studies.13 The first preclinical study to show tumor growth inhibition by targeting the VEGF pathway in vivo was published in 1993.14 Ziv-aflibercept was first developed in 2002 and is a novel recombinant human fusion protein composed of domain 2 of VEGFR1 fused with domain 3 from VEGFR2, attached to the hinge region of the Fc domain of human IgG1 (Figure).15 The prefix “ziv” was added to the name in order to avoid confusion with the ocular product, aflibercept. Ziv-aflibercept binds VEGF-A with higher affinity than its native receptors and bevacizumab, a humanized monoclonal antibody that binds to VEGF ligand15; it also binds to VEGF-B and PlGF, although with lower affinity. The International Journal of Targeted Therapies in Cancer

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PlGF has been implicated in inducing resistance to antiVEGF therapies16 and is upregulated after bevacizumab therapy.17 No biomarkers have been identified to date that can predict benefit from VEGF inhibition.12 The clearance of ziv-aflibercept is mediated through metabolism of the inactive VEGF-aflibercept complex via the Fc receptor. Unlike bevacizumab, both the free and bound form of ziv-aflibercept can be measured. This has been utilized in studies of pharmacokinetics, which have suggested that a ratio >1 for free-over-bound ziv-aflibercept trough concentrations would result in all available VEGF being bound by the trap. The free form has a half-life of 5 to 7 days at doses >2 mg/kg, whereas bevacizumab has a halflife of approximately 20 days, but the free versus bound form of bevacizumab cannot be distinguished. A singleagent, phase I dose-escalation trial included 47 patients where three partial responses were observed (1 in thymic carcinoma, 2 in ovarian cancer). Free ziv-aflibercept was higher than bound ziv-aflibercept at doses > 2.0 mg/kg, indicating that all VEGF is bound at that dose. Rectal ulcer formation and proteinuria were dose-limiting toxicities, seen with dosage of 7.0 mg/kg, and this led to the recommended dosage of 4 mg/kg intravenously administered as a 1-hour infusion every 2 weeks.18

• Ziv-aflibercept is a soluble VEGF trap that binds VEGF-A, VEGFB, and PlGF and prevents their interaction with VEGF receptors 1 to 3. Given a demonstrated survival benefit, ziv-aflibercept is indicated for second-line use with FOLFIRI in patients with metastatic colorectal cancer who have previously progressed on an oxaliplatin-based therapy. • Ziv-aflibercept in combination with FOLFIRI exhibits both VEGF-related toxicities such as hypertension, and non-VEGFrelated toxicities such as diarrhea. Approximately twice as many patients (26.6%) discontinued treatment in the zivaflibercept arm due to adverse events as compared with the FOLFIRI/placebo arm (12.1%) in the VELOUR trial. • It remains unclear where ziv-aflibercept fits in the continuum of care in patients with mCRC who fail first-line therapy, given the positive results from the TML study that demonstrated a benefit to continuing bevacizumab beyond progression.

GI perforation, hypertensive crisis, arterial thromboembolic events, nephrotic syndrome, thrombotic microangiopathy, compromised wound healing, reversible posterior leukoencephalopathy syndrome, or fistula formation.20 Ziv-aflibercept has also been explored in a randomized, phase II study with 5-fluorouracil, leucovorin, and oxali-

Clinical Use Ziv-aflibercept in combination with FOLFIRI in the second-line setting, after progression on an oxaliplatinbased regimen, was explored in the recently published VELOUR trial,19 which eventually led to the FDA approval of ziv-aflibercept in metastatic colorectal cancer (mCRC). In this study, 1226 patients were randomized to FOLFIRI with ziv-aflibercept or placebo in a 1:1 fashion with no crossover permitted. The primary endpoint was median overall survival (mOS). Ziv-aflibercept improved mOS from 12.1 months to 13.5 months (HR = 0.817; 95.34% CI, 0.7130.937). Approximately 30% of patients had previously received bevacizumab, and those patients seemed to continue to benefit from VEGF inhibition with ziv-aflibercept to a similar extent as those who had not been exposed to bevacizumab (summary of efficacy results appear in Table 1). Nearly 27% of patients discontinued treatment due to adverse events in the ziv-aflibercept group compared with 12% in the placebo group, with 83% and 63% reporting grade 3 or 4 adverse events in the two groups (Table 2). Adverse events leading to death in this study were not reported.19 Precautions when using ziv-aflibercept should be observed in cases of uncontrolled hypertension, proteinuria, prior history of arterial thrombosis, bleeding, or gastrointestinal (GI) perforation. Ziv-aflibercept should be stopped for at least 4 weeks prior to elective surgery. Ziv-aflibercept should be discontinued in presence of severe hemorrhage, TargetedHC.com

figure.

Ziv-Aflibercept Structure

Tumor cell Stromal cell VEGF A

VEGF B VEGF A

VEGF C PIGF

VEGF B

PIGF

VEGFR1

Endothelial cell

VEGFR2

Proliferation, migration, survival, angiogenesis, permeability

Aflibercept is made from moiety 2 (in red) from VEGFR-1 and moiety 3 (in blue) from VEGFR-2, bound to the Fc portion of IgG1 (in yellow). It can bind VEGF-A, VEGF-B, and PlGF secreted from tumor and stromal cells (arrows show potential ways of binding to receptors).

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VELOUR Trial: Response Rates, OS, and PFS in Patients With and Without Prior Exposure to Bevacizumab

ta b l e 1.

of 49.1% (95% CI, 39.7-58.6) and 45.9% (95% CI, 36.4-55.7) in the two arms. OS Prior Bevacizumab No Prior Bevacizumab data had limited maturity, with fewer than Placebo/ Aflibercept/ Change Placebo/ Aflibercept/ Change 43% deaths in each arm at presentation of FOLFIRI FOLFIRI FOLFIRI FOLFIRI (n = 426) (n = 427) (n = 186) (n = 187) the data in June 2012. Grade 3-4 adverse events with more than 5% higher inciOS (months) 11.7 12.5 0.8 12.4 13.9 1.5 (95.34% CI) (9.8-13.8) (10.8-15.5) (11.2-13.5) (12.7-15.6) dence in the ziv-aflibercept group versus placebo group were hypertension, proteinPFS (months) 3.9 6.7 2.8 5.4 6.9 1.5 (95.34% CI) (2.9-5.4) (4.8-8.7) (4.2-6.7) (5.8-8.2) uria, neutropenia, diarrhea, and infections. Deaths due to adverse events were 4.2% Response 8.4 11.7 3.3 12.4 23.3 10.9 Rates (%) versus 0.9% in the two groups, respectively. The authors concluded that mFOLFOX6 OS = overall survival; PFS = progression-free survival; CI = confidence interval. with ziv-aflibercept appeared to be similar to mFOLFOX6 alone in efficacy.21 On August 6, 2012, the FDA approved ziv-aflibercept in platin (FOLFOX) in the first-line setting in the AFFIRM trial with a mFOLFOX6 study arm included as a calibrator, combination with FOLFIRI for use in patients who have progressed on oxaliplatin-based therapy in mCRC.22 The but not powered for direct comparison between the two arms.21 The primary endpoint was progression-free surviv- drug was approved in Europe on February 5.23 al (PFS) at 12 months. Two-hundred and thirty-six patients were randomized and stratified by ECOG performance The Complicated Landscape of Second-Line status (0-1 vs 2), prior adjuvant therapy (yes/no), and meTherapy in mCRC Patients With Previous tastases confined to liver (yes/no). The 12-month PFS was Exposure to Bevacizumab 25.8% in the FOLFOX with ziv-aflibercept group and 21.2% VEGF inhibition became a standard component of therapy in the FOLFOX with placebo group, with response rates in mCRC in 2004 following a landmark phase III trial where bevacizumab in combination with irinotecan, bolus 5-fluorouracil, and leucovorin (IFL) improved outcomes in patients versus IFL alone.24 Studies that followed have t a b l e 2 . Adverse Events for Placebo Plus FOLFIRI vs used a more modern backbone (FOLFOX, FOLFIRI) in Aflibercept Plus FOLFIRI combination with bevacizumab, and have generally shown Placebo Aflibercept only modest improvements in OS at best. In the E3200 (n = 605) (n = 611) trial, bevacizumab added to FOLFOX4 in the second-line All Grades Grade 3/4 All Grades Grade 3/4 improved mOS from 10.8 months to 12.9 months (P =.0011) (%) (%) (%) (%) compared with adding placebo.25 In the NO16966 trial, Diarrhea 56.5 7.8 69.2 19.3 bevacizumab added to FOLFOX4 in the first-line setting did not significantly increase mOS, although the trial has Neutropenia 56.3 29.5 67.8 36.7 (complicated) (2.8) (5.7) been criticized for having high numbers of early discontinuation of the drug.26 In a similar manner, ziv-aflibercept Asthenia 50.2 10.6 60.4 16.8 appears to add only a modest improvement to FOLFIRI, Stomatitis/ulceration 34.9 5.0 54.8 13.8 with loss of some benefit in the subgroup of patients preThrombocytopenia 33.8 1.6 47.4 3.4 viously treated with bevacizumab (Table 1). The recently published TML study27 suggests a modest Infection 32.7 6.9 46.2 12.3 OS benefit by continuing bevacizumab beyond progresDecreased appetite 23.8 1.8 31.9 3.4 sion from the first-line setting. In this study, patients who Decreased weight 14.4 0.8 31.9 2.6 had progressed on first-line chemotherapy with bevacizumab were randomized to chemotherapy (choice of Palmoplantar 4.3 0.5 11.0 2.8 erythrodysesthesia oxaliplatin- vs irinotecan-based therapy depending on the first-line regimen) with or without bevacizumab. Median Skin hyperpigmentation 2.8 0 8.2 0 OS was 11.2 months in the bevacizumab group versus Dehydration 3.0 1.3 9.0 4.3 9.8 months in the chemotherapy-alone group (HR = 0.81; Adverse events leading 12.1 26.6 95% CI, 0.69-0.94). Grade 3-5 bleeding (2% vs <1%), GI to discontinuation perforation (2% vs <1%), and venous thromboembolism (5% vs 3%) were more common in the bevacizumab arm, 44

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with four treatment-related deaths in that group versus three in the chemotherapy-alone group.27 The findings of this trial complicate a landscape that would include ziv-aflibercept in patients who were exposed to bevacizumab in the first line. In patients with KRAS-mutated tumors and those with KRAS wild-type tumors, where the treating physician decides against an EGFR inhibitor, bevacizumab continuation will probably be favored over ziv-aflibercept. This preference includes consideration of multiple factors, including the obvious factor of high familiarity with bevacizumab, added to the fact that both provide similar improvements in clinical benefit, with a worse toxicity profile for ziv-aflibercept. The recent media coverage discussing the higher cost of ziv-aflibercept compared with bevacizumab led some influential cancer centers to keep it off their formulary28—despite sanofiaventis’s 50% discount proposal that followed. The National Comprehensive Cancer Network (NCCN) guidelines currently list FOLFIRI with ziv-aflibercept as an option for patients with mCRC who have progressed on oxaliplatin-based chemotherapy.29 However, given the above discussion, it remains unclear where to incorporate its use. Biomarkers are needed to help determine who would best benefit from ziv-aflibercept, and may facilitate further its placement in the continuum of care in patients with mCRC.

RE F ERENCES 1. Senger DR, Perruzzi CA, Feder J, et al. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986;46:5629-5632. 2. Coultas L, Chawengsaksophak K, Rossant J. Endothelial cells and VEGF in vascular development. Nature. 2005;438:937-945. 3. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182-1186. 4. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039-2049. 5. Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science. 1999;284(5422):1994-1998. 6. Werther K, Sørensen S, Christensen IJ, Nielsen HJ; Danish RANX05 Colorectal Cancer Study Group. Circulating vascular endothelial growth factor six months after primary surgery as a prognostic marker in patients with colorectal cancer. Acta Oncol. 2003;42(8):837-845. 7. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721-732. 8. Liang W-C, Wu X, Peale FV, et al. Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J Biol Chem. 2006;281(2):951-961. 9. Kut C, Mac Gabhann F, Popel AS. Where is VEGF in the body? a metaanalysis of VEGF distribution in cancer. Br J Cancer. 2007;97:978-985. 10. Cascinu S, Staccioli MP, Gasparini G, et al. Expression of vascular endothelial growth factor can predict event-free survival in stage II colon cancer. Clin Cancer Res. 2000;6(7):2803-2807. 11. Chin KF, Greenman J, Gardiner E, et al. Pre-operative serum vascular endothelial growth factor can select patients for adjuvant treatment after curative resection in colorectal cancer. Br J Cancer. 2000;83(11):1425-1431. 12. Hegde PS, Jubb AM, Chen D, et al. Predictive impact of circulating vascular endothelial growth factor in 4 phase III trials evaluating bevacizumab [published online ahead of print November 20, 2012]. Clin Cancer Res.2013;19:929-937.

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13. Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010;28(3):453-459. 14. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362(6423):841-844. 15. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99(17):11393-11398. 16. Fischer C, Mazzone M, Jonckx B, Carmeliet P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer. 2008;8(12):942-956. 17. Rini BI, Michaelson MD, Rosenberg JE, et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26(22):3743-3748. 18. Lockhart AC, Rothenberg ML, Dupont J, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol. 2010;28(2):207-214. 19. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499-3506. 20. Zaltrap [package insert]. Bridgewater, NJ: sanofi-aventis; 2012. 21. Pericay C, Folprecht G, Saunders M, et al. Phase 2, randomized, noncomparative, open-label study of aflibercept and modified FOLFOX6 in the first-line treatment of metastatic colorectal cancer (AFFIRM). Presented at: European Society for Medical Oncology 14th World Congress on Gastrointestinal Cancer; June 27-30, 2012; Barcelona, Spain. Ann Oncol. 2012;23(suppl 4: abstr O-0024). 22. National Cancer Institute. FDA approval for ziv-aflibercept. NCI website. http://www.cancer.gov/cancertopics/druginfo/fda-ziv-aflibercept. Accessed January 4, 2013. 23. Regeneron Pharmaceuticals. ZALTRAP® (ziv-aflibercept) approved in the EU for patients with previously treated metastatic colorectal cancer [press release]. February 5, 2013. Available at: http://finance.yahoo. com/news/zaltrap-ziv-aflibercept-approved-eu-060500771.html. Accessed February 16, 2013. 24. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342.25. 25. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539-1544. 26. Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013-2019. 27. Bennouna J, Sastre J, Arnold D, et al; on behalf of the ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial [published online ahead of print November 16, 2012]. Lancet Oncol. 2013;14(1):29-37. 28. Incredible prices for cancer drugs [editorial]. http://www.nytimes. com/2012/11/13/opinion/incredible-prices-for-cancer-drugs. html?ref=opinion&_r=0. The New York Times. November 12, 2012. Accessed January 4, 2013. 29. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. http://www.nccn.org/ professionals/physician_gls/pdf/colon.pdf. Accessed January 4, 2013.

Author Disclosures Dr. Haraldsdottir has no conflicts of interest to disclose. Dr. Bekaii-Saab has been a consultant/advisory board member for sanofiaventis and Genentech.

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New Targets in Advanced Colorectal Cancer: Moving Beyond EGFR and VEGF Safi Shahda, MD, and Ramesh K. Ramanathan, MD

abstr act

The treatment of metastatic colorectal cancer (mCRC) has evolved over the last 20 years, with the addition of targeted agents such as EGFR and VEGF inhibitors improving the outlook for overall survival. More recently, two new agents targeting the VEGF pathway were approved for mCRC and are being integrated into its treatment. Furthermore, advances in molecular biology using high-throughput techniques and genome sequencing have led to the identification of numerous aberrations and mutations in key genetic pathways, and clinicians are challenged to identify key oncogenic events so that patients can be treated with the appropriate targeted therapies. In most cases, however, the appropriate target is new and the treating agent is investigational. This review highlights some of the new, lesser known targets that are undergoing evaluation, with a focus in mCRC.

Safi Shahda, MD Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN

corresponding author R a m e s h K . R a m a n at h a n , M D Medical Director, Clinical Trials Program, Virginia G. Piper Cancer Center, Scottsdale Health Care, Scottsdale, AZ; Clinical Professor of Medicine, Translational Genomics Research Institute, Phoenix, and the College of MedicinePhoenix, University of Arizona; Virginia G. Piper Cancer Center, Scottsdale, AZ; rramanathan@tgen.org

February 2013

The treatment of metastatic colorectal cancer (mCRC) has evolved over the last 20 years. In the 1980s, an overall survival (OS) of 8 to 12 months was seen with 5-fluorouracil (5FU) regimens. The 1990s saw the incorporation of oxaliplatin (FOLFOX) and irinotecan (FOLFIRI) with 5FU, which further improved the OS up to 20 months.1,2 The new millennium saw the integration of targeted agents into the armamentarium such as the EGFR inhibitors cetuximab and panitumumab, and the VEGF inhibitor bevacizumab. The addition of these agents to cytotoxic chemotherapy has improved the outlook, with OS of 22 to 25 months reported in recent studies.3 More recently, two new agents targeting the VEGF pathway, regorafenib and aflibercept, were approved for mCRC and are being integrated into algorithms and pathways for the treatment of mCRC.4,5 Advances in molecular biology using high-throughput techniques and genome sequencing have led to the identification of numerous aberrations and mutations in key genetic pathways. The Cancer Genome Atlas consortium recently published a comprehensive analysis of the colon cancer genome.6 In 276 samples, there were 24 significantly mutated genes, which included the known mutations of APC, TP53, SMAD4, PIK3CA, and KRAS, and previously unknown mutations in ARID1A, SOX9, and FAM123B. Recurrent copy-number alterations of ERBB2 and amplification of IGF2 were also noted. Advances have been rapid in understanding the molecular biology of CRC, and the challenge for the clinician is to identify key oncogenic events or â&#x20AC;&#x153;actionable targets,â&#x20AC;? so that the patient can be treated with an agent to inhibit the identified target. Currently, inhibitors of new targets are mostly investigational and only available through clinical trials. This review highlights some of the new targets that appear promising and are undergoing evaluation, with a focus in mCRC, including HER2/neu, phosphoinositide 3-kinase (PI3K), and Hedgehog (Hh).

Human Epidermal Growth Factor Receptor 2 (HER2)/neu HER2/neu is well established as a target in breast cancer,7 but has also been investigated in colon carcinogenesis.8 A number of studies have evaluated the role of expression of HER2/neu as a prognostic indicator in CRC, but so far the results have been equivocal. In a retrospective evaluation of HER2/neu expression The International Journal of Targeted Therapies in Cancer

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by immunohistochemistry (IHC) in 152 CRC patients, HER2/neu expression was graded as weak, moderate, or strong. Strong HER2/neu overexpression was seen in 43% of samples. A correlation was seen between strong expression and short relapse-free survival and advancedstage disease.9 In another study, HER2/neu expression by fluorescence in situ hybridization (FISH; in 4.5% of samples) correlated with resistance to EGFR-targeted therapy. HER2/neu expression was also correlated with worse progression-free survival (PFS) and a trend toward worse OS in a 266-patient cohort treated with EGFR-targeted therapy alone or in combination with chemotherapy.10 In contrast to the previously described studies, in a retrospective study of 109 patients, HER2/neu expression was seen in 11% of patients with resected stage II CRC and did not correlate with worse outcomes or shorter time to recurrence.11 This is consistent with another study evaluating 80 patients who received adjuvant FOLFOX4 chemotherapy after the resection of primary tumor12; HER 2/neu overexpression was seen in 18.5 % by IHC (3+ in 2.5% and 2+ in 16%). No significant correlation was found between HER2/neu expression and OS. Capecitabine in combination with lapatinib (a dual EGFR/HER2 inhibitor), a widely used regimen in breast cancer,13 was evaluated in a phase II study in 29 patients with mCRC who progressed on first-line therapy. A disease-free survival (DFS) of 2.1 months and an OS of 6.8 months was seen. No radiological responses were seen; best response was stable disease in 44% of cases. However, HER2/neu status was not evaluated in this study.14 Another phase II study evaluated lapatinib in 86 patients with mCRC after progression on a 5FU-based regimen. HER2/neu overexpression by IHC (+1, +2 and +3) was seen in 44%. One patient achieved a partial response (PR), and 5 had stable disease (SD) ≥ 20 weeks. Time to progression (TTP) and OS were disappointing for secondline therapy: 2 and 10.7 months, respectively.15 In both of these studies, patients were not stratified based on HER2/ neu status, which may in part explain the lack of activity. In a small phase II study, the monoclonal antibody trastuzumab was evaluated in combination with irinotecan in patients with mCRC who progressed on first-line therapy and had overexpression of HER2/neu by IHC. Responses were seen (5 of 7 evaluable patients); however, due to the low prevalence of HER2/neu (8%),16 the study was ended early. Continued evaluation of targeting HER2/neu is worthwhile, as overexpression is consistently seen in about 5% to 10% of patients. It is necessary to standardize the definition of HER2/neu overexpression in mCRC and to confine studies to patients with 3+ overexpression by IHC, or to require FISH positivity as done in breast cancer. A number of new HER2/neu targeting agents (T-DM1, TargetedHC.com

• New targeted therapies are needed for the treatment of colon cancer. • Molecular profiling assays need to be standardized and widely available to identify targets. • Combining targeted therapy might help overcome compensating pathways. • Patients with refractory CRC should be considered for clinical trials when appropriate.

pertuzumab) are now available, and HER2/neu inhibition is worthy of continued investigation. An ongoing study of interest is evaluating pertuzumab in combination with cetuximab in patients with advanced CRC (ClinicalTrials. gov Identifier: NCT00551421). Recently, the other member of the HER family, HER3, is becoming recognized as a partner for HER2/neu in tumors that are dependent on HER2/neu signaling. While overexpression of HER3 does not cause tumorigenesis, and mutations have not been reported, it serves an important role in conjunction in tumors with HER2/neu overexpression in activating the PI3K/AKT pathway.17 Multiple HER3 inhibitors are now in phase I clinical trials. A study of interest to the CRC population is RO5479599 alone or in combination with cetuximab or erlotinib in HER3-postive solid tumors (NCT01482377).

Phosphoinositide 3-Kinase (PI3K) PI3K is an essential pathway in CRC tumorigenesis and is deregulated in nearly 40% of CRC cases. Various activating mutations of PIK3CA are present in 32% of CRC,18 where loss of PTEN function is present in 10%.19 Patients with mCRC who have evidence of PI3K activation experience shorter PFS and OS20 and lack response to EGFR-targeted therapy.21-23 PI3K is linked closely to the mammalian target of rapamycin (mTOR) pathway, and its up-regulation enhances prostaglandin-endoperoxide synthase 2 (PTGS2) activity and prostaglandin E2 synthesis, resulting in inhibition of apoptosis in colon cancer cells.24 Data from 964 patients with CRC were reported after stratifying patients based on their aspirin intake and PIK3CA mutation status25 from two large studies: the Nurses’ Health Study26 (NHS; involving 121,701 women who were enrolled in 1976) and the Health Professionals Follow-up Study27 (HPFS; involving 51,529 men who were enrolled in 1986). Patients with tumors harboring PIK3CA mutations and who took aspirin had superior CRC-specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% CI, 0.06-0.61; P<.001 by the log rank test). This beneficial effect may be related to COX-2 inhibition by aspirin, leading to PI3K down-regulation. February 2013

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Some PI3K inhibitors express dual-target properties (ie, PI3K and mTOR): SF-1126, NVP-BEZ 235, NVP-BGT226, and XL765. Others inhibit PI3K only (PX-866, XL-147, NVP-BKM 120, GDC-0941, and GS-1101, a selective PI3K delta inhibitor). These investigational agents are in clinical trials either as single agents (SF-1126, NVP-BGT226) or in combination with other agents (NVP-BEZ235, XL765, PX-866, XL147, NVP-BKM120, GDC-0941, and GS-1101). Clinical data from these ongoing trials specific to mCRC have not been reported yet.

Hedgehog Pathway The Hh pathway is involved in embryogenesis, and its aberrant expression is evident in many human cancers,28 resulting in tumor cell migration, survival, and decreased apoptosis. The Hh pathway can be activated through aberrant expression of Hh ligands (Shh, Ihh, and Dhh), or through the activating mutation in smoothened (Smo) or inactivating mutation in the PCTH1 receptor.29 Under normal conditions, Patched-1 (PCTH1), which is a transmembrane protein, acts as a tumor suppressor gene and applies a negative feedback on Smo. When Hh ligands bind to PCTH1, they relieve the negative feedback leading to downstream activation of the Hh pathway and an increase in protein production important for tumorigenesis. The Hh pathway has been found to be overexpressed in CRC samples, leading to downstream activation of target genes.30 Additionally, positive expression of markers in the Hh pathway (Shh, PCTH1, and Gli-1) in 228 patients with CRC was associated with worse DFS and OS in patients who underwent curative resection for their disease.31 Preclinical studies have demonstrated a significant response to Hh blockade in colon cancer cell lines,32 with an increase in apoptosis.33 More recently, the FDA approved vismodegib for patients with advanced basal cell carcinoma (BCC), where Hh pathway activation is commonly seen secondary to mutations in the PCTH1 gene.34 Hedgehog inhibitors are in clinical trials in BCC and other solid tumors. In a phase I clinical trial of vismodegib in solid tumors, three patients with CRC were enrolled, and none had any response.35 In a recent randomized phase II clinical trial, vismodegib was compared with a placebo in combination with FOLFOX or FOLFIRI and bevacizumab in 199 patients with previously untreated mCRC.36 There was no correlation between Hh ligand expression as assessed by real-time quantitative polymerase chain reaction (qRT-PCR) and PFS as a primary endpoint (14.4 months for placebo vs 10.7 for vismodegib). Mechanisms proposed to explain the lack of benefit are: (1) absence of PTCH/Smo mutations, which are the key oncogenic drivers of the Hh pathway; (2) negative interaction between vismodegib and the che48

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motherapies; and (3) patients who received vismodegib received lower cumulative doses of chemotherapy compared with the placebo arm due to toxicity, which could have impacted response and survival.

Discussion The EGFR and VEGF pathways have been the object of focus for developing targeted therapy in CRC; however, novel targets are being investigated to evaluate their prevalence and impact on survival. We are still in the early stages, and more work is required. Partial or complete blockade of a certain pathway may or may not result in clinically meaningful results. For instance, BRAF, PIK3CA, and PTEN mutations affect the response to EGFR-targeted therapy in patients with tumors that do not harbor a KRAS mutation.21,37-39 We have learned that the cancer genome has many redundant pathways, and blocking one pathway will trigger a compensating measure for tumor survival40-42; therefore, inhibition of dual targets might be clinically effective.43 In addition, current preclinical models do not always predict the clinical benefit of these new therapies,44 which adds to the challenges of drug development. Our understanding of targeted therapy is growing, and learning from ongoing clinical trials targeting HER2 and PI3K will likely expand our knowledge base significantly. Accrual to clinical trials is ever more important, and clinicians should be aware of the molecular subsets in patients with CRC.

RE F ERENCES 1. Gallagher DJ, Kemeny N. Metastatic colorectal cancer: from improved survival to potential cure. Oncology. 2012;78:237-248. 2. Eng C. The evolving role of monoclonal antibodies in colorectal cancer: early presumptions and impact on clinical trial development. Oncologist.2010;15(1):73-84. 3. Van Cutsem E, Köhne CH, Lang I, et al: Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):20112019. 4. Van Cutsem E, Sobrero AF, Siena S, et al. Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC). J Clin Oncol. 2012;30(suppl; abstr 3502). 5. Van Cutsem E, Tabernero J, Lakomy R, et al: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499-3506. 6. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330337. 7. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182. 8. Nathanson DR, Culliford AT 4th, Shia J, et al: HER 2/neu expression and gene amplification in colon cancer. Int J Cancer. 2003;105(6):796-802. 9. Kapitanović S, Radosević S, Kapitanović M, et al. The expression of p185(HER-2/neu) correlates with the stage of disease and survival in colorectal cancer. Gastroenterology. 1997;112(4):1103-1113. 10. Barbara C, Martin V, Molinari F, et al. Use of HER2 gene amplification to identify patients with metastatic colorectal cancer resistant to anti-EGFR monoclonal antibodies. J Clin Oncol. 2012;30(suppl 4; abstr 474).

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11. Ochs AM, Wong L, Kakani V, et al. Expression of vascular endothelial growth factor and HER2/neu in stage II colon cancer and correlation with survival. Clin Colorectal Cancer. 2004; 4(4):262-267. 12. Karaca H, Berk V, Inanc M, et al. The association of human epidermal growth factor receptor-2 (HER-2) expression with clinicopathologic findings in patients with colorectal cancer receiving adjuvant therapy. J Clin Oncol. 2012;30(suppl 4; abstr e14089). 13. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):27332743. 14. Frank DJ, LoConte NK, Brooks W, et al. A phase II trial of lapatinib and capecitabine for patients with refractory advanced colorectal adenocarcinoma. J Clin Oncol. 2010;28(suppl; abstr e14092). 15. Fields AL, Rinaldi DA, Henderson CA, et al. An open-label multicenter phase II study of oral lapatinib (GW572016) as single agent, second-line therapy in patients with metastatic colorectal cancer. Presented at: 2005 American Society of Clinical Oncology Annual Meeting; May 13-17, 2005; Orlando, FL. J Clin Oncol. 2005;23(suppl 16S, pt 1; abstr 3583). 16. Ramanathan RK, Hwang JJ, Zamboni WC, et al. Low overexpression of HER2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. a phase II trial. Cancer Invest. 2004;22(6):858-865. 17. Amin DN, Campbell MR, Moasser MM. The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics. Semin Cell Dev Biol. 2010;21(9):944-950. 18. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554. 19. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28(6):1075-1083. 20. Barault L, Veyrie N, Jooste V, et al. Mutations in the RAS-MAPK, PI(3) K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int J Cancer. 2008;122(10):2255-2259. 21. Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69(5):1851-1857. 22. Perrone F, Lampis A, Orsenigo M, et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol. 2009;20(1):84-90. 23. Ogino S, Nosho K, Kirkner GJ, et al. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol. 2009;27(9):1477-1484. 24. Kaur J, Sanyal SN. PI3-kinase/Wnt association mediates COX-2/PGE(2) pathway to inhibit apoptosis in early stages of colon carcinogenesis: chemoprevention by diclofenac. Tumour Biol. 2010;31(6):623-631. 25. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596-1606. 26. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007;356(21):21312142. 27. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596-1606. 28. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003;3(12):903-911. 29. Yang L, Xie G, Fan Q, Xie J. Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene. 2010;29(4):469481. 30. Douard R, Moutereau S, Pernet P, et al. Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer. Surgery. 2006;139(5):665-670. 31. Xu M, Li X, Liu T, et al. Prognostic value of hedgehog signaling pathway in patients with colon cancer. Med Oncol. 2012;29(2):1010-1016. 32. Mazumdar T, DeVecchio J, Agyeman A, et al. Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells. Cancer Res. 2011;71(17):59045914. 33. Qualtrough D, Buda A, Gaffield W, et al. Hedgehog signalling in colorectal tumour cells: induction of apoptosis with cyclopamine treatment. Int J Cancer. 2004;110(6):831-837. 34. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841-885. 35. LoRusso PM, Rudin CM, Reddy JC, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17(8):25022511. 36. Berlin J, Bendell JC, Hart LL, et al. A randomized phase II trial of vismodegib

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versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin Cancer Res. 2013;19(1):258-267. 37. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26(35):5705-5712. 38. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27(35):5924-5930. 39. Frattini M, Saletti P, Romagnani E, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007;97(8):1139-1145. 40. Ebos JM, Lee CR, Kerbel RS. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res. 2009;15(16):5020-5025. 41. Nahta R, Yu D, Hung MC, et al. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006;3(5):269-280. 42. Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2:227-235. 43. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483(7387):100-103. 44. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457-1461.

Author Disclosures Dr. Shahda has no conflicts of interest to disclose. Dr. Ramanathan has received grants from Bayer Pharmaceuticals, Genentech, Abbott Laboratories, Celgene Corporation, and Vallinex, and has received honoraria from Genentech and Celgene Corporation.

February 2013

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MOA Spotlight Exploring the Ruxolitinib Mechanism of Action: This mechanism of action (MOA) video about ruxolitinib describes myelofibrosis, the JAK pathway, JAK2 mutations, and the role of ruxolitinib (Jakafi) in treating intermediate or high-risk myelofibrosis.

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AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information. 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. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 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

Safety:9.125"

Dr. Ravi Salgia Describes Molecular Applications in Advanced Lung Cancer

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AVASTIN® (bevacizumab)

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).]

• 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.

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%.

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 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:

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4198 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑88 years (median 60 years), 43.6% male and 83.8% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, 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).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).] 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

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 (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were signficantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

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

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

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

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

AVASTIN® (bevacizumab)

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

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.

AVASTIN® (bevacizumab)

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

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and 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. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

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. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

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).]

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

To confront the threat of angiogenesis in first-line metastatic non-squamous NSCLC…

Think Avastin

Because survival matters most

Percentage Surviving

Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991 100

1-year survival: 51% vs 44%2

2-year survival: 23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

OS (Months) Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68– 0.94], P=0.013).1 Clinically meaningful 1- and 2-year survival rates were demonstrated with Avastin plus PC (51% and 23%, respectively, vs 44% and 15% with PC alone).2

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; OS=overall survival; HR=hazard ratio; CI=confidence interval.

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

Boxed WARNINGS 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 Avastintreated 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%)

Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2 Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events Across all studies, the 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

Indication-specific adverse events 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%) You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. Avastin Prescribing Information. Genentech, Inc. November 2012. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

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