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in Cancer

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Clinical Articles The Evolving Role of Brentuximab Vedotin in the Management of CD30Positive Lymphoma Francisco J. Hernandez-Ilizaliturri, MD

Prepare to Attack JAK: Managing Myeloproliferative Neoplasm Constitutional Symptoms Holly L. Geyer, MD, and Ruben A. Mesa, MD

Trastuzumab Emtansine (T-DM 1): A Novel and Effective Immunoconjugate for the Treatment of HER2+ Breast Cancer Jiali Li, MD, Alexa Glencer, and Hope S. Rugo, MD

Clinical Trial Profile: NeuVax Vaccine for the Prevention of Breast Cancer Recurrence in the PRESENT Trial

Antibody-Drug Conjugates Target Drug Delivery

The median age of patients in the VISTAâ&#x20AC; trial was 71 years (range: 48-91).

Survival never gets old VELCADE® (bortezomib) delivered >13-month overall survival advantage in combination with MP* vs MP alone for previously untreated multiple myeloma (median 56.4 vs 43.1 months [HR=0.695; 95% CI, 0.57-0.85; p<0.05]; 60.1-month median follow-up†)

Approved for subcutaneous and IV administration‡ VELCADE® (bortezomib) Indication and Important Safety Information INDICATION

VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS

VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS

Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼

Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment. ▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers. ▼

ADVERSE REACTIONS

Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. Please see Brief Summary for VELCADE on next page. *Melphalan+prednisone.

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma (MM). The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p =0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. ‡ The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL).

†

Living Proof

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

3822_24_milpro_fa3_h_jottc.indd 2

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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Targeted

Healthcare Communications North American Edition, November 2012

Contents

www.TargetedHC.com

Clinical Articles Lymphoma............ 44 The Evolving Role of Brentuximab Vedotin in the Management of CD30-Positive Lymphoma

President Peter Ciszewski pciszewski@targetedHC.com

Editorial & Production 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

Francisco J. Hernandez-Ilizaliturri, MD

Antibody-Drug Conjugates Target Drug Delivery By Jane de Lartigue, PhD New antibody-drug conjugates are emerging, starting with last year’s approval of Seattle Genetics’ Adcetris.

Feature

Clinical Trial Profile:

NeuVax Vaccine for the Prevention of Breast Cancer Recurrence in the PRESENT Trial

Departments 8 From the Editor 13 Clinical Trials in Progress 20 Targeted Therapy Updates 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. TargetedHC.com

The authors review the preclinical and clinical studies that facilitated the FDA approval of brentuximab vedotin for the treatment of relapsed/refractory CD30-positive Hodgkin lymphoma and anaplastic large cell lymphoma, and outline ongoing research aimed at further optimizing the spectrum of activity of brentuximab vedotin.

Web Editor Silas Inman Assistant Web Editor Andrew Roth Oncology Special Projects Editor Devera Pine dpine@onclive.com Art Director. Leighanne Tillman

Sales & Marketing Vice President,. Sales & Marketing Lisa Greene lgreene@targetedHC.com

Directors of Sales Scott Harwood sharwood@targetedHC.com

Digital Media

MPN.. . . . . . . . . . . . . . . . . . 50 Prepare to Attack JAK: Managing Myeloproliferative Neoplasm Constitutional Symptoms

Vice President,. Digital Media Jung Kim

Director,. Digital Content Sean Johnson

Operations & Finance Director of Operations Thomas J. Kanzler

Controller Jonathan Fisher, CPA

Philadelphia chromosome-negative myeloproliferative neoplasms have long been recognized for their burdensome symptom profiles and their adverse impact on both quality of life and life expectancy. The era of direct JAK-2 inhibition has opened new doors for direct symptom management and potential alteration of disease course.

Director of Circulation John Burke jburke@mdng.com

Assistant Controller Leah Babitz, CPA

Breast Cancer......... 57

Chief Financial Officer Neil Glasser, CPA / CFE

Holly L. Geyer, MD, and Ruben A. Mesa, MD

Corporate Chairman/Chief Executive Officer/President Mike Hennessy

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

Chief Operating Officer Tighe Blazier

Vice President/Group Creative Director Jeff Brown

Trastuzumab Emtansine (T-DM 1): A Novel and Effective Immunoconjugate for the Treatment of HER2+ Breast Cancer Jiali Li, MD, Alexa Glencer, and Hope S. Rugo, MD

Trastuzumab-derivative of maytansine-1 (trastuzumab emtansine; T-DM1) is a novel antibody-drug conjugate. Ongoing clinical trials are investigating T-DM1-based therapy in combination with other chemotherapy agents, with other targeted agents, and as treatment for early-stage HER2+ breast cancer and other malignancies.

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

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 Therapy 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 Therapy 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 Therapy 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 Therapy in Cancer.

11.12 / 3

INDICATIONS • DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy • 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 • 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 • 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 • Severe myelosuppression may occur • DOXIL® dosage should be reduced in patients with impaired hepatic function • Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS • Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ADDITIONAL SAFETY INFORMATION • 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) • 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 • DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow • 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 • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy • DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation • DOXIL® can cause fetal harm when used during pregnancy • Because of the potential for serious adverse reactions in nursing infants, discontinue nursing during treatment with DOXIL® • 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

• DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl • 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%) • 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 9 8 Thrombocytopenia 33 11 13 28 Anemia 25 7 2 21 8 2 General disorders and administration site conditions 3 0 Fatigue 36 6 1 28 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders 1 0 Nausea 48 3 0 40 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 4 1 Neuralgia 17 3 0 20 Paresthesia/dysesthesia 13 <1 0 10 0 0

From the Editor

Editorial Board Physician Editor-in-Chief 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

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

Edward Chu, MD Chief, Division of Hematology-Oncology University of Pittsburgh School of Medicine Deputy Director, University of Pittsburgh Cancer Institute Pittsburgh, PA

Joyce A. O’Shaughnessy, MD Co-Director, Breast Cancer Research Baylor Charles A. Sammons Cancer Center/Texas Oncology US Oncology Dallas, TX

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

Roberto Pili, MD Professor of Oncology Chief, Genitourinary Section Leader, Genitourinary Program, 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 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

Alex A. Adjei, MD, PhD

Colleagues, As we reach the end of 2012, this is this year’s third and final issue of The International Journal of Targeted Therapies in Cancer. In this issue, we highlight the exciting area of antibody-drug conjugates both for lymphoma and breast cancer. The JAK-2 inhibitors, which are having a significant impact on the therapy of myeloproliferative neoplasms, are also highlighted. With the initial success of this journal, we plan to publish it bimonthly starting in February 2013. Your feedback and suggestions on how to improve our content and make it useful for you are greatly welcomed. In closing, I would like to thank all of you, our readers, our physician editorial board members, production staff, and in particular Ms Devera Pine, who makes everything come together.

—Alex A. Adjei, MD, PhD PHYSICIAN EDITOR-IN-CHIEF

Oliver Sartor, MD Piltz Professor of Cancer Research Departments of Medicine and Urology Tulane University School of Medicine New Orleans, LA

Jonathan L. Kaufman, MD Assistant Professor Associate Director Fellowship Program Department of Hematology and Medical Oncology Winship Cancer Institute Emory University Atlanta, GA

Interested in joining our editorial board? Contact Devera Pine, Oncology Special Projects Editor, at dpine@onclive.com. To reach Dr. Adjei and/or the journal’s editorial staff, please e-mail: dpine@onclive.com.

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A NEW INDIC ATION

COMING SOON Please see adjacent pages for current indication, Important Safety Information, and brief summary of full Prescribing Information.

Janssen Biotech, Inc. ÂŠ Janssen Biotech, Inc. 2012 8/12 08Z12244

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

www.zytiga.com Please see brief summary of full Prescribing Information on the following pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 8/12 08Z12244

08Z11121R3

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions]. Adrenocortical insufficiency [see Warnings and Precautions]. Hepatotoxicity [see Warnings and Precautions]. Food effect [see Warnings and Precautions].

ZYTIGA® (abiraterone acetate) Tablets

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA). Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions]. Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Placebo with Prednisone Prednisone (N=791) (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort 7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

1 2 3 4

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema

In In ta B B 7 In M a 8 In d E Ca pha or wa in t wit led Ca He tot all >5 dur wh live Wh > 3 ins and exp 6X the rec In hep live of par mo full ele Oth the Lab inte ser the 6

Tab

Lab Hig Hig Low Low Hig Hig

DR Eff of inte we giv dai CY tre of t in f In CY sub

ZYTIGA® (abiraterone acetate) Tablets

Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelﬁnavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms. Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations. In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated. Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%). Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebo-controlled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm. 6

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: ZYTIGA is not indicated in children. Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no speciﬁc antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Speciﬁc Populations]. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012

Revised: July 2012

08Z12237B

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

Hematologic Malignancies Dasatinib combination with smoothened antagonist in leukemia This phase II study will compare response rates in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic-phase (CML-CP) treated with dasatinib plus the smoothened (SMO) antagonist BMS-833923 versus dasatinib alone. BMS833923 selectively blocks hedgehog pathway signaling by binding to and antagonizing SMO, preventing downstream signaling and activation of target genes. Study participants will receive 100 mg of dasatinib daily for 12 months, and are then randomized 1:1 to continuing 100 mg of dasatinib daily with or without the SMO antagonist for up to 24 months, followed by 100 mg of dasatinib daily alone until the end of the 5-year study. Individuals are eligible if they have an ECOG performance status of 0-2 and have previously untreated Ph+ CML-CP diagnosed within 6 months of enrollment. The primary endpoint is a comparison of major molecular response rates for dasatinib alone versus dasatinib plus the SMO antagonist in patients who do not achieve a major molecular response prior to randomization. Additional endpoints include complete molecular response, progression-free survival, event-free survival, transformation-free survival, and safety of the combination regimen. Sponsor: Bristol-Myers Squibb ClinicalTrials.gov Identifier: NCT01357655

Lung Cancer Ipilimumab with paclitaxel/carboplatin for non-small cell lung cancer This phase III study will compare the efficacy of phased ipilimumab with paclitaxel/carboplatin versus placebo with paclitaxel/carboplatin for the treatment of stage IV/recurrent non-small cell lung cancer (NSCLC) of squamous histol-

TargetedHC.com

ogy. Despite extensive research, outcomes for advanced NSCLC of squamous subtype have not improved beyond those of standard platinum doublets. Patients will be randomized to receive two cycles of paclitaxel/carboplatin IV (175 mg/m2 and AUC = 6, respectively), followed by four cycles of study drug with four additional cycles of paclitaxel/carboplatin, for a total of six cycles. Patients without progressive disease after induction receive maintenance therapy with the blinded study drug every 12 weeks until they have evidence of progressive disease per World Health Organization criteria. The primary endpoint is overall survival. Secondary endpoints include overall survival among patients who receive one dose of blinded therapy, progressionfree survival, and best overall response rate. Sponsor: Bristol-Myers Squibb ClinicalTrials.gov Identifier: NCT01285609

Onartuzumab plus erlotinib for nonsmall cell lung cancer This phase III study will compare onartuzumab (MetMAb) plus erlotinib versus placebo plus erlotinib in patients with advanced, MET-positive NSCLC. Onartuzumab is a humanized, monovalent monoclonal antibody that binds to Met with high specificity, preventing HGF ligand binding and blocking downstream signaling. Patients are eligible provided they have Met diagnosticâ&#x20AC;&#x201C;positive tumors and have failed at least one but no more than two prior lines of platinum-based chemotherapy for advanced disease. Following stratification for Met expression, prior lines of therapy, histology, and EGFR-activating mutation status, patients are randomized to erlotinib (150 mg orally daily) plus placebo or onartuzumab (15 mg/kg IV every 3 weeks) until they have disease progression or unacceptable toxicity or death, or if they decide with their physician to drop out of the study. The primary endpoint is overall survival. Secondary endpoints include progressionfree survival, overall response rate, and safety.

1Ovarian Cancer

Single-agent ipilimumab for recurrent platinum-sensitive ovarian cancer This phase II study will examine the use of ipilimumab monotherapy after completion of chemotherapy in recurrent platinum-sensitive ovarian cancer patients with ECOG performance status 0 or 1 and residual measurable disease. The primary outcome measure is the incidence of drug-related adverse events of grade 3 or higher during the induction period of ipilimumab. Ipilimumab as an intravenous (IV) solution, 10 mg/kg, will be administered once every 3 weeks for four doses and then once every 12 weeks starting at week 24 to roughly 40 patients until the onset of disease progression or unacceptable toxicity. Women who have platinum-refractory ovarian cancer or who have had more than four lines of prior therapy are ineligible. Sponsor: Bristol-Myers Squibb ClinicalTrials.gov Identifier: NCT01611558

MM-121 plus paclitaxel in platinumresistant/refractory advanced ovarian cancer This phase II study will compare MM-121 combined with paclitaxel versus paclitaxel alone in patients with locally advanced/metastatic or recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have received at least one prior platinum-based chemotherapy regimen and are platinum-resistant/ refractory. For inclusion, patients must also be eligible for weekly paclitaxel. MM-121 is an investigational, fully human monoclonal antibody that targets the ErbB3 receptor. The primary outcome measure is progression-free survival. The investigators aim to recruit about 210 women and hope to complete their study by April 2015. Sponsor: Merrimack Pharmaceuticals ClinicalTrials.gov Identifier: NCT01447706

Sponsors: Genentech and Hoffman-La Roche ClinicalTrials.gov Identifier: NCT01456325

11.12 / 13

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 b Grade 3 Grade 4 Grades Grade 3 Grade 4 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood 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). a Reactions Grades 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 b Bruising 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 differe Weight Gain 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

1Skin Cancer

T-VEC versus GM-CSF for advanced melanoma This phase III study will compare talimogene laherparepvec (T-VEC) versus subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of patients with unresectable stage IIIb, IIIc, and IV melanoma stratified by typical prognostic factors. T-VEC is an oncolytic HSV1 that selectively replicates in tumors with a proposed mechanism of action involving lytic destruction of injected tumors and induction of a systemic antitumor immune response enhanced by local GM-CSF expression. Patients will be randomized in a 2:1 ratio to T-VEC (priming dose of up to 4 x 106 pfu intratumorally, then 3 weeks later by up to 4 x 108 pfu every 2 weeks) or GM-CSF subcutaneously 125 µg/m2 daily for 14 days every 28 days. Study participants must have ECOG status of 0-1 and at least one injectable cutaneous, subcutaneous, or nodal tumor. The primary endpoint is durable response rate, defined as a complete or partial response continuously maintained for at least 6 months that started within 12 months of treatment initiation. The sole secondary endpoint is overall survival. Sponsor: Amgen CliinicalTrials.gov Identifier: NCT00769704

Sulforaphane for atypical nevi precursor lesions This pilot study will evaluate sulforaphane as a possible nutritional chemopreventive agent for modulating key steps in melanoma progression and the expression of signal transducer and activator of transcription proteins in melanocytic and stromal elements of atypical nevi. Sulforaphanes are bioactive cruciferous compounds rich in the Brassica family, especially broccoli sprouts; topical broccoli sprout extracts reduce ultraviolet radiation (UVR) erythema response in human skin, and may protect against UVR DNA damage. Melanoma patients with more than two atypical nevi will receive oral broccoli sprout extract rich in sulforaphane at dosages of 50 µmol, 100 µmol, or 200 µmol daily. Subjects must avoid dietary glucosinolates and isothiocyanates

TargetedHC.com

throughout the study and maintain food diaries. Blood samples, photography of index atypical nevi, and biopsies of selected atypical nevi and normal skin will be analyzed for changes in atypia, sulforaphane localization histopathology, and STAT 1/3 expression in the nevi and skin harvested at baseline and at study completion. Sponsor: John Kirkwood, MD, University of Pittsburgh ClinicalTrials.gov Identifier: NCT01568996

1Breast Cancer

Denosumab as adjuvant treatment for high-risk, early-stage breast cancer This phase III study will compare denosumab versus placebo as adjuvant treatment for women with stage II or III breast cancer who are at high risk of disease recurrence, and whose hormone and HER2 receptor status is known. Study participants must be scheduled for standardof-care adjuvant or neoadjuvant chemotherapy, endocrine, or HER2 targeted therapy to be administered alone or in combination. Patients will be randomized to receive 120 mg of denosumab or placebo subcutaneously monthly for 6 months, and then every 3 months, for a total of 5 years of treatment, along with vitamin D and calcium supplementation. The primary endpoint of the study is bone metastasis-free survival. Secondary endpoints are overall survival, distant recurrence-free survival, disease-free survival, safety, and tolerability. Sponsor: Amgen CliinicalTrials.gov Identifier: NCT01077154

Aromatase inhibitor combined with lapatinib or trastuzumab or both for metastatic breast cancer This phase III study will randomize postmenopausal women with metastatic breast cancer to one of three treatment arms as first-line therapy: lapatinib plus trastuzumab plus an aromatase inhibitor (AI); trastuzumab plus an AI; or lapatinib plus an AI. Study participants must have HER2+/HR+ metastatic breast cancer and have received trastuzumab and endocrine therapy in

the neoadjuvant and/or adjuvant setting, but must be ineligible for chemotherapy. The AI can be letrozole, anastrozole, or exemestane, with the choice of treatment made by the investigator. The primary efficacy endpoint is OS for lapatinib/trastuzumab/AI versus trastuzumab/ AI. Secondary efficacy measures include a comparison of overall survival between trastuzumab/AI and lapatinib/AI, as well as between trastuzumab/lapatinib/AI and lapatinib/AI; comparisons of progression-free survival, overall response rate; time to response; duration of response; and safety and tolerability for all three treatment groups. Sponsor: GlaxoSmithKline ClinicalTrials.gov Identifier: NCT01160211

1Prostate Cancer

Orteronel for advanced prostate cancer This phase III study will compare the investigational agent orteronel (TAK-700) plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or following docetaxel-based therapy. Orteronel is a selective inhibitor of 17,20-lyase, a key enzyme in the testosterone synthesis pathway. In order to be eligible, patients must have evidence of disease progression during or after receiving a total of 360 mg/m2 or more of docetaxel within a 6-month period. Patients who cannot tolerate docetaxel or who have progressive disease before receiving 360 mg/m2 or more are also eligible if they have received at least 225 mg/m2 of docetaxel within a 6-month period and satisfy the other inclusion criteria, which include radiographically documented metastatic disease and baseline testosterone level lower than 50 ng/dL following surgical or medical castration. The primary endpoint is overall survival. Secondary endpoints include radiographic progression-free survival, 50% prostate-specific antigen response at 12 weeks, and pain response at 12 weeks. Sponsor: Millennium Pharmaceuticals ClinicalTrials.gov Identifier: NCT01193257

11.12 / 17

Bringing New Vision to the Fight Against Cancer

DSNA12100979

“There is nothing impossible to him who will try.” — Alexander the Great

Joining the Fight Chest X-ray with lung cancer tumors color enhanced.

WWW.DAIICHISANKYO.COM

Targeted Therapy Updates

Early-Access Program for Afatinib

Updated BOLERO-2 Data Support Efficacy of Everolimus in Breast Cancer

Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) may be eligible to receive treatment with afatinib through an expanded access program while the investigational compound is still in development. Boehringer Ingelheim Pharmaceuticals said that the drug is being offered in keeping with FDA policies permitting early-access programs for agents in late-stage development for patients with life-threatening illnesses without other therapeutic options. The company said in a press release that it is “working rapidly to prepare and submit a new drug application to the FDA.” Afatinib is an irreversible, pan-HER tyrosine kinase inhibitor that demonstrated markedly improved progression-free survival (PFS) compared with standard chemotherapy in patients with advanced lung adenocarcinomas who tested positive for epidermal growth factor receptor (EGFR) mutations. The LUX-Lung 3 trial found that patients treated with afatinib experienced a 4.2-month PFS advantage over combined pemetrexed and cisplatin chemotherapy (11.1 months vs 6.9 months, respectively), according to results presented at the American Society of Clinical Oncology annual meeting in June.1 Patients with locally advanced or metastatic NSCLC who test positive for EGFR mutations and have a performance status between 0 and 2 may qualify for the program. For further information, call (855) 327-2474, or review NCT01649284 at www.ClinicalTrials.gov, or go to http://goo.gl/S4lwJ.

Updated results from the BOLERO-2 trial support the study’s earlier findings that the mTOR kinase inhibitor everolimus improves survival for postmenopausal patients with breast cancer, according to 18-month follow-up data presented at the American Society of Clinical Oncology (ASCO) Breast Cancer Symposium on September 14.1 The updated investigator assessment of the progression-free survival (PFS) rate for patients treated with exemestane and everolimus was 7.8 months compared with 3.2 months for those treated with exemestane alone (hazard ratio (HR) = 0.45; 95% CI, 0.38-0.54; P < .0001). Independent reviewers found that PFS was 11.0 months for patients taking the drug combination compared with 4.1 months for those taking exemestane alone (HR = 0.38; 95% CI, 0.31-0.48; P < .0001). “These results represent a significant advance in the search for ways to improve response to hormone therapy and counteract acquired resistance,” said Hope S. Rugo, MD, an author of the follow-up study, who presented the results. Rugo is a professor of Medicine and director of Breast Oncology and Hope S. Rugo, MD Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. The phase III BOLERO-2 trial enrolled 724 postmenopausal women with hormone receptor-positive metastatic breast cancer who had progressed on a nonsteroidal aromatase inhibitor, such as anastrozole or letrozole.2 Eligible women were treated with a daily 25-mg dose of exemestane and randomized (2:1) to 10 mg of everolimus or placebo. Women treated with everolimus combined with exemestane compared with exemestane alone showed significant PFS benefits. Based on those results, the FDA approved everolimus in combination with exemestane in July. “We await the mature survival data from this study, as well as additional studies that are planned or under way,” Rugo said.

REFERENCE 1. Yang JC-H, Schuler MH, Yamamoto N, et al. LUX-Lung 3: a randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. J Clin Oncol. 2012;30(suppl; abstr LBA7500).

20 / 11.12

By Andrew Roth

These results represent a significant advance in the search for ways to improve response to hormone therapy and counteract acquired resistance.” —Hope S. Rugo, MD A subanalysis of the BOLERO-2 trial that was also presented at the Breast Cancer Symposium examined disease progression in bone and bone markers in patients with bone metastases.3 After 60 days, the cumulative incidence rate of progressive disease in bone was lower in women treated with exemestane and everolimus (6.16%) compared with exemestane and placebo (3.03%). The trend continued beyond 6 months. At 6 and 12 weeks, bone marker levels increased versus the baseline in the exemestane and placebo group but decreased in patients treated with exemestane and everolimus. Bone-related adverse events were reported with similar frequencies in both groups (everolimus = 2.9%; placebo = 3.8%) and were reported as grades 1 or 2. “For breast cancer patients with bone metastases who have not responded to [nonsteroidal aromatase inhibitors], this study may provide another option for the management of their disease,” Anees B. Chagpar, MD, MPH, said in an ASCO press release on the conference. Chagpar is the director of the Breast Center at Smilow Cancer Hospital at Yale-New Haven, Connecticut. Preclinical studies found a correlation between mTOR inhibition and decreased osteoclast survival and activity. The BOLERO-2 study analyzed the difference in bone marker levels and breast cancer progression between women who had bone metastases at baseline and were treated with everolimus versus placebo. REFERENCES 1. Arena FP, Noguchi S, Pritchard KI, et al. Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 phase III trial. J Clin Oncol. 2012;30(suppl 27; abstr 99). 2. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529. 3. Hart LL, Baselga J, Rugo HS, et al. Effects of everolimus (EVE) on disease progression in bone and bone markers (BMs) in patients (pts) with bone metastases (mets). J Clin Oncol. 2012;30(suppl 27; abstr 102).

The International Journal of TargetedTherapies in Cancer

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

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

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

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

10/12

ZOM-1052241

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

Important Safety Information • ZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported. Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient. • Patients with HCM must be adequately rehydrated prior to use of ZOMETA and loop diuretics (if applicable). Loop diuretics should be used with caution in combination with ZOMETA to avoid hypocalcemia. ZOMETA should be used with caution with other nephrotoxic drugs. Carefully monitor serum calcium, phosphate, magnesium, and serum creatinine following initiation of ZOMETA. Short-term supplemental therapy may be necessary. • In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. Consider individual patient risk/benefit profile before starting ZOMETA therapy in HCM patients with severe renal impairment. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment. Preexisting renal insufficiency and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose. • Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible, as recovery may be prolonged. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. • ZOMETA should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant or plans to breastfeed while taking this drug, the patient should be apprised of the potential harm to the fetus or baby.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

• In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including ZOMETA. Discontinue use if severe symptoms develop, as a subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. There have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. • Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including ZOMETA. These fractures may occur with minimal or no trauma. A number of case reports noted that patients were also receiving treatment with glucocorticoids at time of fracture. Causality with bisphosphonates has not been established. Any patient with a history of bisphosphonate exposure who presents with hip, thigh, or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Drug discontinuation in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit/risk assessment. • Insufficient data exist on how to safely use ZOMETA in HCM patients with hepatic impairment. • Acute-phase reaction symptoms can occur in HCM patients, with fever most commonly reported (44% with ZOMETA vs. 33% with pamidronate). Patients may occasionally experience flu-like syndrome (fever, chills, flushing, bone pain and/or arthralgias and myalgias). The most common adverse events (≥10%) in HCM clinical trials, regardless of causality, with ZOMETA 4 mg (n=86) were as follows: fever (44%), nausea (29%), constipation (27%), anemia (22%), dyspnea (22%), diarrhea (17%), abdominal pain (16%), progression of cancer (16%), insomnia (15%), vomiting (14%), anxiety (14%), urinary tract infection (14%), hypophosphatemia (13%), confusion (13%), agitation (13%), moniliasis (12%), hypokalemia (12%), coughing (12%), skeletal pain (12%), hypotension (11%), and hypomagnesemia (11%). In controlled HCM clinical trials, adverse events (5-10% frequency) occurring in greater incidence with ZOMETA than pamidronate include: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, non-specific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Injection site reactions (redness, swelling) have been infrequently reported. • The most common adverse events (≥15%) in bone metastases clinical trials, regardless of causality, with ZOMETA 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lower-limb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%), and paresthesia (15%). Patients should also be made aware of the potential for abdominal pain.

• Ocular adverse events may occur with bisphosphonates, including ZOMETA. Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inﬂammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids. • Caution is advised when bisphosphonates, including ZOMETA, are administered with aminoglycosides, loop diuretics, and potentially nephrotoxic drugs. • Patients with multiple myeloma and bone metastases due to solid tumors should be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily. Please see brief summary of full Prescribing Information on adjacent pages.

10/12

ZOM-1052241

Zometa® (zoledronic acid) Injection Ready-to-Use Solution for Intravenous Infusion (For Single Use) Concentrate for Intravenous Infusion Initial U.S. Approval: 2001 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin (g/dL)). 1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. 1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established. 4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient or in the Same Drug Class Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast or other bisphosphonates. 5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs. Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary. 5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1)]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine greater than 400 μmol/L or greater than 4.5 mg/dL were excluded. Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine greater than 265 μmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information]. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment

reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)]. 5.5 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2)]. 5.6 Atypical subtrochanteric and diaphyseal femoral fractures Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Zometa. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of Zometa therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy. 5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. 5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients. 5.9 Use in Pregnancy Bisphosphonates, such as Zometa, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypercalcemia of Malignancy The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials. Renal Toxicity Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information]. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 4).

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

Table 4 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug.

Grade 4

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

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

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

86 (100) 81 (94)

103 (100) 95 (92)

38 14

(44) (16)

34 21

(33) (20)

(11)

(2)

25 23 15 14 12 8

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

28 13 17 13 17 14

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

(22)

(18)

(12)

(4)

11 10 9

(13) (12) (11)

2 16 5

(2) (16) (5)

(12)

(10)

13 12 11 11

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

10 8 13 8

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

19 10

(22) (12)

20 12

(19) (12)

(14)

(15)

The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa. Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 5 and 6. Table 5: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

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

(2%) (1%) (51%) —

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

(3%) (2%) (33%) —

Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

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

— — (1%) —

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

(1%) — (5%) (1%)

1Grade

3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) 2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L) Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours. Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)]. Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors. Table 7 describes adverse events that were reported by 10% or more of patients. Adverse events are listed regardless of presumed causality to study drug. Table 7: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%) Patients Studied Total No. of Patients 1031 (100) Total No. of Patients with any AE 1015 (98) Blood and Lymphatic Anemia 344 (33) Neutropenia 124 (12) Thrombocytopenia 102 (10) Gastrointestinal Nausea 476 (46) Vomiting 333 (32) Constipation 320 (31) Diarrhea 249 (24) Abdominal Pain 143 (14) Dyspepsia 105 (10) Stomatitis 86 (8) Sore Throat 82 (8) General Disorders and Administration Site Fatigue 398 (39) Pyrexia 328 (32) Weakness 252 (24) Edema Lower Limb 215 (21) Rigors 112 (11) Infections Urinary Tract Infection 124 (12) Upper Respiratory Tract Infection 101 (10) Metabolism Anorexia 231 (22) Weight Decreased 164 (16) Dehydration 145 (14) Appetite Decreased 130 (13)

Pamidronate 90 mg n (%)

Placebo

556 (100) 548 (99)

455 (100) 445 (98)

175 83 53

(32) (15) (10)

128 35 20

(28) (8) (4)

266 183 162 162 81 74 65 61

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

171 122 174 83 48 31 14 17

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

240 172 108 126 62

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

130 89 114 84 28

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

50 82

(9) (15)

41 30

(9) (7)

81 50 60 48

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

n (%)

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

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

Pamidronate 90 mg n (%)

Placebo n (%)

569 239 216 156 143

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

316 143 131 106 84

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

284 74 73 40 52

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

205

(20)

(17)

(20)

191 180 166 149 127

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

149 91 111 85 65

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

50 58 73 35 43

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

146 112 74

(14) (11) (7)

95 73 39

(17) (13) (7)

49 37 47

(11) (8) (10)

282 224

(27) (22)

155 129

(28) (23)

107 65

(24) (14)

125 114

(12) (11)

80 74

(14) (13)

36 38

(8) (8)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 8 and 9. Table 8: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 3 Laboratory Parameter

Zometa 4 mg n/N

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

(%)

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

Pamidronate 90 mg n/N

(%)

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

Placebo n/N

(%)

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

1Grade

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

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5 1Grade

Zometa 4 mg

Pamidronate 90 mg

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

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

(<1%) (<1%) (<1%) — (<1%)

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

(<1%) (<1%) — — (<1%)

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

— (<1%) (<1%) (<1%) —

Among the less frequently occurring adverse events (less than 15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group. Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear. Renal Toxicity In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (less than 1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (greater than or equal to 1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 10). Table 10: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer Normal Abnormal Total Solid Tumors Normal Abnormal Total Prostate Cancer Normal Abnormal Total

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

27/246 2/26 29/272

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

23/246 2/22 25/268

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

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

17/154 1/11 18/165

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

10/143 1/20 11/163

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

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

12/82 4/10 16/92

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

8/68 2/10 10/78

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

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes. The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5)]. Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5)]. Atypical subtrochanteric and diaphyseal femoral fractures Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including Zometa [see Warnings and Precautions (5.6)]. Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids. Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported.

Additional adverse reactions reported in postmarketing use include: CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: Increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia. 7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. 7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials. 7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia. 7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs. 7.4 Thalidomide No dose adjustment for Zometa 4 mg is needed when co-administered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, Zometa 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of thalidomide with Zometa did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precaution (5.9)] There are no adequate and well-controlled studies of Zometa in pregnant women. Zometa may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as Zometa, are incorporated into the bone matrix and are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. If this drug is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus. In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect. In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study. In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were

observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia. 8.3 Nursing Mothers It is not known whether zoledronic acid is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zometa, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Zoledronic acid binds to bone long term and may be released over weeks to years. 8.4 Pediatric Use Zometa is not indicated for use in children. The safety and effectiveness of zoledronic acid was studied in a one-year activecontrolled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk. Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose. 8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function. 10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information]. 16 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Manufactured by Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2012-66 March 2012

Pazopanib-Erlotinib Combination Slows NSCLC Patients with refractory non-small cell lung cancer (NSCLC) had a statistically significant improvement in progression-free survival (PFS) when treated with the targeted therapy combination of pazopanib and erlotinib versus a single agent, according to a study reported at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology, held in September.1 Patients treated with the combination of pazopanib and erlotinib had a median PFS of 2.6 months versus 1.8 months with erlotinib and placebo (hazard ratio [HR] = 0.59; 95% CI, 0.43-0.83; P = .0016). However, the combination did not improve overall survival [OS]. “Progression-free survival advantages with pazopanib and erlotinib were seen in several biomarkerdefined subgroups,” said David Spigel, MD David Spigel, MD, lead

author and director of Lung Cancer Research at the Sarah Cannon Research Institute in Nashville, Tennessee. “These results warrant additional study of pazopanib in non-small cell lung cancer.” Pazopanib is an oral multikinase inhibitor approved for treatment of advanced renal cell carcinoma. A preliminary study demonstrated activity in NSCLC, as preoperative treatment with pazopanib was associated with a reduction in tumor size in 86% of patients with stage I-II NSCLC.2 Additionally, the safety of pazopanib with either erlotinib or pemetrexed was demonstrated in a phase I clinical trial.3 Spigel reported findings from a randomized phase II trial involving 192 patients who had previously-treated stage IIIB/IV NSCLC. Patients who had received one or two prior lines of therapy were eligible for the trial. The patients were randomized 2:1 to pazopanib plus erlotinib or to erlotinib plus placebo.

The primary endpoint was PFS, and key secondary endpoints included overall survival, objective response rate, and safety. The significant improvement did not translate into an OS advantage for patients treated with the combination of pazopanib and erlotinib. The combination arm had a median OS of 6.8 months compared with 6.7 months with erlotinib alone (HR = 1.1; 95% CI, 0.77-1.55; P = .61). The combination was associated with more grade 3 and higher treatment-emergent adverse events; grade 4 events were uncommon (4%). REFERENCES 1. Spigel D, Burris HA, Greco FA, et al. A randomized phase II study of pazopanib or placebo in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Thorac Oncol. 2012;7(suppl 4; abstr 13.) 2. Altorki N, Lane ME, Bauer T, et al. Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non–small-cell lung cancer. J Clin Oncol. 2010;28(19):3131-3137. 3. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/ show/NCT00619424?term=NCT00619424&rank=1.

Common Mutation in NSCLC Confers EGFR Resistance A common mutation in non-small cell lung (NSCLC) cancer confers resistance to tyrosine kinase inhibitors (TKIs) and worsens survival, creating a need for an alternative approach to treating the subgroup of patients with the mutation, a review of almost 1100 patient records showed.1 Patients with exon 20 insertion mutations in epidermal growth factor receptor (EGFR) had a 60% shorter time to treatment failure with an EGFR inhibitor than after initial platinum-based chemotherapy. They also had a 50% lower overall survival rate as compared with patients who had other common EGFR mutations. Patients with exon 20 insertions had a median survival similar to that of patients with wild-type EGFR, according to Peter Lo, a research data specialist at Dana-Farber Cancer Institute in Boston, Massachusetts, who presented the study findings at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology. “Although patients with EGFR exon 20 insertions have characteristics similar to those of patients with other types of EGFR mutations, we found that exon 20 insertions were associTargetedHC.com

ated with a worse survival,” said Lo. “The lack of structural consistency Although patients with EGFR between different insertion variants exon 20 insertions have indicates a varied biology among this characteristics similar to those of family of mutations.” Exon 20 insertions are the third most patients with other types of EGFR common group of EGFR mutations in mutations, we found that exon 20 NSCLC. Cancers harboring exon 20 insertions were associated with a insertions are thought to be insensitive to the TKIs erlotinib and gefitinib. worse survival.” —Peter Lo Otherwise, little is known about clinical behavior of the mutations, said Lo. In an effort to determine more dian time to treatment failure was 5.9 months about the behavior of exon 20 insertions, inwith platinum-based combination chemotherapy vestigators reviewed medical records of 1086 but was shorter with erlotinib (2.4 months) and patients whose NSCLC tumors had undergone other chemotherapy (2.3 months). EGFR sequencing. The sequencing results Survival analysis for 839 patients showed that showed that 27 patients had tumors harboring patients with exon 20 insertions had a median exon 20 insertions, representing 13 distinct vari- overall survival of 16.5 months compared with 33 ants. Exon 20 insertions accounted for 9% of all months for patients with other EGFR mutations. EGFR mutations identified in the cohort. REFERENCE Treatment data available for 19 patients with 1. Lo, PC, Jackman DM, Butaney M, et al. Clinical behavior of exon 20 insertions showed they received 34 lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 2012;7(suppl 4; abstr 10). different treatments for advanced NSCLC. Me11.12 / 27

Targeted Therapy Updates

Disease Stabilization Now Possible in Metastatic MTC With Targeted Therapies The availability of molecular agents that target oncogenic signaling pathways now offers the possibility of achieving disease stabilization in a proportion of patients with metastatic medullary thyroid cancer (MTC), speakers agreed during the annual meeting of the American Thyroid Association, held in September. The more difficult questions are which patients will benefit the most from targeted therapies such as the recently approved vandetanib, and whether response will be durable enough to justify initiating treatment. “We now have drugs that are active in metastatic MTC, but the selection of who should get the drugs is really the issue, because many of these patients have an excellent quality of life and the drugs do have side effects,” said Matthew Ringel, MD, professor of Medicine at The Ohio State University in Matthew Ringel, MD Mansfield, Ohio. With no perfect tool yet to predict which patients will progress, calcitonin doubling time can be valuable. If calcitonin levels take more than 2 years to double, both 5- and 10-year survival rates are 100%. In contrast, if calcitonin takes less than 6

months to double, survival rates at 5 years are only 23%, and they are only 15% at 10 years—“and the faster the calcitonin is rising, the worse the prognosis,” Ringel noted. In general, guidelines indicate that when calcitonin approaches 100 pg/mL to 150 pg/mL, “that’s about the time where we can find lung and liver metastasis,” he noted. Historically, chemotherapy, the only available systemic therapy, had only a transient effect, with less than a 20% response rate in metastatic MTC. Somatostatin analogues such as octreotide have not generally been effective in clinical trials either. Radioimmunotherapy, used largely in Europe with some success, has generated unexpectedly high rates of bone marrow toxicity, Ringel observed. A significant proportion of patients treated with radioimmunotherapy also develop neutralizing antibodies to the regimen, so they can only be treated once. More recently, investigators have explored the use of tyrosine kinase inhibitors (TKIs)—or what are really multiple kinase inhibitors—in the same MTC metastatic setting. Among the first to be tested was sorafenib. Early trials indicated that sorafenib produced some responses in metastatic MTC but very few partial responses (PRs). Sunitinib appeared to be slightly more active than sorafenib in metastatic MTC, although it too led to

few PRs. Side effects requiring either dose reduction or a drug holiday occurred in as many as 50% of patients in these early TKI trials, Ringel added. The most successful targeted therapy in the treatment of metastatic MTC to date is the multikinase inhibitor vandetanib. Approved in April 2011 for the treatment of unresectable locally advanced or metastatic MTC, the pivotal phase III trial upon which the drug’s approval was based demonstrated a statistically significant 65% reduction in the risk for disease progression with 300 mg of vandetanib daily versus placebo in patients with progressive disease on enrollment (HR = 0.35; 95% CI, 0.24-0.53; P <.0001).1 Median progression-free survival (PFS) in the active treatment arm was 22.6 months versus 16.4 months in controls. While there was no difference in overall survival in the study, the majority of patients originally on placebo were allowed to cross over to vandetanib on disease progression, confounding interpretation of this endpoint, the speakers agreed. A phase III study evaluating the activity of cabozantinib in patients with MTC indicates that cabozantinib also significantly extends PFS versus placebo. Data on overall survival for the cabozantinib-versus-placebo trial are not yet available. REFERENCE 1. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial [published online ahead of print October 24, 2011]. J Clin Oncol. 2012;30(2):134-141

Dabrafenib-Trametinib Combination Therapy in Melanoma: ESMO Phase II Results By Bonnie Gillis Combination therapy with dabrafenib (a BRAF inhibitor) and trametinib (a MEK 1/2 inhibitor) provided a clinically meaningful improvement in patients with melanoma with BRAFV600 mutations, according to results of a phase II study presented at the European Society for Medical Oncology (ESMO) 2012 Congress in Vienna, Austria.1 Full-dose combination Georgina V. Long, BSc, therapy with the drugs imPhD, MBBS 28 / 11.12

proved progression-free survival (PFS), response rate, and duration of response, said lead investigator Georgina V. Long, BSc, PhD, MBBS, clinical researcher at the Melanoma Institute Australia and Westmead Hospital in Sydney. In addition, the combination reduced the side effects associated with BRAF inhibitor monotherapy. Both drugs act on the RAS kinase pathway, dabrafenib at an earlier point than trametinib. About 50% of patients with metastatic melanoma have a BRAF mutation. “Dabrafenib attacks that abnormality and works for about 5 to 7 months, and patients develop resistance to the drug. The rationale for adding a MEK 1/2 inhibitor is that it

blocks the ‘escape route’ for the BRAF inhibitor and allows continued response,” Long said. The study randomized 162 patients with BRAF V600E/K–positive metastatic melanoma to one of three treatment arms: monotherapy with dabrafenib 150 mg twice daily; a combination of dabrafenib 150 mg twice daily with trametinib 1 mg once daily; or full doses of both drugs (dabrafenib 150 mg twice daily and trametinib 2 mg once daily). Median time to follow-up was 14 months. Median PFS was 9.2 months for the full-dose combination versus 5.8 months for the monotherapy arm (P <.0001), representing a 61% reduction in

The International Journal of TargetedTherapies in Cancer

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

BELLE-2 and BELLE-3 BELLE-2 BELLE-2 BELLE-2 and and and BELLE-3 BELLE-3 BELLE-3

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

Postmenopausal Postmenopausal Postmenopausal women women with women HR+/HER2– withwith HR+/HER2– HR+/HER2– locallylocally locally advanced or metastatic breast cancer pretreated advanced advanced advanced or metastatic or metastatic or metastatic breast breast cancer breast cancer pretreated cancer pretreated pretreated with aromatase inhibitor with aromatase withwith aromatase aromatase inhibitor inhibitor inhibitor Archival tumor tissue for analysis of PI3K Archival Archival tumor Archival tumor tissue tumor tissue fortissue analysis for analysis for of analysis PI3K of PI3K of PI3K pathway activation pathway pathway pathway activation activation activation No more than one prior line of No more No No more than more one than than prior one one line prior prior oflineline of of chemotherapy for metastatic disease chemotherapy chemotherapy chemotherapy for metastatic for metastatic for metastatic disease disease disease ECOG Performance Status ≤2 ECOGECOG Performance ECOG Performance Performance StatusStatus ≤2Status ≤2 ≤2

Randomization Randomization Randomization Randomization

BELLE-3 1 1 1 1 BELLE-3 BELLE-3 BELLE-3 Evidence of progression

Evidence Evidence Evidence of progression of progression of progression on or after mTOR on or on after or onmTOR after or after mTOR mTOR inhibitor-based inhibitor-based inhibitor-based inhibitor-based treatment treatment treatment treatment

Buparlisib + fulvestrant Placebo + fulvestrant Buparlisib Buparlisib Buparlisib + fulvestrant + fulvestrant + fulvestrant Placebo Placebo Placebo + fulvestrant + fulvestrant + fulvestrant Primary endpoint: Progression-free survival Primary Primary Primary endpoint: endpoint: endpoint: Progression-free Progression-free Progression-free survival survival survival Key secondary endpoint: Overall survival KeyKey secondary Key secondary secondary endpoint: endpoint: endpoint: Overall Overall Overall survival 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. BuparlisibBuparlisib (BKM120) Buparlisib (BKM120) is an(BKM120) investigational is an investigational is an new investigational drug.new Efficacy drug. newand drug. Efficacy safety Efficacy and have safety and notsafety been have not established. have been not established. been established. 1 There is no There guarantee There is no guarantee isthat no guarantee buparlisib thatcriteria buparlisib will thatbecome buparlisib willcommercially become will become commercially available. commercially available. available. Additional inclusion/exclusion apply. Additional Additional inclusion/exclusion Additional inclusion/exclusion inclusion/exclusion criteria apply. criteriacriteria apply. apply. Group; HER2–, human epidermal growth factor Abbreviations: ECOG, Eastern Cooperative Oncology receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; Abbreviations: Abbreviations: ECOG, Abbreviations: Eastern ECOG, ECOG, Cooperative Eastern Eastern Cooperative Oncology Cooperative Oncology Group; Oncology HER2–, Group; Group; human HER2–, HER2–, epidermal human human epidermal growth epidermal factor growth growth factorfactor PI3K, phosphatidylinositol 3-kinase. receptor 2-negative; receptor receptor 2-negative; HR+, 2-negative; hormone HR+, HR+, hormone receptor-positive; hormone receptor-positive; receptor-positive; mTOR, mammalian mTOR, mTOR, mammalian target mammalian of rapamycin; targettarget of rapamycin; of rapamycin; PI3K, phosphatidylinositol PI3K, PI3K, phosphatidylinositol phosphatidylinositol 3-kinase. 3-kinase. 3-kinase.

Pioneering Research of PI3K inhibitors in Malignancies Pioneering Research Pioneering of PI3K inhibitors Pioneering ResearchinofResearch Malignancies PI3K inhibitors of PI3Kininhibitors Malignancies in Malignancies

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

Novartis 2012

August 2012 August 2012 August August 2012 2012

For more information www.clinicaltrials.gov For more Forinformation more For more information information (NCT01610284 and NCT01633060) www.clinicaltrials.gov www.clinicaltrials.gov www.clinicaltrials.gov Novartis Oncology Trials Hotline: (NCT01610284 (NCT01610284 (NCT01610284 and NCT01633060) and NCT01633060) andClinical NCT01633060) 1-800-340-6843 (USA only) NovartisNovartis Oncology Novartis Oncology Clinical Oncology Trials Clinical Clinical Hotline: Trials Trials Hotline: Hotline: Or contact your representative 1-800-340-6843 1-800-340-6843 1-800-340-6843 (USA only) (USAlocal (USA only)Novartis only) Or contact Or contact your Or contact local your Novartis your local local Novartis representative Novartis representative representative G-BKE-1047878 G-BKE-1047878 G-BKE-1047878 G-BKE-1047878

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

Targeted Therapy Updates risk of disease progression. Median PFS was 9.2 months for the arm using half-dose trametinib, which was also significantly better than monotherapy (P = .005). At 12 months, 41% of the patients who received full doses of both drugs had not progressed versus 9% of the monotherapy arm. Analysis showed PFS benefit from full doses of both drugs for every category: age, sex, baseline disease stage, baseline lactate dehydrogenase (LDH), or presence of brain metastasis. Looking at patients with the most common BRAF mutation, BRAFV600E, PFS was 6.5 months with monotherapy, 7.3 months for the combination with half-dose trametinib, and 10 months for the full-dose combination (P =.0004 vs monotherapy). Median overall survival (OS) had not been reached in any of the three arms at the time the data were presented at ESMO. Twelve-month OS was 70% in the monotherapy arm, 68% in the combined therapy arm with half-dose trametinib, and 78% in the full-dose combination arm. “This has never been seen before in metastatic melanoma,” Long noted.

Confirmed response rates were 54% for monotherapy, 50% for the combination of dabrafenib with half-dose trametinib, and 76% for the full-dose combination. Median duration of response was 5.6 months for monotherapy, 9.5 months for the combination of full-dose dabrafenib and half-dose trametinib, and 10.5 months for the full-dose combination of both drugs. “Using one road block [ie, dabrafenib] and then adding an exit block [ie, trametinib] improves response and duration of response,” said Long. Hyperproliferative skin toxicities (ie, alopecia hyperkeratosis, skin papilloma, and squamous cell carcinoma) associated with BRAF inhibition were reduced in both combination arms. Squamous cell carcinoma occurred in 10 patients on monotherapy, one patient in the combination arm that included half-dose trametinib, and four patients in the full-dose combination arm. Pyrexia and nausea and vomiting were increased in the combination arm. The rate of pyrexia was 67% in the full-dose combination arm and 23% in the monotherapy arm. Long said that

during the evolution of the study it became clear that prophylaxis with corticosteroids was effective in preventing pyrexia, and going forward, that will be the practice. The median time to first episode of pyrexia was less than 6 weeks, and only three patients in the full-dose combination arm developed grade 3 pyrexia. “The majority of patients develop only one episode of pyrexia,” he said. The incidence of vomiting in the full-dose arm was 35%, but these were grades 1 and 2 and easily managed, according to Long. The distribution of other adverse events was similar in the three treatment arms. Two phase III trials of this combination are now ongoing in metastatic melanoma, one comparing the full-dose combination versus dabrafenib alone, and the other comparing the full-dose combination to trametinib alone. REFERENCE 1. Long GV, Sosman JA, Daud AI, et al. Phase II three-arm randomized study of the BRAF inhibitor (BRAFi) dabrafenib alone vs combination with MEK1/2 inhibitor (MEKi) trametinib in pts with BRAF V600 mutation-positive metastatic melanoma (MM). Paper presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA27.

Phase III Trial Supports Pazopanib as First-Line Therapy in Metastatic Renal Cell Carcinoma Pazopanib appears to be another option for firstline therapy of metastatic renal cell carcinoma (mRCC), according to results of the phase III COMPARZ trial, which were presented at the European Society for Medical Oncology (ESMO) 2012 Congress in October.1 The study demonstrated the noninferiority of pazopanib compared with sunitinib, a standard front-line therapy in this setting. The drugs have distinct side-effect profiles, which could affect physician and patient choice of agent. “COMPARZ demonstrated the noninferiority of pazopanib versus sunitinib for progressionfree survival. The efficacy of the two drugs is the same. Pazopanib’s efficacy is further supported by response rates and overall survival in this trial. The differentiated safety profile of pazopanib shows a lower incidence of hand-foot syndrome, fatigue, stomatitis, and mucositis. Higher liver function abnormalities were observed with pazopanib. In general, the adverse events with sunitinib impact quality of life, and this was reflected in the quality of life data,” said lead author Robert 30 / 11.12

In my view, this trial tips the scale from sunitinib, the reference standard, to pazopanib, based on better tolerance.” —Robert Motzer, MD Robert Motzer, MD

Motzer, MD, attending physician, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center in New York City and professor of Medicine, Weill Medical College at Cornell University. Based on side-effect profiles, pazopanib would be Motzer’s preference for first-line treatment: “Treatment for kidney cancer should be individualized. In my view, this trial tips the scale from sunitinib, the reference standard, to pazopanib, based on better tolerance.” Preliminary studies suggested similar efficacy between pazopanib and sunitinib, but lower incidence of several adverse events considered

problematic with sunitinib, Motzer said. This provided the rationale for the head-to-head comparison of the two drugs in COMPARZ, the largest trial to date in mRCC. The study randomized 1110 patients with mRCC to either pazopanib or sunitinib. Baseline demographic and disease characteristics were well balanced between the two arms. Median age was 61 years, about 72% of participants were male, and 83% had prior nephrectomy. All risk groups were included in the open-label trial, and treatment arms were well balanced in this regard; the majority were intermediate risk, and about 12% were poor risk.

The International Journal of TargetedTherapies in Cancer

REFERENCES 1. Motzer RJ, Hutson TE, Reeves J, et al. Randomized, openlabel, phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (mRCC): results of the COMPARZ trial. Paper presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA 8. 2. Escudier BJ, Porta C, Bono P, et al. Patient preference between pazopanib (Paz) and sunitinib (Sun): results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT01064310. J Clin Oncol. 2012;30(suppl; abstr CRA4502).

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The primary endpoint was progression-free survival (PFS), assessed by independent review of scans by radiologists blinded to the treatment arm. Median PFS was 8.4 months with pazopanib versus 9.5 months with sunitinib. “A hazard ratio [HR] of 1 means identical. In this trial, HR was 1.047, which is close to the target and within boundaries of acceptable for claiming noninferiority. This shows similar effectiveness,” Motzer said. Adverse events reported more frequently with pazopanib included liver enzyme elevations and hair color changes. Adverse events reported more frequently with sunitinib included fatigue, hand-foot syndrome (“making it problematic, hard to walk,” Motzer said), taste alteration, and thrombocytopenia. About 12% of patients developed elevated alanine aminotransferase levels on pazopanib. “These are generally asymptomatic. Liver function tests should be monitored, especially during the first 3 or 4 months of treatment. The drug is withheld when enzymes are elevated, and about half of patients recover to baseline levels and can go back on the drug,” Motzer said. Patient-reported quality-of-life measures showed more satisfaction with pazopanib therapy and less fatigue and physical symptoms compared with sunitinib. These results are similar to the smaller PISCES study by Escudier and colleagues presented at the American Society of Clinical Oncology 2012 annual meeting.2 In that trial, 90% of patients expressed a preference for either of the two drugs: 70% of patients preferred pazopanib, and 22% preferred sunitinib. Motzer emphasized that both sunitinib and pazopanib are highly effective and are options in the first-line setting for mRCC, in addition to bevacizumab plus interferon. “In the era of personalized medicine, patients should be given the choice. The safety profile of pazopanib is less compromising for patients in their daily lives, and pazopanib will be the treatment of choice in my opinion,” he said.

Micrographs of squamous carcinoma. FNA specimen of a lung lesion

Tivantinib NSCLC Trial Halted The phase III MARQUEE trial examining tivantinib has been halted following a planned interim analysis because it was not expected to meet its primary endpoint, ArQule Inc. and Daiichi Sankyo announced this October. The randomized, double-blind MARQUEE study (NCT01244191) evaluated erlotinib plus the oral MET inhibitor tivantinib (ARQ 197) versus erlotinib plus placebo in previously treated patients with locally advanced or metastatic, nonsquamous, non-small cell lung cancer (NSCLC). Tivantinib binds to the MET tyrosine kinase receptor and blocks the MET signaling pathway. The result is a disruption in the signals that cause tumor cell proliferation and metastasis. The study’s independent data monitoring committee determined that the primary endpoint of improvement in overall survival (OS) would not be met. The independent group did find improvement in progression-free survival (PFS) in the intent-to-treat (ITT) group and found no safety concerns.

MARQUEE was conducted at more than 200 clinical sites worldwide. Secondary endpoints of the study included OS in the subpopulation of patients with epidermal growth factor receptor wild-type NSCLC, PFS in the ITT group, and further evaluation of tivantinib’s safety in combination with erlotinib. The phase II trial that was the foundation for the MARQUEE trial indicated that the combination of tivantinib and erlotinib improved median OS versus erlotinib alone in patients with nonsquamous NSCLC by 46% (10.1 vs 6.9 months; P = .18). The trial also showed a 91% improvement in average PFS (4.4 vs 2.3 months; P = .12). In the phase I and II studies of the combination, patients tolerated tivantinib and experienced minimal increases in side effects beyond those with erlotinib alone. Tivantinib continues to be studied as monotherapy and as a part of combinations to treat many cancers, including NSCLC, hepatocellular carcinoma, colorectal cancer, and gastric cancer.

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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.

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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

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S T O R Y

The International Journal of TargetedTherapies in Cancer

Antibody-Drug Conjugates Target Drug Delivery

Cover Story

By Jane de Lartigue, PhD

At the turn of the millenium, the first antibody-drug conjugate (ADC) reached the market, Pfizer’s Mylotarg.1 Just a decade later, disappointment struck as Mylotarg was withdrawn from the market.1 Learning from this failure, new and improved ADCs have emerged, and, with last year’s approval of Seattle Genetics’ Adcetris,2 interest in ADCs has been renewed. (See “The Evolving Role of Brentuximab Vedotin in the Management of CD30-Positive Lymphoma” on page 44.)

Antibody-Drug Conjugates: Essential Components The essential components of ADCs are: 1. A monoclonal antibody, which binds to tumor cell-specific antigens or antigens that are overexpressed on the surface of tumor cells. Examples include proteins on the surface of the B and T cells of the immune system, such as CD20 and CD22, the human epidermal growth factor receptor 2 (HER2), and prostate-specific membrane antigen (PSMA). 2. A cytotoxic drug designed to induce tumor cell death by causing irreparable DNA damage or interfering with cell division. 3. A linker that joins the two together. The antibody acts as the ADC’s targeting system, guiding it to the surface of specific cancer cells. Once there, the ADC is taken into the cancer cell and the cytotoxic drug is released to kill the cell.3-5

Lessons Learned From Mylotarg Gemtuzumab ozogamicin (Mylotarg) was approved in 2000 under the FDA’s accelerated approval program, and was indicated for the treatment of patients aged 60 years and over with acute myeloid leukemia (AML) until mid-2010, when the drug was withdrawn from the US market.1 Withdrawal was based on the negative results of a post-approval trial de-

ADCs at a Glance Antibody drug conjugates are made up of three essential parts: a targeting antibody, a cytotoxic chemotherapeutic agent, and a linker that joins the two together. There are three ADCs at the forefront of the market: brentuximab vedotin (Adcetris; Seattle Genetics), trastuzumab emtansine (T-DM1; Genentech), and inotuzumab ozogamicin (CMC-544; Pfizer). Many other agents are in earlier stages of clinical testing. The failure of Mylotarg in 2010 paved the way for improved ADC design; researchers aim to improve the design of all three components in order to produce a more effective overall molecule. The linker technology is crucial and has seen the most substantial amount of development in recent years.

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C O V E R

S T O R Y

Elements of an Antibody-Drug Conjugate (ADC) Antibody

Linker

Specific for a tumor-associated antigen that has restricted expression on normal cells.1,2

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.1-3

Cytotoxic agent Designed to kill target cells when internalized and released.1,2

References: 1. Carter PJ et al. Cancer J. 2008;14(3):154-169. 2. Senter PD. Curr Opin Chem Biol. 2009;13(3):235-244. 3. Polson AG et al. Cancer Res. 2009;69(6):2358-2364.

ADCs’ Mechanism of Action 1 ADC in plasma

4 Cytotoxic agent is released

5 Apoptosis (cell death) References: 1. Carter PJ et al. Cancer J. 2008;14(3):154-169; 2. Teicher BA et al. Clin Cancer Res. 2011; 17:6389-6397.

signed to determine whether adding gemtuzumab ozogamicin to standard chemotherapy improved survival time in AML patients. An interim analysis showed no improvement in survival time and a significant increase in the risk of death due to veno-occlusive disease compared with chemotherapy alone, and the trial was terminated. It is worth noting that based on subpopulation analyses, some researchers still believe that Mylotarg could be promising in patients with favorable cytogenetics, and, indeed, phase III trials are currently under way to test this theory (NCT00860639).6,7 The real silver lining to Mylotarg’s story, however, was that it highlighted some of the pitfalls of early ADC design and paved the way for novel design strategies. Each of the three components of the ADC represents a chance to improve its overall performance. Indeed, as highlighted by T-DM1, collaborations between different companies invested in ADC research have become commonplace, to ensure optimal design of each of the three components.

The antibody Gemtuzumab ozogamicin is composed of an anti-CD33 antibody. This antigen is present on the surface of both normal and cancerous cells to some extent, which means that the specificity of the ADC is somewhat limited. Newer ADC targets are focusing on antigens that are specifically overexpressed on the surface of cancer cells, such as HER2, the epidermal growth factor receptor 36 / 11.12

The cytotoxin The aim of the cytotoxic component of ADCs is to maximize killing potential. The amount of ADC that is taken up into the cell has been found to be a major limiting factor to the potency of these drugs, and, as such, research has been focused on finding more potent cytotoxic agents and understanding the mechanisms of cellular uptake in order to improve the amount of drug taken into the cell, or to ensure that what gets in has the maximum effect.3,9

The linker

2 ADC binds to target antigen 3 ADC-antigen-target complex is internalized

(EGFR), and PSMA, to ensure that the ADC is guided only to tumor cells. Another strategy under investigation is targeting the tumor vasculature with ADCs to reduce the tumor blood supply and restrict tumor growth. Vascular endothelial growth factor (VEGF) is being examined as a possible target for ADCs by incorporating the monoclonal antibody bevacizumab (Avastin) into the design. Research is also directed toward developing vascular-targeting ADCs that are designed to release their cytotoxic component into the extracellular space surrounding the tumor—a strategy that does not rely on the expression of a particular antigen on the surface of a tumor cell or on the ADC being efficiently taken up into the cell, and may effectively target more of the cells that make up a tumor.3,8

The majority of advances in the field of ADC research have come in the form of improved linker technology. The linker is a key component of the ADC because it must ensure a balance between stability in the bloodstream (so that the cytotoxin is not released prematurely) and effective release inside the target cell. Initially, hydrolysable linkers, which were designed to be broken down only in the acidic environment of the cell, were widely used. However, these linkers have notoriously poor stability in the bloodstream. New linker technologies include disulfide-based linkers, which are broken down in the cell where there is a high concentration of thiols, and peptide linkers, which are broken down by intracellular enzymes; both are examples of cleavable linkers. Many companies are now also using noncleavable linkers, which exploit the target cell’s protein degradation machinery; as the ADC is degraded inside the cell, the cytotoxic agent is released. There are advantages and disadvantages to each of the different types of linkers; it is thought that different linker types may be suited to different types of ADCs and to targeting different types of cancer cells.4,5

The Key Players There are currently three major players in the ADC field: the FDA-approved brentuximab vedotin and two others in late-stage clinical testing, trastuzumab emtansine and inotuzumab ozogamicin.

Brentuximab vedotin (Adcetris) Brentuximab vedotin was granted accelerated approval by the FDA in 2011 for use in patients with systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multi-agent chemotherapy regimen, and in patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant or at least two prior multi-agent chemotherapy regimens.2 It comprises a monoclonal antibody against CD30, a membrane protein of the tumor necrosis factor receptor family that is expressed by activated B and T cells and on both ALCL and HL cells, conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE).10 Microtubules are cellular structures that form an important part of the cell division machinery, composed of the protein tubulin. MMAE inhibits cell division The International Journal of TargetedTherapies in Cancer

Table. Therapeutic Landscape: Current and Emerging ADCs Agent

Company

Component Parts

Stage of Development

Seattle Genetics

Anti-CD30 antibody conjugated to the antimitotic agent monomethyl auristatin E (MMAE)

FDA-approved for the treatment of Hodgkin lymphoma and systemic anaplastic large-cell lymphoma

Trastuzumab emtansine (T-DM1)

Genentech/Roche

Anti-HER2 antibody (trastuzumab) conjugated to a derivative of the cytotoxin maytansine (DM1).

Phase III trials in patients with HER2-positive metastatic breast cancer (EMILIA, MARIANNE)

Inotuzumab ozogamicin (CMC-544)

Pfizer

Anti-CD22 antibody conjugated to an antitumor agent from the calicheamicin class

Phase III trials in patients with relapsed/refractory acute lymphoblastic leukemia (NCT01564784) and in combination with the anti-CD20 antibody rituximab in patients with relapsed/refractory aggressive non-Hodgkin lymphoma (NCT01232556)

Lorvotuzumab mertansine (IMGN901)

ImmunoGen

Anti-CD56 antibody conjugated to DM-1

Phase II trials in combination with carboplatin and etoposide in patients with small cell lung cancer (NORTH trial); phase I/II trials in patients with solid tumors (NCT01237678)

Glembatumumab vedotin (CDX-011)

Celldex Therapeutics

Anti-glycoprotein NMB (GPNMB) monoclonal antibody conjugated to MMAE

Phase II trials of patients with advanced GPNMB-expressing breast cancer (NCT01156753, EMERGE)

SAR3419

sanofi-aventis

Anti-CD19 monoclonal antibody conjugated to maytansine

Phase II trials for relapsed/refractory diffuse large B-cell lymphoma (NCT01472887), acute lymphoblastic leukemia (NCT01440179), and in combination with rituximab in patients with relapsed/refractory DLBCL (NCT01470456)

Moxetumomab pasudotox (CAT-8015)

MedImmune LLC

Anti-CD22 antibody conjugated to a fragment of Pseudomonas exotoxin A

Phase I trials in patients with leukemia and non-Hodgkin lymphoma (NCT00586924, NCT00659425)

SGN-75

Seattle Genetics

Anti-CD70 antibody conjugated to monomethyl auristatin F (MMAF)

Phase I trial in patients with non-Hodgkin lymphoma or renal cell carcinoma (NCT01015911)

AGS-16M8F

Astellas Pharma

Anti-AGS16 monoclonal antibody conjugated to MMAF

Phase I trial in patients with advanced renal cell carcinoma (NCT01114230)

ASG-5ME

Astellas Pharma

Anti-AGS5 monoclonal antibody conjugated to MMAE

Phase I trial for the treatment of prostate cancer (NCT01228760)

BIIB-015

Biogen Idec

Anti-Cripto monoclonal antibody conjugated to the maytansine derivative DM4

Recently completed phase I trial in solid tumors (NCT00674947)

BT-062

Biotest Pharmaceuticals Corporation

Anti-CD138 monoclonal antibody conjugated to DM1

Phase I/II trial in patients with relapsed/refractory multiple myeloma (NCT01001442)

IMGN-388

ImmunoGen

Anti-alpha integrin antibody conjugated to DM4

Phase I trial in patients with solid tumors (NCT00721669)

PMSA-ADC

Progenics Pharmaceuticals

Anti-prostate-specific membrane antigen (PSMA) antibody conjugated to MMAE

Phase I trial in patients with prostate cancer (NCT01414283)

Approved Agents Brentuximab vedotin (Adcetris) Late Stage

Early Stage

by blocking the assembly of tubulin proteins into microtubules, leading to cell death. The antibody and cytotoxic agent are joined by a cleavable linker that is broken down by protease enzymes inside the cell.3 This type of linker has been shown to be highly stable in the bloodstream, so that the cytotoxic agent is only released once the ADC is taken up into the cell.11 The preliminary results of several ongoing clinical studies with brentuximab vedotin were reported at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting in Chicago. The success of this agent in ALCL, a type of non-Hodgkin lymphoma (NHL) that is characterized by homogenous CD30 expression, has spurred investigations in other NHLs that express CD30, such as diffuse large B-cell lymphoma (DLBCL) and T-cell lymphoma. A phase II study of patients with relapsed/refractory CD30-posTargetedHC.com

itive NHL, excluding ALCL (NCT01421667), revealed that of the six patients to have completed the study so far, two had complete responses, one had stable disease and three had progressive disease.12 Another phase II study is investigating whether patients who previously responded to brentuximab vedotin could achieve another remission with retreatment (NCT00947856). There was a reported 65% overall response rate (ORR) and a median duration of retreatment response of 10.8 months.13 Brentuximab vedotin is generally well tolerated. Among the most common adverse events (AEs; experienced by at least 20% of patients) reported so far are neutropenia, fatigue, nausea, insomnia, and upper respiratory tract infection.14 Cases of progressive multifocal leukoencephalopathy, a rare but serious brain infection that can result in death, have been reported on occasion.15 11.12 / 37

C O V E R

S T O R Y

Trastuzumab emtansine (T-DM 1) Not far behind Adcetris is Genentech/Roche’s T-DM1, currently in latestage clinical trials. Genentech has announced its intention to submit an application for approval to the FDA, while Roche will also submit a Marketing Authorization Application to the European Medicines Agency.16 T-DM1 utilizes the antibody trastuzumab (Herceptin) for targeting. Trastuzumab binds to the HER2 protein that is frequently overexpressed on the surface of cancer cells, particularly breast cancer cells. The cytotoxic component is a derivative of maytansine, known as mertansine or DM-1. To link trastuzumab to DM-1, Genentech made use of a novel noncleavable thioether linker technology designed by ImmunoGen.17,18 Two phase III trials of T-DM1 are ongoing, the MARIANNE19 and EMILIA20 trials, with EMILIA evaluating T-DM1 versus capecitabine and lapatinib in patients with HER2-positive, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane, while MARIANNE is investigating the combination of T-DM1 and the HER2 monoclonal antibody pertuzumab in HER2-positive breast cancer. Primary results from EMILIA were presented at the ASCO Annual Meeting and demonstrated a significant and clinically meaningful improvement in progressionfree survival (PFS) in patients receiving T-DM1 (9.6 vs 6.4 months; hazard ratio = 0.650; P <.001). Furthermore, the first interim analysis of overall survival (OS) data demonstrated that median OS was 23.3 months for patients receiving lapatinib and capecitabine, but had not yet been reached for those receiving T-DM1.20 Safety assessment in the EMILIA trial also favored T-DM1 over lapatinib, with fewer AEs of grade 3 or higher reported in the T-DM1 group (40.8% vs 57%).20 Cardiac safety is of particular concern for T-DM1 because this has been an underlying issue with the use of trastuzumab. Phase II trials comparing T-DM1 with a regimen of trastuzumab and docetaxel indicated that there were no clinically significant cardiac events in patients receiving T-DM1.21,22 T-DM1 was also associated with fewer grade 3 or higher AEs.21 Results of a phase II trial of T-DM1 following anthracycline-based chemotherapy in the adjuvant or neoadjuvant setting for early-stage, HER2-positive breast cancer were also reported at the ASCO meeting and revealed that T-DM1 was not associated with cardiac toxicity in this patient population.22

Inotuzumab ozogamicin (CMC-544) Following the failure of their flagship ADC, Mylotarg, Pfizer is now pursuing an alternative agent, inotuzumab ozogamicin, which is composed of an antiCD22 monoclonal antibody conjugated to a drug from the calicheamicin class of cytotoxins. CD22 is a cell surface lectin, a sugar-binding protein that plays a role in biological recognition and is expressed on the surface of mature B cells. Calicheamicin is an antitumor antibiotic that causes cell death by inducing breaks in DNA that lead to apoptosis.23 The two components are linked together by a hydrolysable linker.24 Inotuzumab ozogamicin is currently being evaluated in phase III trials in patients with relapsed/refractory acute lymphoblastic leukemia (ALL), as well as in combination with the monoclonal anti-CD22 antibody rituximab in patients with relapsed/refractory aggressive NHL.25,26 A range of phase II trials are also ongoing in patients with indolent NHL (NCT00868608)27 and in combination with rituximab in patients with DLBCL (NCT00867087).28 A report at the ASCO meeting announced that a trial of inotuzumab ozogamicin given weekly for relapsed/refractory ALL produced an ORR of 50%.29 Phase I and II studies that have been published thus far suggest that inotuzumab ozogamicin has a favorable safety profile, both as a monotherapy and in combination with rituximab. The main toxicity is reversible thrombocytopenia.30-32 Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom 38 / 11.12

REFERENCES 1. Pfizer Voluntarily Withdraws Cancer Treatment Mylotarg from US Market. 2010. Available at: http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm216448.htm. Accessed June 20, 2012. 2. FDA Approves Adcetris to Treat Two Types of Lymphoma. 2011. Available at: http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm268781.htm. Accessed June 20, 2012. 3. Beck A. The next generation of antibody drug conjugates comes of age. Discov Med. 2010;10:329339. 4. Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjugate Chem. 2010;21:5-13. 5. Lash A. Making the case for antibody-drug conjugates. In Vivo: The Business and Medicine Report. 2010. 6. Rabiya T. Mylotarg revisited: withdrawal will have major impact on patients, some leukemia experts say. Oncology Times. 2010;32:11-13. 7. ClinicalTrials.gov. Efficacy of gemtuzumab ozogamycin for patients presenting an acute myeloid leukemia (AML) with intermediate risk (LAM2006IR). Available at: http://clinicaltrials.gov/ct2/ show/NCT00860639?term=nct00860639&rank=1. Accessed June 20, 2012 8. Bernardes GJL, Casi G, Trüssel S, et al. A traceless vascular-targeting antibody-drug conjugate for cancer therapy. Angew Chem Int Ed. 2012;51:941-944. 9. Hughes B. Antibody-drug conjugates for cancer: poised to deliver? Nature Rev Drug Disc. 2010;9:665-667. 10. Brentuximab Vedotin. Available at: http://www.seagen.com/clinical_trials_sgn35.shtml. Accessed June 20, 2012. 11. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102:1458-1465. 12. Advani R, Oki Y, Shustov A, Grove L, Bartlett N. Brentuximab vedotin for relapsed or refractory non-Hodgkin lymphoma: preliminary results from a phase II study. J Clin Oncol. 2012;30:(suppl; abstr 8070.) 13. Bartlett N, Brice P, Chen RW, et al. Retreatment with brentuximab vedotin in CD30-positive hematologic malignancies: a phase II study. J Clin Oncol 2012;30(suppl; abstr 8027). 14. Adcetris [package insert]. Bothell, WA: Seattle Genetics, Inc.; 2012. 15. US Food and Drug Administration. Drug Safety Communication - Progressive Multifocal Leukoencephalopathy and Pulmonary Toxicity. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm287710.htm. Accessed June 20, 2012. 16. Genentech Press Releases. Genentech’s Targeted Investigational Breast Cancer Medicine, Trastuzumab Emtansine (T-DM1), Reduced the Risk of Cancer Worsening or Death by 35 Percent in Pivotal Phase III Trial. 2012. Available at: http://www.gene.com/gene/news/press-releases/display. do?method=detail&id=13948. Accessed June 20, 2012. 17. Genentech. Trastuzumab emtansine (T-DM1). Available at: http://www.biooncology.com/pipelinemolecules/trastuzumab-emtansine/index.html. Accessed June 20, 2012. 18. Webb S. Pharma interest surges in antibody drug conjugates. Nature Biotech. 2011;29:297-298. 19. ClinicalTrials.gov. A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE). 2010. Available at: http://clinicaltrials.gov/ct2/show/NCT01120184. Accessed June 20, 2012. 20. Blackwell K, Miles D, Gianni L, et al. Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. J Clin Oncol. 2012;30(suppl;abstr LBA1). 21. Perez E, Dirix L, Kocsis J, et al. Efficacy and safety of trastuzumab-DM1 vesus trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients with no prior chemotherapy for metastatic disease: preliminary results of a randomized, multicenter, open-label phase 2 study (TDM4450G). Ann Onc. 2010;21. Abstract LBA3. 22. Dang CT, Gianni L, Romieu G, et al. Cardiac safety in a phase II study of trastuzumab emtansine (T-DM1) following anthracycline-based chemotherapy as adjuvant or neoadjuvant therapy for earlystage HER2-positive breast cancer. J Clin Oncol. 2012;30(suppl; abstr 532). 23. Walker S, Landovitz R, Ding WD, Ellestad GA, Kahne D. Cleavage behavior of calicheamicin gamma 1 and calicheamicin T. Proc Natl Acad Sci USA. 1992;89:4608-4612. 24. Inotuzumab ozogamicin (CMC-544) fact sheet. 2012. Available at: http://www.pfizer.com/files/ news/asco/inotuzumab_fact_sheet.pdf. Accessed June 20, 2012. 25. ClinicalTrials.gov. Study evaluating inotuzumab ozogamicin in acute lymphocytic leukemia. 2011. Available at: http://clinicaltrials.gov/ct2/show/NCT01363297?term=inotuzumab+ozogamicin+pha se+3&rank=4. Accessed June 20, 2012. 26. ClinicalTrials.gov. A study of inotuzumab ozogamicin plus rituximab for relapsed/refractory aggressive non-Hodgkin lymphoma patients who are not candidates for intensive high-dose chemotherapy. 2010. Available at: http://clinicaltrials.gov/ct2/show/NCT01232556?term=inotuzumab+o zogamicin+phase+3&rank=1. Accessed June 20, 2012. 27. ClinicalTrials.gov. Study evaluating inotuzumab ozogamicin (CMC-544) in indolent non-Hodgkin lymphoma. 2009. Available at: http://clinicaltrials.gov/ct2/show/NCT00868608?term=nct008686 08&rank=1. Accessed June 20, 2012. 28. ClinicalTrials.gov. Study evaluating inotuzumab ozogamicin (CMC-544) plus rituximab in diffuse large B-cell non-Hodgkin lymphoma. 2009. Available at: http://clinicaltrials.gov/ct2/show/NCT008 67087?term=nct00867087&rank=1. Accessed June 20, 2012. 29. Jabbour E, O’Brien SM, Thomas DA, et al. Inotuzumab ozogamycin (IO), a CD22 monoclonal antibody conjugated to calecheamicin, given weekly, for refractory-relapse acute lymphocytic leukemia (R-R ALL). J Clin Oncol. 2012;30(suppl; abstr 6501). 30. Ogura M, Hatake K, Ando K, et al. Phase I study of anti-CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed/refractory B-cell non-Hodgkin lymphoma. Cancer Science. 2012;103:933-938. 31. Advani A, Coiffier B, Czuczman MS, et al. Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study. J Clin Oncol. 2010;28:2085-2093. 32. Goy A, Leach J, Ehmann WC, et al. Inotuzumab ozogamicin (CMC-544) in patients with indolent Bcell NHL that is refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy: preliminary safety and efficacy from a phase 2 trial. Blood. 2010;116:192-193. Abstract 430.

The International Journal of TargetedTherapies in Cancer

NOW ENROLLING

Investigating BKM120 in Patients With Metastatic NSCLC and Activated PI3K Pathway (CBKM120D2201) An Open-Label Two-Stage Study to Determine Efﬁcacy and Safety of Orally Administered BKM120 STUDY DESIGN Stage 1

Stage 2

Metastatic NSCLC Patients

Determine PI3K Pathway Activation

Screening

Enrollment

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

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

BKM120

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

BKM120

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

Docetaxel

BKM120

Docetaxel or Pemetrexed

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

• Progression-Free Survival

FOR MORE INFORMATION ABOUT STUDY DESIGN OR ENROLLMENT:

SECONDARY ENDPOINTS

• US residents can visit www.clinicaltrials.gov [NCT01297491] • For countries outside of the US, please contact your local Novartis Medical Representative

PRIMARY ENDPOINT

• Objective Response Rate • Time to Response • Duration of Response • Disease Control Rate • Overall Survival • Safety

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 –1080

BKM120 is an investigational compound. Efﬁcacy and safety have not been established. There is no guarantee that BKM120 will become commercially available.

Printed in USA

5/12

ONC-1040996

F E A T U R E

NeuVax mechanism of action: active specific immunotherapy (ASI)

T-cell Receptor NeuVax: E75 peptide + GM-CSF

HLA-E75 peptide-TCR complex Induces proliferation of E75-specific T-cell clones

HLA-A2

T-Cell E75 peptide

E75 isolated from HLA in human tumors

Courtesy Galena Biopharma

APC ing

nal

Sig

HER2/new protein

E75 derived from HER2 endogenous pathway

Cancer cells

Activated, cancerfighting “killer T cells”

Millions of HER2-targeted cytotoxic T cell clones seek and destroy HER2expressing cancer cells

Dying cancer cell

Clinical Trial Profile NeuVax Vaccine for the Prevention of Breast Cancer Recurrence in the PRESENT Trial By Tracey Regan

A vaccine therapy designed to prevent breast cancer from recurring in women who have been treated for early-stage disease, but remain at high risk of forming new tumors, is now being evaluated in a multinational phase III trial after it succeeded in reducing relapse rates significantly in earlier trials. The therapy, NeuVax, directs the immune system to target HER2 (human epidermal growth factor receptor 2), an oncogene that promotes tumor growth associated with aggressive disease and poor survival and is expressed to some extent in about two-thirds of breast cancer tumors. The drug represents a departure from the majority of cancer therapies now in clinical trials because of the early stage at which patients are enrolled, as well as its focus on prevention. While most new therapies are evaluated in later-stage patients with metastatic disease, the patients participating in the PRESENT trial (Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low-to-Intermediate HER2 Expression with NeuVax Treatment; Galena Biopharma) have newly diagnosed cancer characterized as local regional disease, or stage 2 to 3a from a clinical perspective. 40 / 11.12

“This trial is for women who have completed standard-of-care therapy and are node-positive with tumors with low to intermediate expression of HER2, defined as 1+ and 2+, for whom there are currently no additional treatment options. It’s an unmet need because these patients are node-positive and have a high risk of recurrence,” said Elizabeth Mittendorf, Elizabeth Mittendorf, MD, PhD, an assistant professor in the Department MD, PhD of Surgical Oncology at University of Texas MD Anderson Cancer Center in Houston, and the trial’s principal investigator. About 40,000 of the approximately 230,000 women diagnosed each year with breast cancer fit this profile, said Mark Ahn, PhD, president and CEO of Galena Biopharma. “About 55% of women are node-positive, and this is the dominant clinical factor for predicting whether their cancer will return. They have a 25% chance of recurrence within 3 years, despite there being no evidence of disease following standard-of-care therapy. These are women with a median age of about 50 who are highly active with lots of life left, and who are keen Mark Ahn, PhD to stay in remission,” he said, adding, “Of HER2positive tumors, 20% to 30% are 3+ (high-level expression), and these patients receive trastuzumab therapy. However, about 50% to 60% are either The International Journal of TargetedTherapies in Cancer

1+ or 2+, and these women are currently sent home to People like the idea of strengthening their watch, wait, and worry about recurrence.” own immune systems and taking measures to The trial is a randomized, double-blind study at 32 sites, with an estimated enrollment of 700 women with operable prevent disease, rather than toxic remedies when they early-stage, node-positive breast cancer who have completare already sick.” ed standard therapies that include surgery, chemotherapy, —Col. George Peoples, MD and radiation. The primary outcome measure for the trial is an assessment of disease-free survival in the vaccine and control groups at 36 months. Secondary endpoints include measurement of disease-free survival and overall survival in both groups at of up to six inoculations of NeuVax on a monthly basis. The trial physi3, 5, and 10 years, and data collection on time to recurrence, time to local cians added a voluntary booster program as the trial progressed, however, recurrence, time to distant recurrence, and time to bone metastases, as when they determined that some patients’ immunity waned after the initial well as an overall safety profile. monthly series, translating to late recurrences of cancer in some. This dePatients seeking to enroll in this trial undergo a two-step qualification clining immunity was identified by monitoring the patients’ T cells. process at one of the test sites to confirm their eligibility, Mittendorf said. The results showed that at a median of 60 months, the disease-free A blood sample is sent to a central lab to determine the patient’s human survival for the booster group was 96% versus 80.5 % in the control group, leukocyte antigen (HLA) status, as the vaccine only works in patients who are with a recurrence rate for the booster group of about 4% versus about 19% A2- or A3-positive for these alleles, molecules that package the vaccine pepin the control group. tide and present it on the cell surface for recognition by the immune system. “In phase III, patients are getting an optimal dose. Phase I participants Patients must also undergo a series of tests, including a mammogram, comwere rolled into phase II, and so those patients received a variety of doses puted tomography scan, and bone scan, to show that they are disease-free. including low doses, and some did not receive boosters,” Mittendorf said. “They must begin their vaccination series within 2 months after standard Patients with HER2 3+ tumors participated in the earlier trials, but have therapy is completed,” she said, noting, “We’re identifying potentially eligible been excluded from the phase III trial as they now receive trastuzumab as trial patients while they are still completing their standard treatment. This standard-of-care therapy. Trastuzumab is a monoclonal antibody that also allows us to appropriately counsel patients and complete the necessary con- targets HER2, but is reserved for women who are HER2 3+, and it has a senting and testing so that they can start their inoculations on schedule.” dose-limiting toxicity of cardiotoxicity, Ahn said. Participants in the experimental arm of the trial are inoculated with a NeuVax appears to be synergistic in combination with trastuzumab, hybrid vaccine that includes NeuVax (nelipepimut-S), an E-75 peptide debased upon the results of a phase II pilot trial that resulted in no recurrencrived from HER2, combined with Leukine (sargramostim), an adjuvant that es with NeuVax plus trastuzumab after 24 months versus 12.5% with trastuboosts the immune system. The mixture is injected intradermally once a zumab alone, and without added toxicity. As a result, Galena Biopharma is month for 6 months, followed by booster shots five more times at 6-month following up with a randomized phase IIb study that will enroll patients with intervals. Participants in the control arm receive injections of Leukine at low and intermediate HER2-expressing breast cancer. the same intervals. While she described the treatment regimen as rigorous, Mittendorf said Ahn described NeuVax as a clone of HER2 that trains the body’s T cells to the side effects were minimal. “Some patients experience redness at the attack the tumor-expressing cells that become the basis for breast cancer injection site, bone pain, and aches that are like flu symptoms, but these relapse. “The body has a trillion T cells and between 15% and 40% are CTLs, typically last for 4 to 5 hours only and are responsive to acetaminophen. or cytotoxic T cells, lymphocytes that can kill cancer cells. These T cells are We see these symptoms with other vaccinations,” Mittendorf said, adding, trainable and can be turned on and directed at HER2; we can have 2% of “The trial is not a hard sell, because the treatment does not replace other CTLs to run around the body for 6 months to look for HER2,” he said. therapies, is easily tolerated, and has potential benefits. We’re finding that Recurrence rates were cut in half for women who were vaccinated patients and their physicians are enthusiastic about this study.” with NeuVax over the course of the earlier clinical trials, said Col. George Cancer researchers describe HER2-positive breast cancers as more agPeoples, MD, a developer of the vaccine who is gressive than other types of breast cancer and less responsive to hormone director and principal investigator for the Cancer treatment. And so for these patients, the stakes are high. Vaccine Development Program at San Antonio Mili“When the cancer comes back after they’ve undergone the best availtary Medical Center and deputy director of the US able therapy, the vast majority of people will succumb to the disease,” Military Cancer Institute. Peoples said. Peoples, the principal investigator for the phase I Mittendorf described the years following treatment as stressful for and II trials, said that the figure reflected outcomes women. These patients must be “very vigilant following care, checking in for all women participating, regardless of dosage for evaluations every 3 months for 2 years, and then every 6 months for 3 Col. George Peoples, MD levels and including those who did not receive years after that, and then every 5 years after that. They begin to worry as boosters. He noted that a series of dosages and schedules were tried with that next checkup gets closer. It’s not an easy way to live,” she said. “The the vaccine before investigators determined which combination produced women enrolling [in the PRESENT trial] don’t know if their disease will recur, the most robust immune response. but that’s the fear of all cancer patients, and their only other choice at this The phase I/II clinical trial of NeuVax recently concluded, with the final point is to go home and do nothing,” she said. patients completing their booster treatments and final follow-up visits in Peoples noted that when he began his immunotherapy research nearly September 2012. Initially, patients in the earlier trials were given a series two decades ago, “there were no products then that used the immune TargetedHC.com

11.12 / 41

F E A T U R E

system as a relevant tool. That the immune system can be actively engaged is emerging as an important modality,” he said. “People like the idea of strengthening their own immune systems and taking measures to prevent disease, rather than toxic remedies when they are already sick. And while it does make sense that late-stage patients are more willing to try experimental treatments, when we’re talking about the immune system, we can’t wait until the cancer has won.” He added, “From the standpoint of a clinical trial, it’s not good either to vaccinate and wait 20 years to see whether a drug works. It has to be a happy medium, targeted at patients who are treated and disease-free, but at a high risk of recurrence based upon their disease profile. If we learn that we can prevent metastatic disease, it’s a natural transition to enlist this therapeutic approach earlier in the process, and that’s when we do start looking at the 20-year trials.” Ahn characterized the marked reduction in the death rate among breast cancer patients over the past decade as “about half attributable to earlier diagnosis and half to better and more aggressive treatments with targeted therapies like Herceptin and Avastin.” He noted that with prophylactic strategies, including surgeries, “we’re entering an era where the question is what we do with the information we have, understanding that we’re often dealing with probabilities and not certainties.” “If we could detect the presence of HER2 before it forms a tumor mass, that would be pretty smart. But we’d have to be able to determine where the cut-off levels are in asymptomatic patients with detectable levels of circulating tumor cells,” he said. “We’re just now acquiring the technology that allows us better assessments of these counts, but we need to make sure treatment is something we can define with it. If we can, this could lead to more prophylactic therapies. The challenge is to make it practical.” Tracey Regan is a freelance medical writer.

Table. Efficacy and Safety Study of NeuVax Vaccine to Prevent Breast Cancer Recurrence (PRESENT Trial) Primary outcome Disease-free survival at 36 months measure: Secondary outcome Assessment of disease-free survival and overall survival at 3, 5, measures: and 10 years; time to recurrence, time to local recurrence, time to distant recurrence, time to bone metastases; overall safety profile Study start date: November 2011 Estimated primary May 2015 (for final data collection on primary outcome measures) completion date: Estimated study May 2022 completion date: Estimated 700 enrollment:

Patients: Adults 18 years or older Pathological diagnosis of invasive adenocarcinoma of the breast Breast cancer completely excised Node-positive disease Primary tumor stage T1-3 HER2-negative (HER2 1+ by IHC or HER2 2+ by IHC/FISH) HLA-A2 or HLA-A3 haplotype Completed NCCN-approved neoadjuvant/adjuvant chemotherapy, or both Completed radiation therapy No evidence of disease No bilateral breast malignancy or suspicious mass in opposite breast No history of prior breast cancer, ductal carcinoma in situ No prior trastuzumab therapy

Dosages: Arm A: Hybrid vaccine of NeuVax mixed with Leukine and injected intradermally once a month for 6 months, followed by booster injections once every 6 months for 5 months Arm B: Leukine injected intradermally once a month for 6 months, followed by booster injections once every 6 months for 5 months Adverse effects: Some patients experience redness at the injection site, bone pain, and aches that resemble flu symptoms typically lasting 4 to 5 hours IHC = immunohistochemistry; FISH = fluorescence in situ hybridization; HLA = human leukocyte antigen; NCCN = National Comprehensive Cancer Network.

42 / 11.12

The International Journal of TargetedTherapies in Cancer

Cabozantinib (XL184) phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases CabOzantinib MET Inhibition CRPC Efficacy Trials KEY ELIGIBILITY CRITERIA •Diagnosis of CRPC •Presence of bone metastases •Prior treatment with docetaxel • Prior treatment with abiraterone and/or MDV3100 (enzalutamide) •No limit to the number of prior therapies

COMET-1

COMET-2

PRIMARY ENDPOINT

Overall Survival

Confirmed Pain Response CRPC (N=246)

CRPC (N=960) • Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies

Cabozantinib (60 mg qd) Randomization Prednisone

Randomized, double-blind, controlled trial

• Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies • Pain related to bone metastases

Cabozantinib (60 mg qd) Randomization Mitoxantrone + Prednisone

Randomized, double-blind, controlled trial

C L I N I C A L

A R T I C L E S

PEER RE VIEWED

CD30-Positive Lymphoma

The Evolving Role of Brentuximab Vedotin in the Management of CD30-Positive Lymphoma Francisco J. Hernandez-Ilizaliturri, MD Brentuximab vedotin is a novel and potent antibody drug conjugate (ADC) directed against the CD30 receptor present primarily in Hodgkin and Reed Sternberg (HRS) cells and in T-cell anaplastic large cell lymphoma (ALCL). Brentuximab vedotin (formerly known as SGN-35; now FDA-approved as Adcetris) was designed to improve the clinical activity of the monoclonal antibody SGN-30 in lymphoma, a monoclonal antibody targeting CD30 antigen. Brentuximab vedotin consists of the anti-tubulin agent monomethyl auristatin E (MMAE) attached to the IgG1 SGN 30 (mAb cAC10) by an enzyme-cleavable dipeptide linker. Preclinical studies demonstrated significant antitumor activity in Hodgkin lymphoma (HL) and ALCL models as single agents or in combination with chemotherapeutic agents. Several clinical trials evaluating the antitumor activity of brentuximab vedotin as a single agent have been completed in patients with relapsed/refractory CD30-positive hematologic malignancies, primarily HL and ALCL. Significant antitumor activity and variable duration of response were observed in patients with heavily pretreated HL and ALCL. In the current contribution, we review the preclinical and clinical studies that facilitated the FDA approval of this targeted agent for the treatment of relapsed/refractory CD30-positive HL and ALCL, and outline ongoing research aimed at further optimizing the spectrum of activity of brentuximab vedotin. A B S T R A C T

Corresponding Author: Francisco J. Hernandez-Ilizaliturri, MD Associate Professor of Medicine and Immunology, Department of Medical Oncology and Immunology,Roswell Park Cancer Institute, Buffalo, NY; Francisco.hernandez@roswellpark.org 44 / 11.12

According to this yearâ&#x20AC;&#x2122;s published cancer statistics, approximately 79,190 new cases of lymphoma will be diagnosed in 2012, and 20,130 patients will die from the cancer, despite currently available treatments.1 Lymphomas are a heterogeneous group of malignancies with diverse biology, clinical behavior, and prognosis. While infrequent, Hodgkin lymphoma (HL; 9060 estimated new cases/year) is commonly diagnosed in younger patients and is curable with appropriate therapy in 85% of cases. On the other hand, patients with relapsed/refractory HL represent a challenge to the treating oncologist. Until recently, active therapeutic options for these patients were limited. In contrast, non-Hodgkin lymphoma (NHL) is the sixth most common cancer in the United States and accounts for 4% of cancer-related deaths in the United States.1 The clinical outcome for patients with lymphoma has improved over the last decade as a result of several factors, including a better understanding of the pathogenesis and biology of lymphoid malignancies; advances in technology resulting in a more precise diagnosis (eg, immunophenotyping, cytogenetic, or gene expression profiling studies) and staging (ie, functional imaging); the identification and validation of clinically-based score indices or biomarkers capable of predicting clinical outcomes and/or response to therapy; and the development and incorporation of novel and effective agents for the management of lymphoid malignancies ( monoclonal antibodies [mAbs] and antibody-drug conjugates [ADCs]). The use of mAbs targeting surface receptors (ie, CD20 or CD52) in B-cell lymphomas has resulted in significant antitumor activity. In particular, rituximab, a chimeric mAb targeting the CD20 antigen present in normal B cells and most B-cell lymphomas, has changed the treatment paradigm for patients with B-cell NHL. The antitumor mechanisms of rituximab have been characterized and include antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CMC), and activation of intracellular pathways leading to apoptosis. Preclinical models have demonstrated that rituximab potentiates the effect of several chemotherapeutic agents in B-cell lymphomas.2 The early use of rituximab as a single agent or in combination with various systemic chemotherapy regimens (eg, CVP, CHOP) has resulted in improved response rates, more durable remissions, and, most importantly, improved survival in patients with follicular lymphoma (FL) or aggressive diffuse large B-cell lymphoma (DLBCL).3-11 These studies have led to the adoption of rituximab plus chemotherapy as the standard of care in the United States. While a significant number of patients benefit from rituximab-based therapies, a high percentage of patients fail to respond to the therapy, or else relapse after initial remission as a result of intrinsic or acquired resistance. In addition, targeted therapies are needed for those patients with CD20-negative lymphomas, such as HL and T-cell lymphoma. Several attempts have been made to improve the therapeutic efficacy of mAbs and include: (1) re-engineering the structure of the constant region of The International Journal of TargetedTherapies in Cancer

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CD30-Positive Lymphoma Figure. Mechanisms of action of brentuximab vedotin mAbs to generate more potent immune responses Monomethyl auristatin E (MMAE), potent anti-tubulin agent or signaling events (eg, apoptosis); (2) the addition of linkers that allow the conjugation of mAbs to Protease-cleavable linker radioisotopes (ibritumomab tiuxetan or 131I tositumomab) or chemotherapy agents (eg, gemtuzumCellular events triggered by brentuximab vedotin: ab ozogamicin, CMC544, or brentuximab vedotin). 1) Apoptosis ADCs are emerging as powerful and clinically 2) G2/M cell cycle arrest active therapeutic strategies for the management of hematologic malignancies (See “Antibody Drug Brentuximab vedotin (Adcetris) is an antibody-drug conjugate Conjugates Target Drug Delivery” on page 34). Anti-CD30 that binds to the CD30 antigen monoclonal antibody CD4+T, Gemtuzumab ozogamicin (Mylotarg) was the first () present in Hodgkin and ReedB-cells, and Sternberg cells. Upon binding to ADC approved by the FDA for the treatment of HRS cells macrophages CD30, brentuximab vedotin is relapsed/refractory acute myelogenous leukemia. internalized via the lysosomes into (+) regulatory However, the drug was withdrawn after postmarthe cytoplasm of malignant cells. immune-effector cells Inside the lysosomes, monomethyl keting studies failed to demonstrate clinical effiCD8+T, auristatin E (MMAE) is released cacy while an increase in treatment-related deaths NK cells into the cytoplasm. Subsequently, MMAE disrupts the microtubule was observed. Subsequent drug discovery studies APCs (-) regulatory system and leads to apoptosis immune-effector cells focused on developing a new generation of ADCs and G2/M cell cycle arrest. and addressing the need for better target antigen selection, drug potency/metabolism, linker stability, and conjugation methods. Brentuximab vedotin and trastuzumab-DM1 060 and SGN-30) in patients with relapsed/refractory HL. Both antibodies (T-DM1) are the result of such discovery programs and have shown signififailed to demonstrate significant antitumor activity. In some cases, anti-CD30 cant antitumor activity in early clinical trials. antibody use was associated with an increase in lung toxicity when combined Brentuximab vedotin (Adcetris) is an ADC designed to improve the cliniwith systemic chemotherapy.17-19 Subsequently, SGN-30 was re-engineered cal activity of the anti-CD30 mAb SGN-30 in lymphomas. Brentuximab into an ADC that demonstrated clinically meaningful antitumor activity. vedotin is composed of the anti-tubulin agent monomethyl auristatin E (MMAE) linked to an anti-CD30 monoclonal antibody to enhance antitumor Brentuximab Vedotin Preclinical Development activity.12 Recently, the FDA approved brentuximab vedotin for the treatThe ADC brentuximab vedotin consists of the anti-tubulin agent MMAE atment of relapsed/refractory HL and CD30-positive T-cell ALCL. In this tached to SGN-30 by an enzyme-cleavable dipeptide linker.20 The ADC is contribution, we summarize the discovery and clinical evolution of brentux- rapidly internalized upon CD30 binding (Figure). Subsequently, the peptide imab vedotin in CD30-positive lymphoma. linker is cleaved and MMAE is released in the intracellular compartment, inducing cell cycle arrest and apoptosis.21 SGN-35 was highly active in HL or CD30 as a Target Antigen in Lymphoid Malignancies ALCL preclinical models.21 CD30 is a cell membrane protein that belongs to the tumor necrosis factor Early preclinical studies in HL suggest that brentuximab vedotin receptor family (TNFR super family 8), which is involved in the activation of the enhances the antitumor activity of various chemotherapy agents (eg, canonical NFκB pathway and promotes tumor cell survival signaling. CD30 is doxorubicin, vinblastine, bleomycin, dacarbazine, gemcitabine).20 The expressed in almost 100% of Hodgkin and Reed Sternberg (HRS) cells and in results of these preclinical studies, in addition to the clinical activity ALCL, thus serving as an attractive target of immunotherapy for classical HL observed in clinical trials, further support the study of brentuximab vedotin and ALCL.13,14 CD30 expression has been described in other hematologic and combined with chemotherapy agents in the relapsed/refractory setting. nonhematologic malignancies such as DLBCL, primary mediastinal lymphoma, immunoblastic lymphoma, multiple myeloma, T-cell leukemia, transformed my- Clinical Development of Brentuximab Vedotin cosis fungoides, germ-cell tumors, and thyroid carcinoma. On the other hand, Several clinical studies have evaluated the efficacy and safety of brentuximab vedotin in CD30-positive hematologic malignancies (Table 1). Younes et al22 CD30 is not expressed in nonhematologic normal cells, resting monocytes, or 15 conducted the first phase I dose-escalation clinical trial in patients with CD30lymphocytes. In addition, CD30 is not expressed in hematologic stem cells. positive relapsed/refractory hematologic malignancies that included HL and The signaling events triggered on CD30 activation have been studied using agonist or antagonist anti-CD30 mAbs in vitro. The function of CD30 ap- ALCL. A total of 45 patients were enrolled and treated with brentuximab vedotin at various dose levels (0.1 to 3.6 mg/kg) administered intravenously every pears to be dependent upon the microenvironment in which CD30-positive 3 weeks. The majority of heavily pretreated patients had relapsed/refractory cells reside, the cell expressing CD30 (activated lymphocyte/monocyte vs HL (n = 42). More than two-thirds of the patients had failed prior high-dose malignant cells), and the interaction of CD30 with its ligand(s) (ie, members chemotherapy and autologous stem cell transplant (HDC-ASCT). The maxiof the TNFR super family). The end result is the activation or inhibition of 16 mum tolerated dose (MTD) was 1.8 mg/kg, and the dose-limiting toxicity NFκB activity, leading to cell proliferation or apoptosis. (DLT) was grade 4 thrombocytopenia. Tumor reduction was observed in 86% Initial clinical studies evaluated naked antibodies targeting CD30 (MDXTargetedHC.com

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CD30-Positive Lymphoma Table 1. Clinical Trials and/or Observational Studies Evaluating the Antitumor Activity of Brentuximab Vedotin in Relapsed/Refractory CD30-Positive Lymphoma Author

Study Design

Patient Population

Response

PFS/OS/DR

Younes et al

Phase I dose escalation; SGN-35 given at dosages ranging from 0.1 mg/kg to 3.6 mg/kg every 21 days

Relapsed/refractory CD30+ hematologic malignancies (N = 45)

ORR = 54% CRR = 39% PRR = 14%

DR = 9.7 mo PFS = 5.9 mo

Younes et al23

Phase II; SGN-35 1.8 mg/kg every 21 days

Relpsed/refractory HL (N = 102)

ORR = 75% CRR = 34%

PFS = 5.6 mo DR = 20.5 mo

Pro et al24

Phase II; SGN-35 1.8 mg/kg every 21 days

Relapsed/refractory ALCL (N = 50)

ORR = 86% CRR = 57%

PFS = 13.3 mo DR = 12.6 mo

Fanale et al25

Phase I, dose escalation; SGN-35 given at doses ranging from 0.4 mg/kg to 1.4 mg/kg every 28 days on days 1, 8, and 15

Relapsed/refractory CD30+ hematologic malignancies (N = 44)

ORR = 59% CRR = 34%

DR = NR at 45 wk

Chen et al26

Case series; patients treated with SGN-35 standard-dose schedule

Relapsed/refractory HL (N = 18)

ORR = 77% CRR = 33% RR reported prior to RIC allo BMT

1-yr PFS = 92.3% 1-yr OS = 100%

HL = Hodgkin lymphoma; ALCL = anaplastic large cell lymphoma; SGN-35 = brentuximab vedotin; ORR = overall response rate; CRR = complete response rate; PRR = partial response rate; RR = response rate; RIC allo BMT = reduced-intensity conditioning allogeneic bone marrow transplant; PFS = progression-free survival; DR = duration of response; mo = months; OS = overall survival.

of evaluable patients (36/42); objective clinical responses were noted in 17 patients (including 12 patients achieving a complete response [CR]). The median duration of response was 9.7 months for the entire group of patients and 17.3 months for patients with objective responses. The median progressionfree survival (PFS) was 5.9 months for all patients.22 Subsequently, a pivotal phase II study of brentuximab vedotin in patients with relapsed/refractory HL reported similar results.23 All patients (N = 102) had failed HDC-ASCT and had a median of 3.5 prior treatments. Patients received brentuximab vedotin at 1.8 mg/kg intravenously every 3 weeks until disease progression, prohibitive toxicity, or up to a maximum of 16 infusions. The ORR was 75% (76/102) with 34% of the patients achieving a CR (35/102). Partial response (PR) was observed in 40% of the patients. The median time to objective response was 5.7 weeks, and the median time to achieve a CR was 12 weeks. The median PFS was only 5.6 months for all patients and 20.5 months for those patients who achieved a CR. For the most part, brentuximab vedotin was well tolerated. The toxicity profile was similar to other brentuximab vedotin studies (Table 2). The median number of cycles administered was 9 (range, 1-16). The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, neutropenia, diarrhea, and fatigue. The only clinically relevant grade 3 or higher adverse event noted was neuropathy (8%). Only two patients discontinued treatment due to adverse events, and treatment delay due to neutropenia was observed in 16% of patients. Parallel to the HL pivotal study, brentuximab vedotin was formally evaluated in patients with relapsed/refractory ALCL. Pro et al24 reported the results of a phase II study. A total of 58 patients with pretreated ALCL (median number of previous treatments was 2) received brentuximab vedotin at the standard dose of 1.8 mg/kg every 21 days for up to 16 cycles, until disease progression, or until unacceptable toxicity. Objective response was observed in 86% of the patients, and 57% of the patients achieved a CR. The median duration of response was 12.6 months. Toxicity was similar to what had been observed in prior clinical trials, with only 24% of patients discontinuing treatment due to adverse events. The most common grade 46 / 11.12

3-4 adverse events were peripheral neuropathy, neutropenia, and thrombocytopenia (Table 2). Based on these three clinical studies, brentuximab vedotin received FDA approval for the treatment of relapsed/refractory HL and ALCL. While the overall response rates (ORRs) and CR rates for brentuximab vedotin are higher than second- or third-line chemotherapy agents, historical controls, or other novel agents tested in clinical studies, the duration of response is rather short, further stressing the need to develop strategies to optimize this agent in the management of relapsed/refractory HL or ALCL. Two strategies have been tested recently with various degrees of success. Fanale et al25 conducted a phase I study to determine the MTD and DLT of brentuximab vedotin administered on a weekly dosing schedule in hematologic malignancies. A total of 44 patients (38 HL patients) with relapsed/refractory CD30-positive hematologic malignancies received weekly brentuximab vedotin at dosages ranging between 0.4 mg/kg to 1.4 mg/kg. The MTD was observed at the 1.2-mg/kg dose level, and grade 3 peripheral neuropathy was found to be the DLT. Clinically significant neuropathy was observed in 66% of the patients. In contrast to prior clinical studies with brentuximab vedotin administered on a 21-day cycle, the median time to onset of neuropathy was shorter, and its severity was higher in the weekly dosing schedule. On the other hand, the response rate was similar to prior brentuximab vedotin studies (ORR = 59%). Based on this study, it appears that the standard 21-day schedule of administration confers the best antitumor activity with the lowest incidence of grade 3 hematologic and nonhematologic toxicities. Given the higher incidence of CR rates, brentuximab vedotin has been evaluated as a therapeutic strategy in preparation for reduced-intensity conditioning (RIC) allogeneic bone marrow transplant in patients with relapsed/refractory HL who had previously failed HDC-ASCT. Chen et al26 reported the clinical outcome of 18 patients with relapsed/refractory HL treated with brentuximab vedotin followed by RIC allogeneic bone marrow transplant. All but one patient had failed HDC-ASCT prior to enrollment and received brentuximab vedotin 1.8 mg/kg every 21 days. The duration The International Journal of TargetedTherapies in Cancer

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Clinical Pearls of brentuximab vedotin was at the discretion of the treating physician, but the median number of cycles prior to RIC allogeneic bone marrow transplant was 7 (range, 2-16). Significant antitumor activity was observed in this heavily pretreated group of patients (median number of prior treatments was 4.5); 14 patients exhibited tumor regression prior to RIC allogeneic bone marrow transplant. Six patients achieved a CR, and 8 patients achieved a PR. The 1-year survival post-RIC allogeneic bone marrow transplant was 100%, and the PFS was 92.3%. Brentuximab vedotin did not appear to adversely affect engraftment, graft-versus-host disease (GVHD) rates, or survival. The incidence of acute (27.8%) and chronic (56.3%) GVHD did not appear to be any different from historical controls.26 Currently, a randomized, double blind, placebo-controlled phase III study is evaluating brentuximab vedotin versus placebo in patients at high risk for residual disease after HDC-ASCT (NCT01100502).27 Brentuximab vedotin in combination with standard chemotherapy (ABVD) is now being evaluated in patients with newly-diagnosed HL stage IIA-IV (NCT01060904).28 Additional clinical studies are determining the antitumor activity of brentuximab vedotin in other CD30-positive malignancies (eg, subtypes of DLBCL, transformed mycosis fungoides). Ongoing preclinical and clinical studies are focusing on: (1) correlating the CD30 surface levels and antitumor activity of brentuximab vedotin in

• Brentuximab vedotin is a novel antibody-drug conjugate targeting the CD30 antigen, with significant activity in relapsed/refractory HL and ALCL. • A high response rate, including meaningful complete remission, has been observed in clinical trials. • Brentuximab vedotin has an excellent toxicity profile with minimal grade 3-4 hematologic and nonhematologic adverse events observed. • The limited duration of response observed in relapsed/refractory CD30positive lymphomas stresses the need for additional preclinical and clinical research in order to further optimize this novel agent.

hematologic malignancies; (2) evaluating the safety of brentuximab vedotin retreatment for previously responding patients; (3) combining brentuximab vedotin with systemic chemotherapy agents; (4) evaluating its antitumor activity in different clinical settings (eg, front-line therapy in combination with chemotherapy, front-line therapy as single agent for elderly or unfit patients, in the posttransplant setting for high risk patients). In summary, brentuximab vedotin is emerging as a potent, clinically active, and well-tolerated targeted agent for the management of relapsed/refractory CD30-positive HL and ALCL. Significant scientific and clinical efforts were dedicated to the successful development of this ADC, and the results observed in early clinical trials are paving the way for subsequent development of other ADCs for the management of hematologic Table 2. Summary of the Toxicity Profile of Brentuximab Vedotin in Clinical Studies and solid tumor malignancies. While the Most Common Median antitumor activity of brentuximab vedoHematologic and Number tin has been well established, additional Nonhematologic of Cycles Treatment studies are needed to further optimize its Author Toxicities Grade 3-4 Toxicities (range) Discontinuation antitumor activity and to further identify Younes et al22 Fatigue (36%) Thrombocytopenia NR 27% of patients additional subtypes of patients with CD30CD30 + relapsed/ Fever (33%) Neutropenia positive malignancies who may benefit refractory Diarrhea (22%) Hyperglycemia hematologic Nausea (22%) from this novel and exciting ADC. malignancies

Neutropenia (22%) Neuropathy (22%)

Younes et al23 relapsed/ refractory HL

Fatigue (34%) Fever (14%) Diarrhea (18%) Nausea (35%) Neutropenia (19%) Neuropathy (42%)

Neuropathy (8%) Laboratory abnormalities

9 (1-16)

20 patients

Pro et al24 relapsed/refractory ALCL

Fatigue (38%) Fever (34%) Diarrhea (29%) Nausea (40%) Neutropenia (21%) Neuropathy (41%)

Neutropenia (21%) Thrombocytopenia (14%) Neuropathy (12%) Anemia (7%)

8 (1-16)

24% of patients

Fanale et al25 relapsed/refractory CD30+ malignancies

Fatigue (52%) Fever (25%) Diarrhea (32%) Nausea (50%) Neuropathy (66%)

Neutropenia (7%) Neuropathy (14%) Anemia (7%)

4 (1-12)

8 patients

REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29. 2. Alas S, Emmanouilides C, Bonavida B. Inhibition of interleukin 10 by rituximab results in downregulation of bcl-2 and sensitization of B-cell nonHodgkin’s lymphoma to apoptosis. Clin Cancer Res. 2001;7:709-723. 3. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825-2833. 4. Piro LD, White CA, Grillo-Lopez AJ, et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol. 1999;10:655-661. 5. Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999;17:268-276.

HL = Hodgkin’s lymphoma; ALCL = anaplastic large cell lymphoma; SGN-35 = brentuximab vedotin; NR = not reported.

TargetedHC.com

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CD30-Positive Lymphoma 6. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106:3725-3732. 7. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as firstline treatment for advanced follicular lymphoma. Blood. 2005;105:1417-1423. 8. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group (GLSG). Blood. 2006;108:4003-4008. 9. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 10. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379-391. 11. Czuczman MS, Weaver R, Alkuzweny et al. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004;22:4711-4716. 12. Okeley NM, Miyamoto JB, Zhang X, et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res. 2010;16:888-897. 13. Gruss HJ, Pinto A, Gloghini A, et al. CD30 ligand expression in nonmalignant and Hodgkin’s disease-involved lymphoid tissues. Am J Pathol. 1996;149:469-481. 14. Pinto A, Aldinucci D, Gloghini A, et al. Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin’s disease cell line. Blood. 1996;88:3299-3305. 15. Durkop H, Foss HD, Eitelbach F, et al. Expression of the CD30 antigen in non-lymphoid tissues and cells. J Pathol. 2000;190:613-618. 16. Duckett CS, Gedrich RW, Gilfillan MC, Thompson CB. Induction of nuclear factor kappaB by the CD30 receptor is mediated by TRAF1 and TRAF2. Mol Cell Biol. 1997;17:1535-1542. 17. Forero-Torres A, Leonard JP, Younes A, et al. A Phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol. 2009;146:171-179.

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18. Blum KA, Jung SH, Johnson JL, et al. Serious pulmonary toxicity in patients with Hodgkin’s lymphoma with SGN-30, gemcitabine, vinorelbine, and liposomal doxorubicin is associated with an FcgammaRIIIa-158 V/F polymorphism. Ann Oncol. 2010;21:2246-2254. 19. Ansell SM, Horwitz SM, Engert A, et al. Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin’s lymphoma and anaplastic large-cell lymphoma. J Clin Oncol. 2007;25:2764-2769. 20. Oflazoglu E, Kissler KM, Sievers EL, et al. Combination of the anti-CD30-auristatin-E antibody-drug conjugate (SGN-35) with chemotherapy improves antitumour activity in Hodgkin lymphoma. Br J Haematol. 2008;142:69-73. 21. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102:1458-1465. 22. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363:1812-1821. 23. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30:2183-2189. 24. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30:2190-2196. 25. Fanale MA, Forero-Torres A, Rosenblatt JD, et al. A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies. Clin Cancer Res. 2011;18:248-255. 26. Chen R, Palmer JM, Thomas SH, et al. Brentuximab vedotin enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed or refractory Hodgkin lymphoma. Blood.2012;119:6379-6381. 27. ClinicalTrials.gov. A phase 3 study of brentuximab vedotin (SGN-35) in patients at high risk of residual Hodgkin lymphoma following stem cell transplant (The AETHERA Trial). Available at: http://clinicaltrials.gov/ct2/show/NCT01100502?term=NCT01100502&rank=1. Accessed July 10, 2012. 28. ClinicalTrials.gov. A phase 1 study of brentuximab vedotin combined with multi-agent chemotherapy for Hodgkin lymphoma. Available at: http://clinicaltrials.gov/ct2/show/NCT010609 04?term=NCT01060904&rank=1. Accessed July 10, 2012.

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

For For more For more more information, information, information, please please please contact contact contact the the Pfi the Pfi zerzer Pfi Oncology zer Oncology Oncology Clinical Clinical Clinical Trial Trial Information Trial Information Information Service Service Service at:at: at: 1-877-369-9753 1-877-369-9753 1-877-369-9753 in in the the inUnited the United United States States States and and Canada and Canada Canada (toll-free) (toll-free) (toll-free) +1-646-277-4066 +1-646-277-4066 +1-646-277-4066 outside outside outside the the United the United United States States States For For more For more more information, information, information, please please please visit visit www.pfi visit www.pfi www.pfi zercancertrials.com zercancertrials.com zercancertrials.com oror www.clinicaltrials.gov www.clinicaltrials.gov or www.clinicaltrials.gov (NCT01360554) (NCT01360554) (NCT01360554) * Stratifi * Stratifi *ed Stratifi ed by histology byedhistology by histology (adenocarcinoma (adenocarcinoma (adenocarcinoma vs non-adenocarcinoma), vs non-adenocarcinoma), vs non-adenocarcinoma), race race (Asian race (Asian vs (Asian non-Asian vs non-Asian vs non-Asian andand and Indian Indian subcontinent), Indian subcontinent), subcontinent), ECOG ECOG performance ECOG performance performance status status score status score (0-to-1 score (0-to-1 (0-to-1 vs 2), vs 2), smoking vssmoking 2), smoking status status (never-smoker status (never-smoker (never-smoker vs vs vs everever smoker). ever smoker). smoker). NSCLC NSCLC NSCLC = non-small = non-small = non-small cellcell lung lung cell cancer; lung cancer; cancer; ECOG ECOG = ECOG Eastern = Eastern = Eastern Cooperative Cooperative Cooperative Oncology Oncology Oncology Group. Group. Group. Reference: Reference: Reference: 1. Data 1. Data 1. onData on file.fiPfi on le. zer Pfi file.zer Inc, PfiInc, zer New New Inc, York, New York, NY. York, NY. NY. ThisThis information This information information is current is current is current as of as October ofasOctober of October 2011. 2011. 2011.

Dacomitinib Dacomitinib Dacomitinib (PF-00299804) (PF-00299804) (PF-00299804) is is anan is investigational an investigational investigational compound compound compound

PFW PFW 00029-B PFW 00029-B 00029-B

All All rights rights Allreserved. rights reserved. reserved.

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PEER RE VIEWED

Myeloproliferative Neoplasms

Prepare to Attack JAK

Managing Myeloproliferative Neoplasm Constitutional Symptoms Holly L. Geyer, MD, and Ruben A. Mesa, MD Philadelphia chromosome-negative myeloproliferative neoplasms have long been recognized for their burdensome symptom profiles and their adverse impact on both quality of life and life expectancy. For years, treatment options have provided minimal relief for the broad range of symptoms experienced by patients. The era of direct JAK-2 inhibition has opened new doors for direct symptom management and potential alteration of disease course. A B S T R A C T

Polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are recognized subclasses of myeloproliferative neoplasms (MPNs).1 Though each manifests through a unique set of symptoms, all carry burdensome symptom profiles that compromise both quantity and quality of life. Symptom severity is greatest in primary and antecedent ET and PV myelofibrosis.2 The discovery in 2005 of the JAK2V617F mutation in MF (occurring in 50% of patients), PV (95%), and ET (50%) was a key discovery for MPN researchers who had long been searching for a cohesive pathway explaining disease development. Prior to its discovery, treatment options for MPN symptoms were limited, carrying secondary toxicities of their own. The addition of JAK-2 inhibitors to the therapeutic armory has revolutionized our ability to intervene at the nidus of symptom development and mitigate the deleterious courses that characterize MPNs. Disease Development Under normal circumstances, the Janus kinase (JAK) receptors function to promote hematogenous cell line differentiation and proliferation. Through complex intracellular signaling pathways, they activate signal transducer activator of transcription (STAT) factors, which, in turn, upregulate genes functioning in cellular differentiation and proliferation. The JAK2V617F mutation results in a persistently activated molecule, rendering cells with cytokine-independent growth capabilities.3 The result is indiscriminate proliferation of hematogenous cell lines. JAK2 inhibitors target Janus kinase 2 via competitive inhibition with ATP at the ATP-binding catalytic site, preventing constitutive signaling. Given that JAK2 inhibitors disrupt cell signaling early in the pathway, their downstream effects on symptoms are extensive. Collective attempts to unifocally attack JAK have opened a new era of gene-targeted therapies boasting improvements in symptom management with limited secondary toxicities. In the following sections, we discuss the most prevalent MPN symptoms and the efficacy of JAK-2 inhibitors in addressing them.

Holly L. Geyer, MD Department of Hospital Internal Medicine, Mayo Clinic, Scottsdale, AZ

Corresponding Author: Ruben A. Mesa, MD Professor of Medicine, Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ; Mesa.ruben@mayo.edu 50 / 11.12

Splenomegaly Splenomegaly can be source of numerous MF symptoms.4 In addition to debilitating abdominal pain from both visceral compression and splenic infarcts, splenomegaly may lead to early satiety, bloating, weight loss, portal hypertension, and life-threatening cytopenias. The historical treatment of choice has been hydroxyurea, demonstrating relief in up to 40% of patients.5 Hydroxyurea-resistant patients may be candidates for cladribine, busulfan, and melphalan. Immunomodulatory agents (thalidomide, lenalidomide, pomalidomide) have shown increased response rates by 33%, and appear to work uniquely well in the setting of concomitant cytopenias when combined with steroids.6 Splenectomy offers the greatest symptomatic benefit, with improvements seen in up to 75% of The International Journal of TargetedTherapies in Cancer

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A R T I C L E S

Clinical Pearls patients in the areas of abdominal pain, transfusion dependency, and thrombocytopenia.7 Its application is, however, limited to MF patients with marked splenomegaly and acceptable performance status. The procedure has furthermore failed to demonstrate efficacy in promoting survival or altering disease course. The first evidence of the effectiveness of JAK2 inhibition was demonstrated in the COMFORT-I 8 and COMFORT-II9 trials of ruxolitinib, which were the prequel to FDA approval of the drug for treatment of intermediate- to high-risk MF. In COMFORT-I, ruxolitinib was shown to reduce splenic size by more than 35% in 41% of patients at 24 weeks of therapy.8 The COMFORT-II trial similarly showed 32% of patients achieving splenic reduction of more than 35% at 24 weeks.9 SAR302503 (TG101348), a more selective JAK2 inhibitor than ruxolitinib, demonstrated a 47% splenic response rate by 12 cycles of treatment, despite minimal effect on cytokine levels.10 Pacritinib (SB1518) also showed a 44% response rate, with a more than 50% reduction in palpable splenomegaly. A study of CYT387 found similar results (45%).11,12 Given their robust effectiveness, JAK2 inhibitors have emerged as the treatment of choice for splenomegaly in patients who qualify. Symptomatic responses were also observed. In a phase I/II study of ruxolitinib, 52% of patients experienced an improvement in abdominal pain or discomfort within one month of initiating treatment, and results persisted for six months.13 Fatigue The most commonly cited MPN-associated complaint (93%), fatigue is a universal symptom that remains exceptionally difficult to treat.14 Its complex origins, including elevated circulating cytokines, anemia, treatment toxicity (hydroxyurea and anagrelide), and tumor-related cachexia, make tailoring treatment difficult. Questionnaires capturing the severity of fatigue have focused on fatigue symptoms, as well as performance status and exercise capacity. The burden of fatigue in MPNs was captured in a 2007 international Internet-based survey of 1179 MPN patients that determined that fatigue was present across the spectrum of disease severity, and was independent of age or comorbidity.15 Historical treatment approaches have focused only on symptom management. Although not routinely applied, stimulants, including methylphenidate, armodafinil, and modafinil, have provided occasional benefit at the expense of deleterious psychoactive and cardiovascular side effects that further compound age-related comorbidities. JAK-2 inhibitors were the first drug class to gain FDA approval for the treatment of MPN-related fatigue, and arguably remain the best therapy for it. In a phase I/II study, 27 patients taking ruxolitinib underwent a 6-minute walk test and improved their ability to walk by 34 meters after one month, 57 meters after three months, and 71 meters after six months of therapy.13 In the COMFORT-1 study, 25.2% of patients reported fatigue while taking ruxolitinib versus 33.8% of patients on placebo.8 In COMFORTII, ruxolitinib was shown to provide a 12.8% improvement in fatigue.9 Other JAK2 inhibitors have also shown benefit in alleviating fatigue. SAR302503 (TG101348) demonstrated improvement in 63% of symptomatic patients after six cycles of treatment, with 25% reporting complete resolution.10 JAK2 inhibitors, in combination with lifestyle modifications, appear to offer the greatest therapeutic effect in treating MPN-related fatigue. TargetedHC.com

• Myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are recognized for their burdensome symptom profiles. • MPNs carry the JAK2V617F mutation, which leads to unregulated cellular differentiation and proliferation with cytokine-independent growth capabilities. • MPN symptoms include splenomegaly, abdominal pain, early satiety, fatigue, pruritis, fevers, and night sweats. • Discovery of the JAK2 mutation in MPNs has led to new therapeutic advancements boasting greater efficacy for symptom treatment over standard treatment efforts. • JAK2 inhibitors have demonstrated improved efficacy in reducing splenomegaly and constitutional symptoms over standard treatment options.

Pruritus Usually described as itching, burning, or tingling, this disabling symptom is common with MPNs. Although most frequently reported by PV patients (69%), it is also well recognized in patients with ET (39%) and PMF (50%). The mechanisms that initiate its development remain obscure but may be related to JAK2V617F -induced constitutive activation via agonist hypersensitivity in basophils. Treatments have historically involved antihistamines with variable results. Some trials tout success rates of up to 66%, while others fail to demonstrate benefit.16,17 Interferon-alfa has also been applied with success in up to 81% of patients. Correction of underlying erythrocytosis may offer relief, along with the addition of selective serotonin reuptake inhibitors (SSRIs). Fluoxetine, in particular, has resulted in complete resolution of symptoms in 80% of patients within 48 hours of administration.18 Given their anti-inflammatory effects, JAK2 inhibitors hold theoretical potential to assuage pruritus. Although formal studies are limited, the drugs have displayed some level of efficacy in this area. In the COMFORT-I trial, the mean reduction in pruritus from baseline according to symptom scoring was 42.8%.8 TG101348 has also shown benefit in pruritus, with improvements occurring even prior to improvements in hematologic parameters.19 SAR302503 (TG101348) demonstrated effectiveness in 75% of affected patients, with 50% reporting complete resolution with durable responses.10 Data for SB1518 and CYT387 have yet to be reported. Thus, preliminary data suggest JAK-2 inhibitors work well for pruritus and should be considered for use either singly or in conjunction with other effective therapies, such as SSRIs. Fever/Night Sweats Fever and night sweats are bothersome constitutional symptoms described by up to 20% of patients with MPN. Circulating cytokines, including interferon-gamma, TNF-alpha, and interleukin-6, are significantly elevated in MPN populations, likely accounting for the development of fever and night sweats. Management has been limited to antipyretics with mixed results. Accordingly, hydroxyurea, anagrelide, and interferon-alfa have failed to demonstrate sustainable relief. (continued on page 55) 11.12 / 51

In advanced prostate cancer

TREAT FIRST LINE WITH PROVENGE TO PROVENGE

Activate PROVENGEactivated T cells

Resting T cell

T-cell activation

Amplify Activated T cell attacks prostate cancer

Attack Prostate cancer cell cell Prostate cancer

EXTEND SURVIVAL

OVERALL SURVIVAL BENEFIT OF PROVENGE1,2 PROVENGE (n=341)

100

Control* (n=171) PROVENGE (n=341)

100

Control (n=171)

22.5%

25.8

75 Survival (%)

Survival (%)

RISK REDUCTION

months 25.8

months

21.7

months 21.7 21.7 months

months21.7

months

HR=0.775 HR=0.775

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

0 0

12 24

012

24 36 36

4848

60 60

72 72

Time From Randomization (Months)

*64% of patients in the control group, following progression, crossed over to a nonrandomized, open-label protocol to receive an investigational autologous immunotherapy made from cryopreserved cells. Data originally published in The New England Journal of Medicine: 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 1 1

Extends median survival beyond 2 years1 years

and only

line

First and only FDA-approved immunotherapy for advanced prostate cancer First-line treatment for men with asymptomatic or minimally symptomatic metastatic CRPC (NCCN Category 1 recommendation) 3

INDICATION: PROVENGEÂŽ (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence â&#x2030;Ľ15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache. For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages.

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.)

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Myeloproliferative Neoplasms

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

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

A R T I C L E S

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.

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JAK-2 inhibitors yet again show benefits in yielding pluripotent systemic effects, in part through cytokine reduction. In the COMFORT-I study, the mean change in night-sweat symptom scores from baseline was 51% in patients taking ruxolitinib.8 SAR302503 (TG101348) demonstrated improvement, with 64% of patients describing complete resolution of symptoms after just one cycle.10 This rose to 89% after six cycles of treatment. Studies of SB1518 and CYT387 have yet to release data regarding their efficacy. Conclusion JAK-2 inhibitors have taken center stage in the MPN arena, with potent evidence demonstrating their palliative effects on disease-related symptoms. Much has yet to be learned about these unique agents and their long-term sustainability. However, as traditional therapies have proven inadequate, JAK-2 inhibitors represent the first great step at utilizing gene-targeted therapy to abate the disruptive signaling pathways that culminate in the MPN symptom profile. REFERENCES 1. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22(1):14-22. 2. Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer. 2007;109(1):68-76. 3. James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144-1148. 4. Koch CA, Li CY, Mesa RA, Tefferi A. Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc. 2003;78(10):1223-1233. 5. Sirhan S, Lasho TL, Hanson CA, et al. The presence of JAK2V617F in primary myelofibrosis or its allele burden in polycythemia vera predicts chemosensitivity to hydroxyurea. Am J Hematol. 2008;83(5):363-365. 6. Mesa RA, Steensma DP, Pardanani A, et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood. 2003;101(7):2534-2541. 7. Mesa RA, Nagorney DS, Schwager S, et al. Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic. Cancer. 2006;107(2):361-370. 8. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. 9. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. 10. Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011;29(7):789-796. 11. Komrokji RS, Wadleigh M, Seymour JF, et al. Results of a phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis. Presented at the 53rd Annual ASH Meeting; December 10-13, 2011; San Diego, CA. Blood. 2011;118:(suppl; abstr 282). 12. Pardanani AD, Caramazza D, George G, et al. Safety and efficacy of CYT387, a JAK-1/2 inhibitor, for the treatment of myelofibrosis. Presented at the 47th Annual American Society of Clinical Oncology Annual Meeting; June 4-8, 2011; Chicago, IL. J Clin Onc. 2011;29;(suppl; abstr 6514). 13. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117-1127. 14. Scherber R, Dueck AC, Johansson P, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood. 2011;118(2):401-408. 15. Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myelofproliferatve disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer. 2007;109(1):68-76. 16. Gilbert HS, Warner RRP, Wasserman LR. A study of histamine in myeloproliferative disease. Blood. 1966;28(6):795-806. 17. Reid CD. Pruritus preceding the development of polycythaemia vera. Lancet. 1988;2(8617):964. 18. Diehn F, Tefferi A. Pruritus in polycythaemia vera: prevalence, laboratory correlates and management. Br J Haematol. 2001;115(3):619-621. 19. Pardanani AD, Gotlib JR, Jamieson C, et al. A phase I evaluation of TG101348, a selective JAK2 inhibitor, in myelofibrosis: clinical response is accompanied by significant reduction in JAK2V617F allele burden [abstract]. Presented at the 51st American Society of Hematology Annual Meeting; December 5-8, 2009; New Orleans, LA. Blood. 2009;114:(suppl; abstr 755).

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Breast Cancer

Trastuzumab Emtansine (T-DM 1): A Novel and Effective Immunoconjugate for the Treatment of HER2+ Breast Cancer Jiali Li, MD, Alexa Glencer, and Hope S. Rugo, MD Trastuzumab-derivative A B S T R A C T of maytansine-1 (trastuzumab emtansine; T-DM1) is a novel antibody-drug conjugate that combines an antibody targeted specifically to HER2overexpressing cancer cells with maytansine, a potent cytotoxic agent. In comparison with lapatinib and capecitabine in patients with trastuzumab-resistant HER2+ advanced breast cancer, treatment with T-DM1 resulted in improved progression-free and overall survival, with a superior safety profile. Ongoing clinical trials are investigating T-DM1-based therapy in combination with other chemotherapy agents, with other targeted agents, and as treatment for early-stage HER2+ breast cancer and other malignancies.

Between 20% and 25% of all breast cancers overexpress the HER2/neu receptor or have amplification of the HER2 (ErbB2) gene, with about half also expressing the estrogen receptor. Before the introduction of targeted therapy, HER2-expressing (HER2+) breast cancers were associated with a high risk of short-term recurrence and shorter overall survival (OS).1,2 Trastuzumab, a humanized monoclonal antibody targeting the HER2/neu receptor, was approved by the FDA in 1998 for the treatment of HER2+ metastatic breast cancer (mBC),3,4 and in 2006 for the treatment of earlystage disease. In the advanced-disease setting, trastuzumab administered as monotherapy exerts a modest antitumor effect but has marked synergistic antiproliferative effects when combined with cytotoxic agents.5-7 Although trastuzumab combined with chemotherapy has become the standard of care for the treatment of HER2+ mBC, up to 50% of patients present with de novo resistance.8 Progression-free survival (PFS) following treatment with trastuzumab combined with taxane-based chemotherapy is only about 1 year.9,10 PFS can be extended to about 18 months with the addition of pertuzumab, a novel HER2-targeted antibody approved in this setting by the FDA in June 2012.11 Chemotherapy combined with trastuzumab in the early-stage setting has significantly improved disease-free survival (DFS) and OS; however, relapses continue to occur even years after initial treatment.6,7,12 In addition, improved OS in both early- and late-stage disease with trastuzumab has been seen only when the antibody is given in combination with chemotherapy, and hence, concomitant chemotherapy toxicity. Antibody-drug conjugates, which combine the specific targeting capacity of antibodies with the cytotoxic effects of highly potent fusion agents, offer a novel alternative that has the potential to both overcome resistance and reduce systemic toxicity. (See â&#x20AC;&#x153;Antibody-Drug Conjugates Target Drug Deliveryâ&#x20AC;? on page 34) To date, only brentuximab vedotin (Adcetris) has been approved by the FDA and is used in clinical practice for the treatment of Hodgkin lymphoma and anaplastic large-cell lymphoma, although multiple agents are being studied in clinical trials.

Drug Design and Preclinical Studies From the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA Corresponding Author: Hope S. Rugo, MD Professor of Medicine and Director, Breast Oncology and Clinical Trials Education, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Hrugo@medicine.ucsf.edu TargetedHC.com

Three challenges exist in the creation of an effective antibody-drug conjugate. These include identification of a target uniquely expressed in the cancer of interest, a cytotoxic agent with potency at low concentration, and a linker that can deliver a toxin to the cancer cell without releasing drug into the systemic circulation. HER2 is an ideal target for this approach, given that it is not overexpressed in the majority of normal cells (the heart being a notable exception), and overexpression is preserved in tumors progressing on trastuzumab-based therapy. Microtubule function is necessary for cell division, as well as for a number of other essential functions. Drugs that interfere with this function are 11.12 / 57

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Breast Cancer effective cytotoxic agents and are highly active in the treatment of breast cancer. Both paclitaxel and docetaxel have demonstrated preclinical synergy, as well as significant antitumor efficacy when given in combination with trastuzumab for the treatment of HER2+ breast cancer.10,13 Maytansinoids, which are derivatives of the antimitotic drug maytansine, represent a novel class of agents that disrupt microtubule function. These agents bind directly to microtubules to inhibit polymerization in a manner similar to the vinca alkaloids. Efforts to develop maytansine into a clinically useful anticancer drug proved disappointing due to severe toxicities in phase II trials.14 Antibodydrug conjugates offer a means of introducing a highly potent drug while reducing systemic toxicity by allowing delivery of a small dose of cytotoxic agent directly to cancer cells, making maytansine an ideal choice for this purpose. The linker selected to bridge antibody and toxin must be capable of maintaining molecular stability while in circulation but must be amenable to proteolytic cleavage once inside cancer cells.15 The thioether (MCC) linker protein (Figure), which contains a cyclohexane carboxylate spacer, was found after considerable research to fit both requirements and was selected as the conjugate linking trastuzumab to a derivative of maytansine to create trastuzumab-MCC-DM1 (T-DM1).16 T-DM1 is internalized upon binding to HER2+tumor cells and is postulated to then undergo intracellular proteolytic degradation to release active maytansinoid (lysine-NεMCC-DM1). Since it is a zwitterion (a neutral molecule with a positive and a negative electrical charge at different locations within that molecule), lysine-Nε-MCC-DM1 does not readily cross the plasma membrane of adjacent normal cells, which limits nontarget toxicity.

Figure. Schematic of Trastuzumab-DM1 (T-DM1) with MCC ([N- maleimidomethyl] Cyclohexane-1-Carboxylate) Linker

DM1 (derivitive of maytansine)

MCC (Linker)

Trastuzumab

In vivo, T-DM1 has been shown to selectively inhibit cell growth and induce cell death in HER2+ cancer cell lines. In addition, T-DM1 has been shown to inhibit growth and cause tumor regression in HER2+ breast cancer xenograft animal models.17

Clinical Studies

In the first-in-human phase I study, 24 heavily pretreated patients with HER2+ mBC who had previously progressed on trastuzumab received T-DM1 every 3 weeks in dosages ranging from 0.3 mg/kg to 4.8 mg/kg.18 The maximum tolerated dose (MTD) was determined to be 3.6 mg/kg; the dose-limiting toxicity was transient grade 3 thrombocytopenia. Table 1. Featured Completed Studies on T-DM 1 Among the 15 patients who received the MTD, the clinical benAuthor Phase Trial Design Results efit rate (CBR) was 73%, and the Burris20 II Single-arm, T-DM1; ORR: 37.5% objective response rate (ORR) 112 pts with HER2+ mBC PFS: 4.6 mo was 44%. In a second phase I progressed on T-based CTX DOR: 9.4 mo study exploring weekly dosing of 21 Krop II Single arm T-DM1; ORR: 34.5% T-DM1, the MTD was determined 110 pts with HER2+ mBC CBR: 48.2% to be 2.4 mg/kg; ORR was 46%, Prior treatment with T, L, A, PFS: 6.9 mo TAX & C DOR: 7.2 mo CBR was 57%, and median duration of response (DOR) was 18.6 Hurvitz22 II Randomized, open-label ORR: 64% T-DM1 vs 58% D/T months.19 In both trials, T-DM1 T-DM1 vs D/T in the PFS: 14.2 mo T-DM1 vs 9.2 mo 1st-line setting; D/T (HR = 0.59 (0.36, 0.97); P =.035) was relatively well tolerated (see 137 pts with HER2+ mBC DOR: NR T-DM1 vs 9.5 mo D/T “Toxicities” section below). Verma24 III Randomized, open-label PFS: 9.6 mo T-DM1 vs 6.4 mo L/C (HR = 0.65 (0.55, 0.77); P <.001) Based on these remarkable TDM-1 vs L + C , 2nd line OS (331 deaths): 30.9 mo T-DM1 vs 25.1 mo L/C (HR = 0.68, P <.001) results, two sequential phase following trastuzumab/ CTX ORR: 43.6% T-DM1 vs 30.8% L/C (P <.001) II studies exploring dosing of 991 pts with HER2 mBC DOR: 12.6 mo T-DM1 vs 6.5 mo L/C T-DM1 every 3 weeks were conDiéras28 I Single-arm, T-DM1 + P; ORR: 1st line: 42% (19/45 pts); ducted in over 100 patients with 67 pts with HER2+ mBC previous treatment with T: 41% (9/22 pts) heavily pretreated HER2+ mBC. Beeram19 I Multicenter, open-label, MTD: 2.4 mg/kg (weekly dosing) The first trial included patients weekly T-DM1 doseORR: 46.4 (13/28 pts) progressing on prior trastuescalation study, DOR: 16.6 mo zumab and chemotherapy,20 28 pts with HER2+ mBC CBR: 57.1% (6 mo) and the second trial included T-DM1 = trastuzumab emtansine; mBC = metastatic breast cancer; ORR = objective response rate; PFS = progression-free survival; CTX = chemotherapy; patients progressing on trastuDOR = duration of response; CBR = clinical benefit rate; T = trastuzumab; L = lapatinib; A = anthracycline; TAX = taxane; C = capecitabine; D = docetaxel; NR = not reported; HR = hazard ratio; OS = overall survival; P = pertuzumab; survival; pts = patients; MTD = maximum tolerated dose; mo = months. zumab, the oral tyrosine kinase 58 / 11.12

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Breast Cancer Table 2. Selected Toxicities Associated With T-DM1 Compared

With Lapatinib Plus Capecitabine from the EMILIA trial inhibitor lapatinib, taxanes, anthracyclines, and capecitabine.21 In the first trial, ORR was 37.5% Lapatinib + Capecitabine T-DM1 and PFS was 4.6 months, with a median DOR of Adverse Event All Grades, % Grade ≥ 3, % All Grades, % Grade ≥ 3, % 9.4 months. In the second trial, results were similar despite the extensive prior treatment, with an Diarrhea 79.7 20.7 23.3 1.6 ORR of 34.5%, CBR of 48.2%, PFS of 6.9 months, HFS 58.0 16.4 1.2 0 and median DOR of 7.2 months. Vomiting 29.3 4.5 19 0.8 These trials enrolled patients who had previHypokalemia 8.6 4.1 8.6 2.2 ously progressed on trastuzumab-based therapy 22 and chemotherapy. Hurvitz and colleagues Nausea 44.7 2.5 39.2 0.8 reported a randomized, phase II study that comMucosal inflammation 19.1 2.3 6.7 0.2 pared T-DM1 to the combination of docetaxel and Increased AST 9.4 0.8 22.4 4.3 trastuzumab as first-line therapy for 137 patients with treatment-naïve HER2 + mBC. Preliminary Increased ALT 8.8 1.4 16.9 2.9 results, which were reported at the European Thrombocytopenia 2.5 0.2 28.0 12.8 Society for Medical Oncology (ESMO) meeting in AEs leading to treatment discontinuation 10.7 5.9 2011, demonstrated a significant improvement in both ORR and PFS in patients treated in the LVEF <50% and ≥ decrease from baseline 1.6 1.7 T-DM1 arms compared with those treated with T-DM1 = trastuzumab emtansine; HFS = hand-foot syndrome; AST = aspartate aminotransferase; ALT = alanine aminotransferase; AEs = adverse events; LVEF = left ventricular ejection fraction. docetaxel and trastuzumab (Table 1). Interestingly, there was less toxicity in the T-DM1 arm, as detailed in the “Toxicities” section. Results of the first phase III trial to demonstrate superiority of T-DM1 was transient thrombocytopenia, with the most common grade 3 toxicities compared with standard therapy were recently presented at the American being transaminitis and thrombocytopenia. The phase II trials reported Society of Clinical Oncology meeting in June 2012.23 EMILIA is a randomized, an 8% rate of grade 3/4 thrombocytopenia20 and a 6% rate of grade 3/4 phase III study comparing T-DM1 (3.6 mg/kg every 3 weeks) to capecitabine transaminitis.21 plus lapatinib in nearly 1000 patients with advanced breast cancer proIn the recently reported EMILIA phase III trial, 89% of patients in the gressing on trastuzumab and a taxane. The primary endpoint, PFS, was lapatinib/capecitabine arm experienced grade ≥3 adverse events, comsignificantly longer in patients receiving T-DM1 compared with those treated pared with only 46% of patients in the T-DM1 arm; only 5.9% (29 patients) with capecitabine plus lapatinib (9.6 months vs 6.4 months; P < .001). With required treatment discontinuation due to toxicity in this arm compared the exception of the 138 patients older than age 65 years, this benefit was with 10.7% (52 patients) treated with lapatinib plus capecitabine (Table maintained across all subgroups. At the time of the initial presentation, OS 2).23 Both thrombocytopenia and transaminase elevation responded to was 23.3 months for the capecitabine and lapatinib group, while OS had not holding drug and dose reductions, when necessary. Patients treated with yet been reached in the T-DM1 group (hazard ratio [HR] = 0.621; P = .0005, lapatinib/capecitabine had a higher incidence of grade 3/4 diarrhea (20. not considered significant based on the EMILIA statistical plan). 7 vs 1.6%) and hand-foot syndrome (16.4 vs 0%). In contrast, grade 3/4 Updated survival results were presented at the ESMO meeting in Septhrombocytopenia was more common in patients treated with T-DM1 (12.8 tember 2012, and were published with the full study results on the same vs 0.2%) but rarely led to hemorrhage. Transaminases were increased day in The New England Journal of Medicine.24 At a median follow-up of more frequently with T-DM1 as well, but grade 3/4 elevations occurred in about 19 months, and after 331 deaths, OS was significantly longer in less than 5% of study patients. patients treated with T-DM1 compared with those treated with lapatinib Thrombocytopenia associated with T-DM1 has a predictable cyclical and capecitabine, reaching the prespecified study endpoint (30.9 vs 25.1 pattern; in most patients, platelet counts are lowest at day 8 and recover months, respectively; HR = 0.682; P < .001). Final survival data are exby day 18. The etiology of T-DM1–associated thrombocytopenia is not well understood, although a recent article describes a model that can be used pected in 2014. These data are summarized in Table 1. An application has been submitted to the FDA for T-DM1 based on these data, and approval is to predict the time course of this effect.25 Cardiotoxicity, which is known to be associated with HER2-targeted therapy, was not increased in the T-DM1 expected in late 2012 or early 2013. arm compared with the control arm (1.7% vs 1.6%, respectively).23 Patientreported outcomes documented a significantly shorter time to symptom Toxicities progression using the Functional Assessment of Cancer Therapy-Breast Since the targeted specificity of the antibody-drug conjugate design al(FACT-B ) Trial Outcome Index in patients treated with capecitabine and lows targeted delivery of highly potent cytotoxic agents, side effects are lapatinib versus T-DM1 (4.6 vs 7.1 months; HR = 0.8; P = .012). In addition, significantly moderate. In clinical trials, the most common adverse events and particularly important to patients with both advanced and early-stage in patients treated with T-DM1 were grade 1/2 fatigue and nausea. In the phase I trial, with dosing every 3 weeks, the dose-limiting toxicity of T-DM1 disease, treatment with T-DM1 is not associated with significant hair loss. 23

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Breast Cancer Clinical Pearls • When given as monotherapy, 3.6 mg/kg every 3 weeks, T-DM1 has demonstrated efficacy in patients with metastatic HER2+ breast cancer who were heavily pretreated with trastuzumab-based regimens, and in those who were trastuzumab-naïve. Most recently, T-DM1 has been shown to be superior to lapatinib and capecitabine, demonstrating less toxicity and improved response, progression-free survival, and overall survival in patients with progressive disease following first-line trastuzumab-based chemotherapy. • T-DM1 is well tolerated compared with standard chemotherapy, with unique side effects that include transient thrombocytopenia and elevated liver function tests. • Ongoing clinical studies are testing the safety and efficacy of T-DM1 in early-stage breast cancer and the feasibility of combining T-DM1 with both chemotherapy and other HER2-targeted agents in the advanceddisease setting.

setting. The ability of T-DM1 to overcome at least some aspect of resistance in advanced disease also makes the post-neoadjuvant setting appealing, as treatment for patients with extensive residual disease following neoadjuvant therapy containing trastuzumab. In addition, T-DM1 will be tested in HER2+ gastric cancer, another malignancy that benefits from HER2-targeted therapy.27

Conclusion Given on a dosing schedule of 3.6 mg/kg every 3 weeks, T-DM1 appears to be well-tolerated and has demonstrated marked clinical efficacy in patients with HER2+ mBC who have previously progressed on other HER2-targeted therapies. The expected approval of T-DM1 will change our approach to treating patients with HER2+ mBC, further improving therapeutic efficacy and reducing toxicity. Ongoing studies are anticipated to determine the efficacy of T-DM1 in combination with other HER2-targeted agents, in combination with chemotherapy, in early-stage disease, and in other HER2+ malignancies.

Ongoing Trials A number of clinical trials are being conducted in both the HER2+ earlystage and metastatic settings (Table 3). In these studies, T-DM1 is either given as a monotherapy or is combined with cytotoxic agents or other HER2-targeted therapy. One area of interest is treatment of small (T1b), node-negative, HER2+ breast cancers. Recent studies have reported a higher risk of recurrence in these tumors compared with patients with HER2-negative disease,26 but standard chemotherapy with trastuzumab seems potentially too aggressive for the extent of disease. The favorable toxicity seen with T-DM1 marks it as an attractive agent to study in this

REFERENCES 1. 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. 2. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707-712. 3. McNeil C. Herceptin raises its sights beyond advanced breast cancer. J Natl Cancer Inst. 1998;90(12):882-883. 4. Pegram MD, Lipton A, Hayes DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy

Table 3. Featured Ongoing Trials of T-DM1 Trial Name

Phase Patient Selection

Treatment

Endpoints

MARIANNE NCT01120184 (N = 1095)

III

First-line with HER2+ mBC or LABC (closed to accrual)

Randomize 1:1:1 to 3 arms T + taxane (open-label) vs T-DM1 + P (blinded) vs T-DM1 (blinded)

Primary: PFS + AEs Secondary: OS, ORR, DOR, TTF, CBR

TH3RESA NCT01419197 (N = 600)

III

Previously treated with HER2-targeted therapy (≥ 2 lines) HER2+ mBC or LABC

Randomized, open-label T-DM1 vs TPC

Primary: PFS, OS Secondary: ORR, CBR, DOR, AEs

NCT00928330 (N = 57)

T-pretreated pts with HER2+ mBC or LABC

Three-arm GDC-0941 (PI3K inhibitor) + T-DM1 GDC-0941 + T GDC-0941 alone

Primary: Toxicity, AEs Secondary: PK, PFS, ORR, DOR

NCT 00934856 (N = 50)

HER2+ mBC or LABC

Nonrandomized, open-label T-DM1 + D +/- P

Primary: DLT, AEs Secondary: PFS, ORR, CBR, DOR, TTF, PK

NCT 00951665 (N = 74)

Ib/IIa

HER2+ mBC or LABC

Single-arm, open-label T-DM1 + Pac +/- P

Primary: AEs, PK, DLT Secondary: ORR, PFS, CBR, DOR

Approved, not yet active II (N = 500)

Early-stage, small HER2+ BC

Non-randomized 3:1: T-DM1 vs. Pac + T

Primary: Toxicity, DFS

NCT 01641939 (N = 412)

Advanced gastric cancer

Phase II/III randomized T-DM1 (3.6 mg/kg every 3 weeks) vs T-DM1 (2.4 mg/kg weekly) vs taxane

Primary: OS Secondary: ORR, PFS, DOR, AEs, PK

II/III

T-DM1 = trastuzumab emtansine; PFS = progression-free survival; mBC = metastatic breast cancer; T = trastuzumab; AEs = adverse events; LABC = locally advanced breast cancer; P = pertuzumab; OS = overall survival; ORR = objective response rate; DOR = duration of response; TPC = treatment of physician’s choice; CBR = clinical benefit rate; pts = patients; DLT = dose-limiting toxicity; D = docetaxel; Pac = paclitaxel; BC = breast cancer; DFS = disease-free survival; TTF = time to treatment failure; PK = pharmacokinetics.

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Breast Cancer treatment. J Clin Oncol. 1998;16(8):2659-2671. 5. Pegram MD, Slamon DJ. Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity. Semin Oncol. 1999;26(4 suppl 12):89-95. 6. Perez EA, Romond EH, Sumanet VJ, al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011;29(25):3366-3373. 7. Slamon D, Eiermann W, Robert N, et al for the Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-1283. 8. Hurvitz SA, Hu Y, O’Brien N, Finn RS. Current approaches and future directions in the treatment of HER2-positive breast cancer. Cancer Treat Rev. Published online ahead of print May 31, 2012. 9. Slamon DJ, Leyland-Jones B, Shaket S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. 10. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005;23(19):4265-4274. 11. Baselga J, Cortés J, Kimet S-B, et al for the CLEOPATRA study group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119. 12. Gianni L, Dafni U, Gelber RD, et al, for the Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011;12(3):236-244. 13. Seidman AD, Fornier MN, Esteva FJ, et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol. 2001;19(10):2587-2595. 14. Annual Report to the FDA by DCT, NCI, on Maytansine. NSC 153858, IND 11857; February 1984. 15. Chari RV. Targeted delivery of chemotherapeutics: tumor-activated prodrug therapy. Adv Drug Deliv Rev. 1998;31(1-2):89-104. 16. Erickson HK, Park PU, Widdison WC, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66(8):4426-4433. 17. Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280-9290. 18. Krop IE, Beeram M, Modiet S, et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2010;28(16):2698-2704. 19. Beeram M, Krop IE, Burris HA, et al. A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer. Published online ahead of print May 30, 2012. doi:10.1002/cncr.27622. 20. Burris HA 3rd, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29(4):398-405. 21. Krop IE, Lorusso P, Miller KD, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2012;30(26):3234-3241. 22. Hurvitz S, Dirix L, Kocsiset J, et al. Trastuzumab emtansine (T-DM1) vs trastuzumab plus docetaxel (H+T) in previously-untreated HER2-positive metastatic breast cancer (MBC): primary results of a randomized, multicenter, open-label phase II study (TDM4450g/B021976). Eur J Cancer. 2011;47(suppl 330; abstr 5001). 23. Blackwell KL, Miles D, Giannet L, et al. Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. J Clin Oncol. 2012;30(18 suppl; LBA1). 24. Verma S, Miles D, Gianni L, et al for the EMILIA Study Group. Trastuzumab emtansine for HER2positive advanced breast cancer. N Engl J Med. Published online ahead of print October 1, 2012. 25. Bender BC, Schaedeli-Stark F, Koch R, et al. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer. Cancer Chemother Pharmacol. 2012;70(4):591-601. 26. Chia S, Norris B, Speers C, et al. Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol. 2008;26(35):5697-5704. 27. Bang YJ, Van Cutsem E, Feyereislova A, et al for the ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697. 28. Diéras V, Harbeck N, Albain K, et al. A phase Ib/II trial of trastuzumab-DM1 with pertuzumab for patients with HER2-positive, locally advanced or metastatic breast cancer: interim efficacy and safety results. Cancer Res. 2011;70(24 supplement):P3-14-01.

TargetedHC.com

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.

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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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TargetedHC.com provides content focused on nextgeneration therapeutics and their molecular targets. As the field of oncology continues to trend toward systemic biology and molecular aberrations, the challenge facing many oncologists is staying up-todate with cancer therapeutics. TargetedHC.com meets that challenge by providing oncology professionals with videos, interviews, peer-reviewed articles, and more on the latest developments in cancer therapeutics. Here’s a brief review of some of the content that you’ll find on the website.

Featured Videos Dr. Howard A. Burris on the Potential of T-DM1 in Breast Cancer Dr. Alex Adjei Discusses the Evolution of Cancer Therapeutics Dr. Peter Choyke on Using F-18 to Measure Antiangiogenic Response

Articles On the Web Regorafenib Granted FDA Priority Review for Patients With GIST Ramucirumab Achieves Primary Endpoint as Single Agent in Metastatic Gastric Cancer Researchers Determine Four Distinct Subtypes of Breast Cancer

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil– based chemotherapy. 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin

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Dr. Ravi Salgia Describes Molecular Applications in Advanced Lung Cancer

Safety:2.6875"

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AVASTIN® (bevacizumab)

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).]

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.

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%.

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.

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.

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).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning,

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 Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients

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.

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

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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).]

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).]

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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).]

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).]

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AVASTIN® (bevacizumab)

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%

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.

21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 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

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

T:10.75”

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%).

IFN‑α + Avastin (n = 337)

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).]

Safety:10”

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.

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)

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)

To confront a common threat across approved indications...

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

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

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

Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil– based chemotherapy.

Most common adverse events

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

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,† the incidences of Avastin-related adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastintreated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Avastin is not approved for use in combination with irinotecan.

†

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. Reference: 1. Avastin Prescribing Information. Genentech, Inc. December 2011.

AVA0000488301

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