Targeted Therapy News May 2013 by Intellisphere, LLC

ASCO 2013: Key Targeted Trials

An Interview with Douglas Yee, MD, Scientific Program Chair

Targeted TherapyNews (see page 24)

Personalized Medicine For the Practicing Oncology Professional

™

Vol. 2 No. 3

In this issue... Prostate Cancer • Biomarkers Still Needed Ovarian Cancer • Possible Mechanism of Platinum Resistance in Ovarian Cancer Identified Genetic Research • Metabolic Gene Expression Altered in Cancer, Providing Potential Drug Targets Hematologic Malignancies • Numerous Drug Classes Studied for Use in Follicular and Other Lymphomas • Seeking a Standard in the Treatment of Elderly Patients With CLL AACR Meeting • Spotlight on Novel Agents in Early Development Breast Cancer • Trials Examine Use of T-DM1 as Combination Therapy for HER2 Breast Cancer • FDA Grants Breakthrough Therapy Designation for Palbociclib in Breast Cancer Lung Cancer • HER2-Targeted Agents May Benefit Patients With Non-Small Cell Lung Cancer

Feature

Researchers Identify How Nongenetic Mechanisms of Cancer Cell Diversity Can Affect Treatment Response By Anna Azvolinsky, PhD

new study suggests that even tumor cells with a common genetic background can display functional heterogeneity. The results point to nongenetic mechanisms, such as microenvironment and epigenetic differences, that contribute to tumor growth as well as tolerance to therapy. The research, led by Antonija Kreso, PhD, Catherine O’Brien, MD, and John Dick, PhD, of the Princess Margaret Cancer Centre and the University of Toronto, Canada, was published in the February 2013 issue of Science. “Genetic mutations are thought to account for tumor formation and growth, but our results indicate intra-clonal diversity with respect to functional properties also plays a role,” said Kreso. The predominant theory of solid tumor heterogeneity states that tumor cell diversity is a result of progressive mutational changes that form distinct tumor cell clones, with each type of subclone thought to be genetically similar. But how nongenetic factors contribute to tumor heterogeneity along with genetic diversity is not clear. Kreso and colleagues addressed whether these genetic clones are functionally equivalent and respond in the same manner to chemotherapy treatment by tracking individually labeled human colorectal cancer (CRC) cells in mice. They found that individual tumor cells within the same lineage had a spectrum of survival

Feature

New Developments in Oral Targeted Agents for Advanced Colorectal Cancer By Anna Azvolinsky, PhD

n September 2012, the FDA approved regorafenib (Stivarga) as a salvage treatment for metastatic colorectal cancer (mCRC) previously treated with chemotherapy, an anti-

(continued on page 17)

BRCA Patenting Case Reaches the Supreme Court By Ben Leach

he question of the validity of gene patents has reached the Supreme Court, and the impending decision could transform the current research landscape. The company on the defensive end of the case is Utah-based Myriad Genetics, a molecular diagnostic company responsible for the development of the BRACAnalysis test. In 1994, it was discovered that the BRCA1 and BRCA2 genes were linked to an increased risk of breast cancer and ovarian cancer. As the patent holder, Myriad requires that all testing for the genes be done with the company’s test only.

Peter Meldrum

(continued on page 17)

Axel Grothey, MD vascular endothelial growth factor (VEGF) therapy, or an anti-epidermal growth factor receptor (EGFR) therapy. Regorafenib had received a fast-track FDA review status and was approved after only a three-month review process. The drug is the first targeted oral therapy to receive an FDA approval for treatment of advanced CRC, and the second drug to be approved for mCRC in 2012. Although progress has been made in treating colorectal cancer, including the development of biologic agents that target EGFR and angiogenesis, the median survival in mCRC remains about two years. The five-year survival rate for a patient with stage II

(continued on page 18)

After 2 prior lines of MBC chemotherapy,

DISCOVER OVERALL SURVIVAL HALAVEN: The FIRST and ONLY single-agent therapy proven to significantly extend OVERALL SURVIVAL after 2 prior lines of MBC therapy1-9

UPDATED OVERALL SURVIVAL (OS) ANALYSIS (UNPLANNED): MEDIAN OS, MONTHS (95% CI)1,10,a

P R O P O R T I O N O F PAT I E N T S A L I V E

1.0

The updated OS analysis was consistent with the primary analysis1 The primary analysis, conducted when ~50% of events (deaths) had been observed, demonstrated a median OS for Halaven vs TPC of 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR*=0.81 (95% CI: 0.66, 0.99) (P=0.041)1,10 Results from an updated, unplanned survival analysis of the Phase III, randomized, open-label, multicenter, multinational EMBRACE† trial of Halaven versus TPC in patients with metastatic breast cancer (MBC) (N=762), conducted when 77% of events (deaths) had been observed. The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxanebased chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy), and 3% hormonal therapy.

0.9 0.8

Halaven

0.5

Treatment of Physician’s Choice

0.4

(n=254)

0.3

10.6

0.2

(9.2, 12.0)

0.1

Deaths=203

0.0 6

Number of patients at risk

508 254

406 178

QT Prolongation

• Patients should be monitored closely for signs of peripheral motor and sensory neuropathy • Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less • Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days) • Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

Please see accompanying brief summary of Halaven full Prescribing Information. To learn more about Halaven, visit www.halaven.com

274 106

142 61

54 26

11 5

0 Halaven 0 TPC

CI=confidence interval; Treatment of Physician’s Choice (Control arm)=TPC. Conducted in the intent-to-treat (ITT) population.

Halaven is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Peripheral Neuropathy

TIME (MONTHS)

Pregnancy Category D

• Monitor complete blood counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days • Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels • Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

IN MEDIAN OS

Deaths=386

Indication

Neutropenia

INCREASE

(12.1, 14.4)

0.6

Important Safety Information

25% (2.6 month)

(n=508)

13.2

0.7

• Halaven is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks • In an uncontrolled ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities • Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment

• For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Most Common Adverse Reactions

• Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%) • The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%) References: 1. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2012. 2. Saad ED et al. J Clin Oncol. 2010;28(11):1958-1962. 3. Slamon DJ et al. N Engl J Med. 2001;344(11):783-792. 4. Geyer CE et al. N Engl J Med. 2006;355(26):2733-2743. 5. von Minckwitz G et al. J Clin Oncol. 2009;27(12):1999-2006. 6. Miller K et al. N Engl J Med. 2007;357(26):2666-2676. 7. Robert NJ et al. J Clin Oncol. 2011;29(10):1252-1260. 8. Sparano JA et al. J Clin Oncol. 2010;28(20):3256-3263. 9. Jones SE et al. J Clin Oncol. 2005;23(24):5542-5551. 10. Cortes J et al. Lancet. 2011;377(9769):914-923.

*HR=hazard ratio. † EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus E7389 (Eribulin).

HALAVEN® (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information. 2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. Recommended dose delays • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: – ANC <1,000/mm3 – Platelets <75,000/mm 3 – Grade 3 or 4 non-hematological toxicities. • The Day 8 dose may be delayed for a maximum of 1 week. – If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later. Recommended dose reductions • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1. • Do not re-escalate HALAVEN dose after it has been reduced. Table 1 Recommended Dose Reductions Recommended Event Description HALAVEN Dose Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following: ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 1.1 mg/m2 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. 5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia. Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3. 5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less. 5.3 Embryo-Fetal Toxicity There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus. 5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome. 6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: • Neutropenia • Peripheral neuropathy • QT interval prolongation The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%). The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group. Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Blood and Lymphatic System Disordersa Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders b 35% 8% 16% 2% Peripheral neuropathy Headache 19% <1% 12% <1% General disorders and administrative site conditions Asthenia/Fatigue 54% 10% 40% 11% Mucosal inflammation 9% 1% 10% 2% Pyrexia 21% <1% 13% <1% Gastrointestinal disorders Constipation 25% 1% 21% 1% Diarrhea 18% 0 18% 0 Nausea 35% 1% 28% 3% Vomiting 18% 1% 18% 1% Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Investigations Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders Anorexia 20% 1% 13% 1% Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders c 10% NAc Alopecia 45% NA

Table 2 (cont'd) MedDRA ver 10.0

HALAVEN (n=503) All Grades ≥ Grade 3

Control Group (n=247) All Grades ≥ Grade 3

Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia). Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy. Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVENtreated group: • Eye Disorders: increased lacrimation • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth • General Disorders and Administration Site Conditions: peripheral edema • Infections and Infestations: upper respiratory tract infection • Metabolism and Nutrition Disorders: hypokalemia • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness • Nervous System Disorders: dysgeusia, dizziness • Psychiatric Disorders: insomnia, depression • Skin and Subcutaneous Tissue Disorders: rash 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose. Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption. 8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established. 8.6 Hepatic Impairment Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). 8.7 Renal Impairment For patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min). 10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for HALAVEN overdose. 12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics Specific Populations Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that geometric mean dose-normalized systemic exposure is similar for patients with mild renal impairment (CrCl 50-80 mL/min) relative to patients with normal renal function. However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dosenormalized systemic exposure increased 2-fold compared to patients with normal renal function. 12.6 Cardiac Electrophysiology The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay. The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling • Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination. • Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN. –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– a

In This Issue...

Targeted

Features

News

esearchers Identify How R Nongenetic Mechanisms of Cancer Cell Diversity Can Affect Treatment Response

Prostate Cancer

By Anna Azvolinsky, PhD

7P ossible Mechanism of Platinum Resistance in Ovarian Cancer Identified

A new study suggests that even tumor cells with a common genetic background can display functional heterogeneity. This may mean that nongenetic mechanisms, such as microenvironment and epigenetic differences, may contribute to tumor growth and therapy resistance.

RCA Gene Patenting Case Reaches B the Supreme Court

By Ben Leach

An impending court decision could change the research landscape.

18 New Developments in Oral Targeted Agents for Advanced Colorectal Cancer

By Anna Azvolinsky, PhD

Leonard Gomella, MD

Although progress has been made in treating colorectal cancer, the median survival remains about two years. New, targeted oral agents are in development.

By Devera Pine

Ovarian Cancer

By Beth Fand Incollingo

In the wake of the approval of several novel treatments for prostate cancer—including antiandrogens enzalutamide and abiraterone and immunotherapy sipuleucel-T, physicans must now focus on how to best integrate new therapies into prostate cancer treatment.

24 A Guide to ASCO 2013: Key Targeted Trials

By Anna Azvolinsky, PhD

An Interview with Douglas Yee, MD, Scientific Program Chair Douglas Yee, MD

Targeted Therapy News • 5.13

Daniel P. Petrylak, MD

President

By Ben Leach

Peter Ciszewski pciszewski@TargetedHC.com

Genetic Research

8M etabolic Gene Expression Altered in Cancer, Providing Potential Drug Targets

Editorial & Production Editor Devera Pine dpine@onclive.com

By Andrew J. Roth Dennis Vitkup, PhD

Hematologic Malignancies

9N umerous Drug Classes Studied for Use in Follicular and Other Lymphomas 13 Seeking a Standard in the Treatment of Elderly Patients With CLL By Beth Fand Incollingo

Associate Editors Lauren M. Green Ben Leach Web Editor, Social Strategy Manager Silas Inman Assistant Web Editor Andrew J. Roth Design Director Jennifer Rittmann

Sales & Marketing

AACR Annual Meeting

14 S potlight on Novel Agents in Early Development

Bruce D Cheson, MD

By Anna Azvolinsky, PhD

Breast Cancer

15 Trials Examine Use of T-DM1 as Combination Therapy for HER2 Breast Cancer

Executive Vice President Rob Braun rbraun@TargetedHC.com

Director of Sales Scott Harwood sharwood@TargetedHC.com

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

National Accounts Representative Nicole Jussen njussen@TargetedHC.com

Digital Media Vice President, Digital Media Jung Kim

By Ben Leach

15 FDA Grants Breakthrough Therapy Designation for Palbociclib in Breast Cancer

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

By Beth Fand Incollingo

Mark Pegram, MD

Operations & Finance

By Ben Leach

Director of Operations Thomas J. Kanzler

Controller Jonathan Fisher, CPA

Lung Cancer

Director of Circulation John Burke jburke@mdng.com

Assistant Controller Leah Babitz, CPA

20 Integrating Novel Agents into the Treatment of Prostate Cancer Case-Based Discussion

Healthcare Communications

7B iomarkers Still Needed

16 HER2-Targeted Agents May Benefit Patients With Non-Small Cell Lung Cancer

Corporate

By Ben Leach

Chairman/Chief Executive Officer Mike Hennessy Richard Finn, MD

Chief Operating Officer Tighe Blazier

Departments

Chief Financial Officer Neil Glasser, CPA / CFE

28 Research Profile: Notch Holds Promise, but Presents Obstacles as Cancer Target

Vice President, Executive Creative Director Jeff Brown

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

Benjamin W. Purow, MD

Evidence-Based Oncology

29 Bundled Payment: Practice Savior or Killer?

By Kurt Ullman

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

In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

STARTS THE FIGHT

AND HELPS HIS IMMUNE SYSTEM SUSTAIN* IT 1

• Targets and attacks prostate cancer cells • Statistically significant overall survival advantage1,2 • Sustained* immune response *A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1 INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group 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 ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache. For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages. www.PROVENGEHCP.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. In 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.

PROF35855_ProvengeAd_TarTherNews_DR2.indd 2

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.)

3/8/13 11:13 AM

From the Publisher

Key Targeted Therapy Trials From ASCO 2013

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

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

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

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)

his year’s annual meeting of the American Society of Clinical Oncology (ASCO) will feature the presentation of new data that advances our understanding and targeted treatment of cancer. In this issue of Targeted Therapy News, we speak with Douglas Yee, MD, chair of ASCO’s Scientific Program Committee, about key presentations and new features at this year’s meeting. This issue also offers an in-depth look at some of the intriguing research results that came out of the American Association for Cancer Research (AACR) annual meeting held in April. For breaking news from ASCO, check TargetedHC.com daily, follow TargetedHC on Twitter, or find us on Facebook. Expert perspectives and reports on ASCO findings will be featured in our next issue, in July, as well as in the June issue of our sister publication, The International Journal of Targeted Therapies in Cancer. Thank you for reading.

*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.)

Peter Ciszewski 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

Follow us! REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011. 2. 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.

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Targeted Therapy News • 5.13

Targeted

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

Targeted Therapy News • 5.13

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

Healthcare

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

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

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

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

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

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

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

Lee Schwartzberg, MD The West Clinic Memphis, TN

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

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

Janaki Moni, MD Michiana Hematology Oncology South Bend, IN

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

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

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

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

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

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

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

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

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

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

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

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

Philip Villiotte, MD Spectrum Medical Group Scarborough, ME

Mahendra Gupta, MD Medical Oncology Innovis Health Fargo, ND

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

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

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

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

News

Targeted Therapies: Prostate Cancer

Biomarkers Still Needed By Devera Pine

lthough a variety of biomarkers hypermethylation was associated with have been shown to correlate a shorter time to biochemical relapse with survival in men with pros(disease-free survival) in patients treattate cancer, the use of biomarkers in the ed with prostatectomy (P=.043), but not management of these patients may be in patients treated with external-beam dependent upon the clinical state and radiation therapy or ADT. the class of drug evaluated. Speaking Okegawa et al assessed whether cirat the 6th Annual Interdisciplinary Prosculating tumor cells (CTCs) with tumortate Cancer Congress, held in New York related methylated DNA could be used City on March 16, Daniel P. Petrylak, MD, to predict survival in patients with hordirector of the Genitourinary Oncology mone-refractory prostate cancer.3 The researchers analyzed blood samples Program at Yale Cancer Center in New from 76 patients; CTC Haven, Connecticut, reevaluations occurred 3.5 viewed the evidence to 78.5 months after the for biomarkers to date. initial diagnosis. Serum “There is nothing at this DNA methylation status point that has fallen out was assessed for APC, as absolutely prognostic GSTP1, RASSF1A, MDR1, or predictive in an inand PTGS2. dividual situation,” he A total of 47 patients said. (62%) had 5 or more One area of interest is CTCs and a median the prognostic value of overall survival (OS) of promoter methylation 12 months compared of genes associated with with 26 months for pavarious parameters of tients with fewer than 5 prostate cancer progresCTCs (P<.001). The pression.1,2 Henrique et al Daniel P. Petrylak, MD evaluated methylation ence of 5 or more CTCs of APC, CCND2, GSTP1, was significantly corRARB2, and RASSF1A as biomarkers related with the detection of 1 or more for prognosis.2 High-level methylation methylated loci (P <.001). The median of APC was the only epigenetic event OS for patients with methylated DNA significantly associated with a worse was 12 months versus 48 months or disease-free or disease-specific surmore for patients without methylated vival. There was a trend toward worse DNA (P <.001). outcome in patients treated with androPosttreatment CTC levels were shown gen-deprivation therapy (ADT) who had to predict OS in a study of 231 patients APC hypermethylation (P=.079). APC with progressive CRPC4; data from the

study led to FDA approval of the CellSearch assay. However, in his talk, Petrylak said that although CTCs are useful for predicting treatment response or survival with cytotoxic and hormonal therapies, about half of patients do not have detectable CTC levels by current detection methods. More-sensitive CTC detection techniques are needed, he said. The TMPRSS2-ERG gene fusion, which is present in approximately half of newly diagnosed prostate cancer cases, has also been investigated as a biomarker, though the clinicopathologic impact of the fusion is not clear, Petrylak said. Different subtypes of TMPRSS2-ERG have been detected, and the Edel subtype may represent a more lethal genotype, susceptible to higher recurrence, more likely to evolve to CRPC and to progress to metastasis.5 A role has been postulated for TMPRSS2-ERG as a predictive biomarker for sensitivity to abiraterone acetate; however, a phase II trial found that the fusion has a limited role in this area.6 In summary, Petrylak said, although a variety of biomarkers correlate with survival, none are “ready for prime time.” However, he said, research on biomarkers should be an element in all subsequent phase III trials. TTN 1. Roupret M, Hupertan V, Catto JW, et al. Promoter hypermethylation in circulating blood cells identifies prostate cancer progression. Int J Cancer. 2008;122(4):952-956. 2. Henrique R, Ribeiro FR, Fonseca D, et al. High

Key Points: • Use of biomarkers in the management of prostate cancer may be dependent upon the clinical state and the class of drug evaluated • Approximately half of patients do not have detectable CTC levels by current detection methods • Research on biomarkers should be an element in phase III trials promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients. Clin Cancer Res. 2007;13(20):61226129. 3. Okegawa T, Nutahara K, Higashihara E. Association of circulating tumor cells with tumor-related methylated DNA in patients with hormone-refractory prostate cancer. Int J Urol. 2010;17(5):466475. 4. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):63026309. 5. Mehra R, Tomlins SA, Yu J, et al. Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Res. 2008;68(10):3584-3590. 6. Danila DC, Anand A, Sung CC, et al. TMPRSS2ERG status in circulating tumor cells as a predictive biomarker of sensitivity in castration-resistant prostate cancer patients treated with abiraterone acetate. Eur Urol. 2011;60(5):897-904.

Targeted Therapies: Ovarian Cancer

Possible Mechanism of Platinum Resistance in Ovarian Cancer Identified By Ben Leach

esearchers have determined that the P-type ATPase membrane protein ATP11B may play a role in cisplatin resistance in ovarian cancer and propose that inhibition of ATP11B expression could help overcome cisplatin resistance. The research was published online by The Journal of Clinical Investigation.

Although platinum-based chemotherapy is a standard of care across many tumor types, eventually, patients develop primary or acquired resistance to these drugs. This can be caused by reduced platinum uptake and increased platinum export, which in turn limit the extent of the DNA damage that the

chemotherapy causes. Patients with platinum-resistant ovarian cancer have a poor prognosis and few treatment options, with only about 10% to 15% of patients responding to treatment with therapies such as paclitaxel, pegylated liposomal doxorubicin (PLD), and topotecan.

In searching for candidate genes that could cause cisplatin resistance, researchers found that expression of ATP11B was markedly increased in cisplatin-resistant cells. After examining 111 ovarian cancer specimens and 10 normal ovarian surface epithelial cell specimens, the researchers determined

Targeted Therapy News • 5.13

News

Targeted Therapies: Ovarian Cancer that there was a significant relationship between higher tumor stage and ATP11B expression (P = .04). High ATP11B expression was also associated with worse overall survival compared with low ATP11B expression, with a median overall survival of 2.75 years in those with high expression compared with 9.25 years in those with low expression (P < .001). To determine whether any effect was observed if ATP11B expression was lowered, the researchers examined the effect of ATP11B silencing in vitro and

found that it restored the sensitivity of ovarian cancer cells to cisplatin. When this was tested in mice, the mice with ATP11B-silenced RNA showed significant decreases in cell proliferation and higher apoptotic rates. The researchers also determined that ATP11B enhances the export of cisplatin from cells, suggesting that the protein contributes to the secretory vesicular transport of cisplatin from Golgi to the plasma membrane. “Collectively, our data demonstrate that overexpression of ATP11B confers

cisplatin resistance in ovarian cancer cells by enhancing the efflux of cisplatin via the vesicular secretory pathway,” the authors wrote. “On the basis of these findings, ATP11B appears to be an important target for overcoming cisplatin resistance.” TTN Moreno-Smith M, Halder JB, Meltzer PS, et al. ATP11B mediates platinum resistance in ovarian cancer [published online ahead of print April 15, 2013]. J Clin Invest. doi:10.1172/JCI65425.

Key Points: • P-type ATPase membrane protein ATP11B may play a role in cisplatin resistance in ovarian cancer • Silencing ATP11B in vitro restored the sensitivity of ovarian cancer cells to cisplatin • Inhibition of ATP11B expression could help overcome cisplatin resistance

Targeted Therapies: Genetic Research

Metabolic Gene Expression Altered in Cancer, Providing Potential Drug Targets By Andrew J. Roth associate professor of Biomedical Informatics at CUMC and the study’s lead investigator, in a statement. “So far, people have focused mainly on a few genes involved in major metabolic processes. Our study provides a comprehensive, global view of diverse metabolic alterations at the level of gene expression.”

Global mapping of cancer gene expression changes to the human metabolic network; increased enzymatic expression in red; decreased in blue.

Targeted Therapy News • 5.13

The analysis found multiple metabolic expression changes in tumors. Some of the changes, including upregulation of nucleotide biosynthesis and glycolysis, were frequently found across tumor types. Others, such as expression changes in oxidative phosphorylation, were heterogeneous. “Our study clearly demonstrates that there are no single and universal changes in cancer metabolism,” said MatDennis Vitkup, PhD thew Vander Heiden, MD, PhD, assistant proA fundamental fessor at the Massachusetts Institute of change in meTechnology and a coauthor, in a statetabolism is one ment. of the emergIn some cases, the researchers found ing hallmarks that gene expression changes worked of cancer. Howwith cancer mutations, driving tumor ever, researchers formation. For instance, in several do not yet know cancer types, including acute myeloid how the expresleukemia, mutations in the isocitrate sion of metabolic dehydrogenase enzyme produces 2-hygenes differs in droxyglutarate, a metabolite that procancerous versus motes tumor growth. The researchers normal cells, or found that in tumors with recurrent whether metamutations, isocitrate dehydrogenase bolic changes are expression was significantly increased, the same across leading to overproduction of 2-hydroxytumor types. glutarate. The CUMC team The analysis also identified hunaimed to identify dreds of metabolic isoenzymes with metabolic prosignificant and tumor-specific expresgramming differsion changes that could potentially ences. be targeted for anticancer therapy. For

Key Points: • An analysis of metabolic gene expression patterns in 22 human tumors types identified multiple metabolic expression changes associated with cancer • There were no single and universal changes in cancer metabolism • The analysis also identified hundreds of metabolic isoenzymes with significant and tumor-specific expression changes that could potentially be targeted for anticancer therapy example, in kidney and liver cancers, a quick-acting aldolase isoenzyme was more prevalent than the slow-moving version found in normal kidney and liver tissue. This quick-acting version is suitable for fast cell proliferation and tumor growth. Prior to the study, a few isoenzyme expression discrepancies were known, but this research identified hundreds more. “Inhibiting specific isoenzymes in tumors may be a way to selectively hit cancer cells without affecting normal cells, which could get by with other isoenzymes,” said Jie Hu, PhD, a postdoctoral researcher at CUMC and coauthor, in a statement. TTN Hu J, Locasale JW, Bielas JH, et al. Heterogeneity of tumor-induced gene expression changes in the human metabolic network [published online ahead of print. April 21, 2013]. Nature Biotechnol. doi:10.1038/nbt.2530.

Image provided by Dr. Vitkup

n analysis of metabolic gene expression patterns in 22 human tumors types identified multiple metabolic expression changes associated with cancer, as well as hundreds of potential drug targets for disrupting the fuel supply of tumors or interrupting the synthesis of essential building blocks. The study, conducted at Columbia University Medical Center (CUMC), was published online in Nature Biotechnology. “The importance of this new study is its scope,” said Dennis Vitkup, PhD,

News

Targeted Therapies: Hematologic Malignancies

Numerous Drug Classes Studied for Use in Follicular and Other Lymphomas By Beth Fand Incollingo

ollicular lymphoma (FL) is charantibody GA101, which was tested in acterized by repeated treatment patients with relapsed FL, and generresponses and then relapses, and ated response rates and PFS results until more effective frontline therapies similar to those associated with rituxbecome available, researchers will need imab.2,3 “Whether that will go anywhere remains to be demonstrated by the onto generate a growing list of drug choicgoing trial of [alkylating agent] bendaes to keep pace with patients’ needs, mustine with or without GA101 in rituxaccording to Bruce D. Cheson, MD, of imab-refractory patients,4” he said. the Lombardi Comprehensive Cancer Meanwhile, two antibody drug conCenter at Georgetown University, Washjugates that showed promise in phase I ington, DC, and chair of the Lymphoma trials—DCDT2980S, an anti-CD22 agent, Committee of the Alliance for Clinical and DCDS4501A, an anti-CD79b agent— Trials in Oncology/Cancer and Leukeare being tested in a randomized phase mia Group B (CALGB). II study.5 Investigators are combining Cheson, who spoke at the 17th Aneither of the drugs with nual International Conrituximab in patients gress on Hematologic with FL and diffuse large Malignancies, held in B-cell lymphoma, and February in New York are allowing crossover City, noted that although at progression to check there are no new chefor non–cross-resistance motherapy drugs in debetween the two molvelopment for FL, work ecules, Cheson said. is being done to bring Also on tap is a phase other classes of agents II study of ibrutinib, a into the treatment arspecific and irreversmamentarium—particible inhibitor of Bruton’s ularly monoclonal antityrosine kinase that bodies, signaling pathBruce D. Cheson, MD demonstrated an ORR way-targeting agents, of about 40% in patients apoptosis-inducing with FL in an earlier study, Cheson said. compounds, and immunomodulatory The pill-a-day regimen has been sucdrugs. cessful for as long as 2 years in patients Rituximab, a monoclonal antibody with relapsed or refractory FL, he said, approved to treat FL, will soon go off and the trial will shed more light on the patent, but other anti-CD20 antiboddrug’s toxicity and response rate and ies are in development, Cheson said. duration.6 However, to have value, he noted, such Another promising development is drugs will need to be more effective idelalisib (GS-1101), a delta isoformthan rituximab or work in rituximabspecific PI3 kinase inhibitor, Cheson resistant disease. said. In a single-agent, phase I trial, 59% Ofatumumab, a novel humanized of heavily pretreated patients with inmonoclonal anti-CD20 antibody that is dolent non-Hodgkin lymphoma (iNHL) approved for use in chronic lymphosubtypes responded to a dosage of cytic leukemia (CLL), has shown some 100 mg or more of the drug twice a promise as a single agent in patients day.7 The drug’s tolerability was “exwith rituximab-resistant FL. In a multiceptional,” Cheson said. Grade 3-4 adcenter study of patients with rituximabverse events occurring in 5% or more refractory FL (N=116), ofatumumab was of patients and due to any cause were well tolerated and modestly active.1 In the study, 27 patients had an overneutropenia (9%), lymphopenia (5%), all response rate (ORR) of 22% to the and thrombocytopenia (5%) with uncerantibody. For all participants, median tain relationship to the study drug. No progression-free survival (PFS) was 5.8 pattern of drug-related symptomatic months. PFS jumped to 9.1 months in adverse events was seen. the 46% of patients who demonstrated A separate phase I trial combined idetumor reduction 3 months after the lalisib with rituximab, bendamustine, or start of therapy. a combination of the two in previously Cheson said “the jury is still out” on treated patients with iNHL.8 All com-

binations resulted in “profound reductions” in lymphadenopathy. The ORR in the intent-to-treat group was 77% to 85% with any regimen, and the PFS at 1 year was 78% to 90% with any regimen. There were no overlapping toxicities with the drugs. The results indicate that “maybe you don’t need the chemotherapy after all,” Cheson said. Due to some data indicating that simultaneously inhibiting two pathways may lead to better results, agents including PI3K/mTOR inhibitors and delta/gamma inhibitors are being investigated, Cheson said. In the arena of apoptosis-inducing drugs, Cheson mentioned six agents in development, including ABT-199, which induces cancer cell death by targeting BCL-2. In an early study, 4 of 5 patients with FL had a partial response to the drug, but the agent may work better if combined with another treatment, Cheson pointed out.9 Cheson was part of the CALGB team that conducted study 50401 of the immunomodulatory drug lenalidomide, with or without rituximab, in patients whose FL had relapsed after one or more rituximab-based regimens.10 The ORR was 72.7% in the experimental arm versus 51.1% in the control arm. The complete response rate was 36.4% for the experimental arm versus 13.3% for the control arm; the partial response rate was 36.4% versus 37.8%, respectively; and the 2-year event-free survival was 44% versus 27%, respectively. While there was “no real difference in overall survival,” Cheson noted that some “astounding” results came out of a phase II study of lenalidomide and rituximab in untreated indolent lymphoma, conducted by Fowler et al.11 In 46 patients with FL, the ORR was 98%, with 87% of those responses complete. PFS was 89% at 36 months, and the toxicity profile was mild, with manageable hematologic side effects. “This has the potential to totally change the way we approach follicular lymphoma,” Cheson said. Those results led to the randomized, phase III RELEVANCE trial,12 which is testing rituximab and lenalidomide against rituximab and any of several chemotherapy regimens, Cheson said. The study is scheduled to continue through 2024.

Key Points: • Ofatumumab, a novel humanized monoclonal anti-CD20 antibody, has shown promise as a single agent therapy for rituximabresistant FL • In NHL, pending trials include a study of rituximab and lenalidomide plus ibrutinib in untreated follicular NHL, and another testing rituximab and lenalidomide plus idelalisib in relapsed or refractory follicular NHL Pending CALGB trials include a study testing rituximab and lenalidomide plus ibrutinib in untreated follicular NHL, and another testing rituximab and lenalidomide plus idelalisib in relapsed or refractory follicular NHL after at least one anti-CD20-based regimen. Looking ahead, challenges will involve determining how to develop rational combinations of new drugs, choosing appropriate endpoints for clinical trials, and figuring out who will pay for studies, Cheson said. “We need to recognize the heterogeneity of lymphomas and do correlative studies to figure out which drugs and combinations will most likely benefit each individual patient,” he said, adding that it is important to enroll eligible patients in trials to support research efforts. TTN 1. Czuczman MS, Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood. 2012;119(16):3698-3704. 2. Salles GA, Morschhauser F, Thieblemont C, et al. Efficacy and safety of obinutuzumab (GA101) monotherapy in relapsed/refractory indolent nonHodgkin’s lymphoma: results from a phase I/II study (BO20999). Presented at the 53rd Annual Meeting and Exposition of the American Society of Hematology; December 10-13, 2011; San Diego, CA. Blood. 2011;118(suppl; abstr 268). 3. Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing GA101 (obinutuzumab) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: preliminary analysis of the GAUSS study. Blood. 2011;118(suppl; abstr 269). 4. Clinical Trials Identifier NCT01059630. www. clinicaltrials.gov.

Targeted Therapy News • 5.13

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

40 20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

-100

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

50% Improvement Upper 50th Percentile

Placebo (n = 153)

Upper 50th Percentile

Jakafi (n = 145)

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

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

At Week 24, significantly more patients receiving Jakafi vs placebo had — A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a — A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive patients and JAK2 V617F-negative patients, relative to placebo2

Visit www.jakafi.com/explore

for more information on Jakafi and MF, plus valuable educational resources.

and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS

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

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

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

JAK targeted to make a difference

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

News

Targeted Therapies: Hematologic Malignancies 5. Clinical Trials Identifier NCT01691898. www. clinicaltrials.gov. 6. Advani RH, Buggy JJ, Sharman JP, et al. Bruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/ refractory B-cell malignancies [published online ahead of print October 8, 2012]. J Clin Oncol. 2013;31(1):88-94. 7. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110δ, in patients with relapsed

or refractory non-Hodgkin lymphoma. Blood. 2010;116(21)(suppl; abstr 1777). 8. Fowler NH, de Vos S, Schreeder MT, et al. Combinations of the phosphatidylinositol 3-kinase-delta (PI3Kδ) Inhibitor GS-1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in previously treated, indolent non-Hodgkin lymphoma: results from a phase I study. Presented at the 54th Annual Meeting of the American Society of Hematology; December 8-11, 2012; Atlanta, GA. Blood. 2012;120(suppl; abstr 3645).

9. Davids MS, Roberts AW, Anderson MA, et al. The BCL-2-specific BH3-mimetic ABT-199 (GDC0199) is active and well-tolerated in patients with relapsed non-Hodgkin lymphoma: interim results of a phase I study. Presented at the 54th Annual Meeting of the American Society of Hematology; December 8-11, 2012; Atlanta, GA. Blood. 2012;120(suppl; abstr 304). 10. Leonard J, Jung S-H, Johnson JL. CALGB 50401: a randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: final results of a

phase II study. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. J Clin Oncol. 2012;30(suppl; abstr 8000). 11. Fowler N, Hagemeister F, McLaughlin P, et al. High response rates with lenalidomide plus rituximab for untreated indolent B cell non-Hodgkins lymphoma. Ann Oncol. 2011;22(suppl 4; abstr 137). 12. Clinical Trials Identifier NCT01476787. www. clinicaltrials.gov.

Seeking a Standard in the Treatment of Elderly Patients With CLL By Beth Fand Incollingo

entle yet effective therapies are called for when treating patients with chronic lymphocytic leukemia (CLL) who are age 65 years and older. While there is no standard treatment for most of those patients, several regimens are being tested in clinical trials, according to Alessandra Ferrajoli, MD, who spoke at the 17th Annual International Congress on Hematologic Malignancies, held in February in New York City. The treatment of elderly patients with CLL is an important area of study because 69% of patients with the disease fit into that category at the time of diagnosis, making them more likely to have comorbidities that compromise their ability to tolerate aggressive treatments, said Ferrajoli, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. In fact, she said, at age 70 years, one-third of such patients have two or more comorbidities. Compared with people age 65 years and older in the general population, people in that age group who have CLL face a significantly increased mortality rate, she added. For the healthiest elderly patients with CLL, the standard of treatment is a regimen of fludarabine, cyclophosphamide, and rituximab (FCR), a combination tested in the recent CLL8 trial,1 versus treatment with fludarabine plus cyclophosphamide. The overall response rate was 90% in the three-drug arm versus 80% in the two-drug arm, and the complete response rate in the experimental arm was double that of the control arm, at

44% versus 22%, respectively. As a result, Ferrajoli said, the threedrug combination is the preferred treatment for patients who boast physical fitness, a lack of comorbidities, and excellent renal function, regardless of age. Elderly patients with CLL who do not fit into that group, however, should be treated with the regimens they can withstand based on their age and health: supportive therapies for the frailest, reduced-intensity regimens for those whose health is somewhat compromised, and more aggressive treatments for healthier patients, Ferrajoli said. She cited a number of clinical trials aimed at developing tolerable standard treatments for those subgroups. A study by Hillmen et al2 found that adding rituximab to chlorambucil produced better results than chlorambucil alone. The investigators compared their data to that generated in an earlier study of single-agent chlorambucil in patients with CLL. The overall response rate (ORR) in the intent-to-treat population was 82%, which was 16% higher than the ORR in the study of single-agent chlorambucil. The majority of responses, 68%, were partial. “These data confirm that, in previously untreated CLL patients who are unable to tolerate a more intensive chemotherapy regimen, the combination of rituximab and chlorambucil is an efficacious therapy with an acceptable tolerability profile resulting in a better ORR than chlorambucil monotherapy,” the authors wrote. In another study that is now in press, Ferrajoli and colleagues tested whether granulocyte-macrophage colony-stimulating factor (GM-CSF) would increase the activity of rituximab in untreated, elderly CLL patients.

The combination sparked a response rate of 68%, better than that of rituximab alone, with minimal toxicity. The regimen improved symptoms including fatigue, and the combination also increased the surface expression of CD20 in CLL cells, potentially making them better targets for rituximab, Ferrajoli said. “At 3 years follow-up, over 80% of the patients are alive, and that means that, if needed, they can then be treated with subsequent or more aggressive approaches,” Ferrajoli said during her talk. Another phase II study, CLL11,3 being conducted in Germany, is evaluating whether a combination of chlorambucil and obinutuzumab (GA101), an anti-CD20 monoclonal antibody, will generate better progression-free survival in elderly patients with CLL than chlorambucil plus rituximab or chlorambucil alone. Finally, Ferrajoli expressed excitement about the promise of lenalidomide, an immunomodulatory drug, in elderly patients with CLL. In a phase II study by Badoux et al,4 60 patients age 65 years and older with untreated CLL experienced a 65% ORR when treated with single-agent lenalidomide. In a recent update of the data, on file at MD Anderson, the patients had a 38% overall complete response rate, 52% had remained progression-free for more than 3 years, and 37% were still taking lenalidomide. In an evaluation after 6.5 years, investigators pinpointed median progression-free survival at 52 months; overall survival had not been reached, Ferrajoli reported. She called the results “very remarkable, considering the median age of these patients.” Other promising agents that could eventually become frontline treatments include ibrutinib, GS-1101, and Tru-016.

In continuing to test new agents for the treatment of elderly patients with CLL, researchers should consider survival, rather than type of response, as the ideal endpoint for studies, Ferrajoli suggested. She added that investigators need to determine whether treatments should be continuous or intermittent. Ferrajoli also cautioned that the “demands” associated with each therapy should be considered when treating elderly patients. “The number of trips they need to make to their oncology office, the need to arrange for transportation, the idea of receiving intravenous infusion and being in the infusion chair for hours, is very important for this population,” she said. “They have a strong preference for treatment they feel they are managing without going to the office.” TTN 1. Molica S. Clinical trial report. Progress in the treatment of chronic lymphocytic leukemia: results of the German CLL8 trial. Expert Rev Anticancer Ther. 2011;11(9):1333-1340. 2. Hillmen P, Gribben JG, Follows, GA, et al. Rituximab plus chlorambucil in patients with CD20-positive B-cell chronic lymphocytic leukemia (CLL): final response analysis of an openlabel phase II study. Presented at the American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL. Blood. 2010;116(21). Abstract 697. 3. Goede V, Fischer K, Busch R, et al. Chemoimmunotherapy with GA101 plus chlorambucil in patients with chronic lymphocytic leukemia and comorbidity: results of the CLL11 (BO21004) safety run-in [published online ahead of print August 31, 2012]. Leukemia. doi: 10.1038/ leu.2012.252. 4. Badoux XC, Keating MJ, Wen S, et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood. 2011;118(13):3489-3498.

Targeted Therapy News • 5.13

News

Targeted Therapies: AACR Annual Meeting

Spotlight on Novel Agents in Early Development By Anna Azvolinsky, PhD

he American Association for Cancer Research (AACR) is an annual showcase of the latest scientific cancer research, with updates on phase I, often first-in-human clinical trials. This year’s meeting theme, “Personalizing Cancer Care Through Discovery Science,” featured many presentations of novel mechanisms of action for targeting cancer. Following is a review of several studies that delved into how specific therapies work against cancer.

Tyrosine Kinase Inhibitor Targets Bone Metastasis The oral therapy cabozantinib has been shown to stabilize and even resolve metastatic bone lesions in patients with metastatic castration-resistant prostate cancer (mCRPC).1 Although the study was initially set to randomize all patients to either oral cabozantinib or placebo, the randomization was stopped after an interim analysis showed cabozantinib was able to effectively shrink bone lesions. Of the 154 patients who could be evaluated, 72% had regression of their soft tissue lesions and 68% had improvements in bone lesions, including 12% who had complete resolution.

Several presentations at AACR investigated potential mechanisms for the antigrowth effects of eribulin. At AACR, a poster presentation by researchers from the Institute of Cancer Research in London, England, revealed some of the ways in which cabozantinib is able to target prostate cancer bone lesions.2 The researchers used a mouse model of prostate cancer that produces measurable bone metastases. By injecting the mouse model with prostate

Targeted Therapy News • 5.13

cancer cells labeled with a bioluminescent marker, researchers were able to track the cancer cells as they destroyed normal bone tissue and developed into bone lesions in the mouse—lesions with the same features as bone tumors that occur in human patients. When these bone metastases-positive mice were treated with cabozantinib, the animals showed evidence of inhibition of tumor growth and tumor cell death, similar to what has been seen in clinical trials. Radiological scans of the bones of the mice showed a fair amount of normal bone tissue returning compared to mice were treated with a placebo. Cabozantinib (Cometriq), an inhibitor of multiple tyrosine kinases including RET, MET, and VEGFR2, is being investigated as a treatment for advanced prostate cancer in two phase III trials and is already approved by the FDA for treatment of progressive metastatic medullary thyroid cancer.

Mechanisms for the Antineoplastic Effects of Eribulin Eribulin mesylate (Halaven) is approved for advanced metastatic breast cancer and is undergoing clinical testing for other cancers, including phase III trials in soft-tissue sarcoma and lung cancer. Eribulin is a synthetic version of a molecule derived from a marine sponge that is able to arrest cell division by inhibiting cells’ ability to polymerize the protein tubulin, an essential component for cell replication. Although treatment with eribulin can cause tumor regression via its cell cycle arrest function, exactly how the drug works is still not clear. Several presentations at AACR investigated potential mechanisms for the antigrowth effects of eribulin. The combined results suggest eribulin may have antimetastatic effects. Researchers demonstrated evidence supporting a previous observation that eribulin can disrupt vascular activity.3 Using a rat model of human breast xenograft tumors, researchers from Eisai Co., which manufactures eribulin, found that the drug can improve blood perfusion within the core of these xenograft tumors, preventing hypoxic conditions. This supports the role of eribulin in inhibiting hypoxia, and therefore potentially inhibiting metastasis

of tumor cells, a process that has been shown to occur under hypoxic conditions. The results also support the role of eribulin in remodeling vasculature morphology. Another study, also presented at AACR, demonstrated that eribulin is able to change the expression level of genes that may function in the epithelial-mesenchymal transition (EMT).4 The EMT is the process by which tumor cells acquire several characteristics, such as the ability to migrate, that are common to mesenchymal cells. This transition is thought to facilitate the process of tumor metastasis. The study measured the expression level changes of sets of genes among breast cancer cell lines treated with either eribulin or paclitaxel, a cytotoxic chemotherapy agent also known to target tubulin and cause cell-cycle arrest. Genes associated with the EMT were upregulated in breast cancer cell lines that had resistance to eribulin. The study also identified active pathways in breast cancer lines that were particularly sensitive to eribulin. Overall, the results showed that gene expression may be used to predict the sensitivity of breast cancer to eribulin, but additional studies are needed.

Ibrutinib Reduces Lymph Node Tumor Burden in Mouse Model Ibrutinib, a selective inhibitor of Bruton’s tyrosine kinase (Btk) is currently in phase II development for hematologic malignancies, including nonHodgkin lymphoma and mantle cell lymphoma (MCL). In a presentation at AACR, researchers demonstrated that the drug is able to inhibit the adhesion and migration of malignant MCL cells using a mouse cell model, although more studies on this mechanism are needed.5 In clinical trials, patients treated with ibrutinib had an observed increase of MCL cells in the circulating blood that was followed by a reduction in tumor burden, suggesting that malignant cells were traveling from the tumor to the peripheral blood. The results presented at AACR showed that mice treated with ibrutinib had lower levels of malignant cells that traveled to and grew in lymph nodes and in the bone marrow. TTN

Key Points: • In mouse model of prostate cancer with bone metastases, cabozantinib inhibited tumor growth and tumor cell death • Results of two preclinical studies indicate that eribulin may have antimetastatic effects • In a mouse cell model, ibrutinib inhibited adhesion and migration of malignant MCL cells 1. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31(4):412-419. 2. Graham TJ, Box G, Attard G, et al. Multimodality imaging investigation of response to cabozantinib in a VCaP model of prostate bone metastasis. Presented at American Association for Cancer Research Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract 3924. 3. McCracken PJ, Ito K, Yanagimachi M, et al. Eribulin alters vascular function in human triplenegative (TN) breast MX-1 and MDA-MB-231 tumor xenograft models as measured by DCEMRI. Presented at American Association for Cancer Research Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract 4502. 4. Dezso Z, Oestreicher J, Weaver A, et al. Gene expression profiling (GEP) reveals epithelial mesenchymal transition (EMT) genes selectively differentiating eribulin sensitive breast cancer cell lines. Presented at American Association for Cancer Research Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract 1522. 5. Chang BY, Francesco M, Steggerda S, et al. Ibrutinib inhibits malignant cell adhesion and migration and reduces tumor burden in lymph node and bone marrow in a murine model of mantle cell dissemination and progression. Presented at American Association for Cancer Research Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract 923.

News

Targeted Therapies: Breast Cancer

Trials Examine Use of T-DM1 as Combination Therapy for HER2 Breast Cancer By Ben Leach

do-trastuzumab emtansine (Kadcyla, or T-DM1 in clinical trials) received FDA approval in February, and a number of ongoing trials now seek to determine whether the antibody-drug conjugate (ADC) can be combined with other agents. Mark Pegram, MD, director of the Breast Cancer Program at the Stanford Women’s Cancer Center in California, discussed the promise of ADCs and ongoing research with T-DM1 at the Annual Miami Breast Cancer Conference in March. Although targeted antibodies in cancer have been promising, with a few exceptions, most have only marginal activity in their targeted cancer and must be paired with a chemotherapeutic agent to maximize their efficacy. Researchers who worked on monoclonal antibodies during their early development had hoped that the new drugs would serve as a “magic bullet” in cancer, something that would prove to be effective in treating the disease without the side effects frequently caused by chemotherapy, Pegram said. His research in the 1990s included work on trastuzumab, a monoclonal antibody that targets HER2 on tumor cells, and he found the drug to be somewhat disappointing because it had to be combined with cytotoxic agents in order to provide patients with any substantial benefit. However, even just a few years ago, the thought of combining trastuzumab with the cytotoxic agent emtansine

(DM1) would have been unthinkable, breast cancer previously treated with Pegram said. Following early research trastuzumab and a taxane were ranin the 1980s, emtansine sat on the shelf domized in a 1:1 ratio to receive T-DM1 for many years after being developed or the combination of lapatinib and because it was deemed too toxic to be capecitabine. given to patients parenterally. In results presented at the European “Now, we have the opportunity to Society for Medical Oncology (ESMO) recapture the promise of targeted an2012 Congress, and concurrently pubtibody therapeutics because these anlished in The New England Journal of tibody-drug conjugates, at least in the Medicine, T-DM1 was shown to reduce case of T-DM1, are very well tolerated,” the mortality risk in women with HER2Pegram said. positive, unresectable, When emtansine is locally advanced or conjugated to trastumetastatic breast canzumab, the total amount cer by 32% when comof the cytotoxic agent pared with lapatinib and is trivial when comcapecitabine (hazard pared to the traditional ratio [HR] = 0.68; 95% CI, delivery method for 0.55-0.85; P <.001), with chemotherapy drugs, a 6-month difference faPegram said. Additionvoring T-DM1.1 Median overall survival was 30.9 ally, trastuzumab has months for T-DM1 vera tight binding affinity sus 25.1 months for lapato HER2-overexpressing tinib and capecitabine. tumor target cells, so The survival benefit emtansine ends up in Mark Pegram, MD comes with an excellent the tumor bed and not safety profile, according to Pegram. The scattered in normal tissues, where it is only toxicities that have been observed prohibitively toxic. in clinical trials are transient transami“The therapeutic index, which is effinase elevation and thrombocytopenia, cacy divided by toxicity, is exceptionally which Pegram said are both reversible. wide and really lives up to the promise Pegram highlighted the fact that paof the ‘magic bullet’ finally in the case of tients did not experience common side T-DM1 because you get so much theraeffects, including alopecia and neutropeutic response with so little toxicity,” penia, and very little gastrointestinal Pegram said. toxicity was observed. The phase III EMILIA trial confirmed Stanford is one site for a phase I trithe efficacy of T-DM1. In that trial, 991 al that is currently enrolling patients. patients with HER2-positive advanced

Key Points: • T-DM1 reduced mortality risk by 32% vs lapatinib/capecitabine in HER2-positive, unresectable, locally advanced or metastatic breast cancer • Toxicities observed in clinical trials included transient transaminase elevation and thrombocytopenia • Trials of T-DM1 in combination therapies and in earlier-stage disease are ongoing Pegram and his colleagues are studying whether T-DM1 can be given in combination with paclitaxel with or without pertuzumab, another monoclonal antibody. Results are expected to be presented at the 2013 San Antonio Breast Cancer Symposium in December. Results from the phase III MARIANNE trial should also be presented sometime within the coming year. In that trial, patients were randomized to T-DM1 plus pertuzumab, T-DM1 plus placebo, or trastuzumab plus a taxane (either paclitaxel or docetaxel). TTN 1. Verma S, Miles D, Gianni L. Updated overall survival results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer. Presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA12.

FDA Grants Breakthrough Therapy Designation for Palbociclib in Breast Cancer

albociclib (formerly known as PD 0332991), a novel oral and selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6, has received a Breakthrough Therapy designation from the FDA for the treatment of patients with breast cancer. The FDA can assign a Breakthrough Therapy designation to drugs that treat a lifethreatening condition and demon-

strate a substantial improvement over existing therapies. The designation promotes an expedited review process by allowing for more meetings between the FDA and the manufacturer during development, requiring fewer patients for clinical trials, and reducing the amount of time required for trials. Pfizer, palbociclib’s manufacturer, is still able to seek fast-track designation, ac-

celerated approval, and priority review for the drug. CDK 4 and 6 play an important role in regulating cell cycle progression, and preclinical models have shown that palbociclib has activity in patients with ERpositive breast cancer, including those with HER2-amplification. “CDK4/6 proteins are very important in regulating cell cycle progres-

Key Points: • Palbociclib has received a Breakthrough Therapy designation from the FDA for the treatment of patients with breast cancer • A randomized, multicenter, double-blind phase III trial is now open and enrolling

Targeted Therapy News • 5.13

News Targeted Therapies: Breast Cancer

sion,” said Richard Finn, MD, Division of Hematology/Oncology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS). “In evaluating a potential role for this molecule in breast cancer, we used preclinical models and determined that there appeared to be a preferential activity for this molecule and this novel mechanism of action in models representing ER-positive breast cancer as well as those representing HER2-amplified breast cancer.” The results from a two-part phase II study of palbociclib were presented at SABCS. Postmenopausal women with

ER-positive/HER2-negative advanced breast cancer were randomized 1:1 to receive letrozole plus palbociclib or letrozole alone. Pooled results from both parts demonstrated a median progression-free survival of 26.1 months with the combination (95% CI, 12.7–26.1) compared with 7.5 months with letrozole alone (95% CI, 5.6–12.6). This represented a 63% improvement in risk of progression (hazard

Richard Finn, MD

ratio [HR]=0.37; 95% CI, 0.21–0.63, P < .001). The most commonly reported adverse events were neutropenia, leukopenia, anemia, and fatigue. Response rates in patients with measurable disease were 45% for the combination arm versus 31% for letrozole alone. The clinical benefit rate, which represented complete and partial response rates plus stable disease, was 70% compared with 44%, respectively.

Study 1008, a randomized, multicenter, double-blind phase III trial, is now open and enrolling. The study will compare palbociclib and letrozole to letrozole alone as first-line treatment for postmenopausal patients with ERpositive, HER2-negative breast cancer with locally advanced or metastatic disease. TTN Finn RS, Crown JP, Lang I, et al. Results of a randomized phase 2 study of PD 0332991, a cyclindependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4 – 8, 2012; San Antonio, Texas. Abstract S1-6.

Targeted Therapies: Lung Cancer

HER2-Targeted Agents May Benefit Patients With Non-Small Cell Lung Cancer By Ben Leach

large retrospective study has found that rare mutations of the human epidermal growth factor receptor 2 (HER2) gene in patients with non-small cell lung cancer (NSCLC) potentially could be treated with HER2targeted drugs. The study was published in the Journal of Clinical Oncology. HER2 mutations are more closely associated with certain types of breast cancer, but HER2 protein overexpression occurs in 6% to 35% of patients with NSCLC, and HER2 gene amplification occurs in 10% to 20% of patients. Actual mutations of the HER2 gene only occur in 1% to 2% of patients with NSCLC, and are more frequently observed in female patients, nonsmokers, and patients with the adenocarcinoma subtype. Because a number of HER2-targeted agents, including trastuzumab, pertuzumab, and lapatinib, have already been approved to treat other tumor types, it may be that these agents could be used to successfully treat HER2-mutated NSCLC. Previous studies of HER2targeted therapies in patients with NSCLC showed only a minimal benefit, but those studies were done in patients with HER2 overexpression, but not necessarily a HER2 mutation. In this retrospective study, mutations of HER2 were identified in 65 out

Targeted Therapy News • 5.13

of 3800 (1.7%) patients with NSCLC in France, Switzerland, and Spain. Patients with mutated HER2 were mainly female (45 women vs 20 men), neversmokers (n=34; 52.3%), and had adenocarcinomas, with approximately 50% of patients identified as having stage IV disease at the time of diagnosis. These characteristics matched the patient profile of HER2-mutated NSCLC suggested by previous studies. A total of 33 patients with stage IV or recurrent NSCLC received conventional chemotherapy (a platinum-based doublet with or without bevacizumab). Of those, 16 patients also received HER2targeted therapies. Some patients received either two (n=3) or four (n=1) different HER2-targeted drugs, so that a total of 22 individual anti-HER2 treatments were evaluable across the 16 patients. Of the 16 patients, four had progressive disease, seven had disease stabilization, and 11 had partial responses, with an overall response rate of 50% and a disease control rate of 82%. The disease control rate was 93% in patients who received trastuzumab-based therapies (n=15) and 100% in patients who received afatinib (n=3). However, no response to other targeted therapies was observed (n=3). The median progression-free survival for patients who re-

ceived HER2-targeted therapies was 5.1 months. The median survival was 89.6 months in patients with early-stage disease and 22.9 months in patients who had stage IV disease.

“Our study suggests that many patients with HER2 mutations may benefit from antiHER2 drugs.” —Julien Mazières, MD, PhD

“Our study suggests that many patients with HER2 mutations may benefit from anti-HER2 drugs,” said Julien Mazières, MD, PhD, professor of Pulmonology at Larrey Hospital in Toulouse, France, and lead author of the study, in a statement. “While this benefit still needs to be confirmed in a prospective clinical trial, we hope that, based on this and other studies, HER2 status will

Key Points: • HER2 mutations in NSCLC potentially can be treated with HER2-targeted drugs, according to the results of this small preliminary study • Prospective clinical trials are needed

be taken into account when making treatment decisions.” Mazières said that more data should be available to evaluate the efficacy of HER2-targeted agents in NSCLC within the next year or two. TTN Mazières J, Peters S, Lepage B, et al. Lung cancer that harbors a HER2 mutation: epidemiologic characteristics and therapeutic perspectives [published online ahead of print April 22, 2013]. J Clin Oncol. doi:10.1200/JCO.2012.45.6095.

Feature

Nongenetic Mechanisms (continued from cover) and growth patterns and responded differently to chemotherapy. The findings suggest that there are more mechanisms that contribute to cancer treatment failure than simply acquired genetic mutations of the tumor. To understand whether the cells of a tumor that drive tumor growth are genetically the same, and whether these cells could have different functions, the authors both dissected the genetic sequences of the cells and performed functional tests on individually marked cells to measure how well each cell could drive tumor growth. Fluorescently labeled CRC cells derived from 10 human colorectal tumors were transplanted into mice and allowed to grow into a new tumor with the same genomic makeup as the original, tumor-initiating cells. Cells from these tumors were then serially transplanted, up to five times, into other mice and allowed to form new tumors. Each time, the genome of the CRC tumor remained stable. The time to form a stable tumor was the same over serial transplants, and each clone retained characteristics of the original human tumor. The authors found that genetics could not explain the different behaviors of the tumors. The genetic clones that were selected in the mouse models remained very stable, yet the tumor cells displayed markedly different types of growth behaviors. While some cells divided rapidly when transplanted into new mice, others did not reproduce well through serial transplantations. Still other cells did not grow well upon a first or second serial passage, but then regained the ability to grow well upon

subsequent passages. A total of five distinct functional behaviors were observed among the clones. “The distinct proliferative kinetics of the five clonal behaviors we observed underscore the functional variability of individual cells,” the authors wrote. Both deep sequencing of mutational hotspots and copy number alteration analysis were used to assess genomic diversity. When the transplanted tumor cells were exposed to chemotherapy, they also exhibited a range of distinct responses. Mice with established CRC tumors that were marked to distinguish single cells were treated with the chemotherapy oxaliplatin, and these chemotherapy-exposed cells were then transplanted into a new mouse. The resulting tumors were generated predominantly by previously slow-growing and dormant clones, similar to the behavior of the nonchemotherapy-exposed cells in the original experiment. This suggests that chemotherapy may select for the survival of those cells that are slow-growing or even dormant. These cells can then re-initiate tumor growth posttreatment, which could account for disease recurrence after initial response to chemotherapy. “The biggest surprise was when we found that quiescent or slowly cycling cells survive chemotherapy better than their highly proliferative counterparts,” said Kreso. These chemotherapy-exposed cells still had very similar genetic profiles to the original, nontreated cells, suggesting a nongenetic way in which cells can outlive anticancer therapy. The genetic variability of subclones within a tumor contributes to tumor

growth and survival. Different types of stress and exposure to anticancer therapy can select for the growth of subclones that are able to overcome treatment, resulting in outgrowth of tumor cells and contributing to disease recurrence. But while researchers have presumed that genetic driver mutations—those either selected or acquired—result in therapy resistance, acquired driver mutations may not always be associated with tolerance or resistance to a therapy, according to the new study. Kreso and colleagues are now working to understand the nongenetic factors that play an important role in tumor cell behavior, especially response to chemotherapy. “We want to identify the epigenetic or environment factors that influence [a cell’s functional properties],” Kreso explained. One approach is to compare the epigenetic marks between cells with different growth kinetics observed in this study. “If we can gain a better understanding of the factors that control cancer cell behavior, we may be able to design more specific therapies.” The researchers are also determining both the number and the functions of genetically different clones, as well as the heterogeneity between the different clones. Kreso believes that the basic principles observed in their analysis are likely to extend to other epithelial cancers. These results have implications about how to identify novel anticancer targets. “We have to broaden our search and look for more than just genetic mutations to target tumor growth,” said Kreso. Techniques to test novel thera-

other companies from developing tests that identify BRCA1 and BRCA2 mutations. In a statement from the Association for Molecular Pathology, a plaintiff in the case, patents on genes have the potential to cause monopolies and restrict access to databases containing genetic information acquired through these tests. “Gene patents prevent pathologists from reading their patients’ DNA sequences to assess their risks for disease, their prognoses, or their potential responsiveness to therapy,” said Iris Schrijver, MD, director of the Molecular Pathology laboratory at Stanford University and past president of the Association of Molecular Pathology, in a statement released when the association appealed a ruling in favor

of the patent in September. “The result of this lack of competition is increased test costs, decreased patient access, reduced innovation in the development of new test methods, and dramatically reduced knowledge dissemination.” However, not all physicians who use the test feel as though the patent is harmful to patients or researchers. In an interview at the 30th Annual Miami Breast Cancer Conference in March, Patrick I. Borgen, MD, chair of the department of Surgery at Maimonides Breast Cancer Center at Maimonides Medical Center in Brooklyn, New York, said that in his personal experience with frequent use of the test for research, Myriad has not impeded his ability to get work done. Likewise, he

Key Points: • Researchers have been able to track the growth of single human tumor cells into tumors over time in mice • Tracking human colorectal cancer cells, the researchers were able to show that not just genes, but other biological factors can contribute to the growth and behavior of the colorectal tumor cells and contribute to failure of therapy and cancer relapse • The results challenge the traditional notion that the properties of tumor cells, including resistance to treatment, are dictated only by the genetic makeup and spectrum of tumor mutations pies also need to move beyond in vitro cell line growth assays to testing the ability of tumor cells to form new tumors. Particularly, identification of ways to prevent metastasis remains a major hurdle in cancer treatment. “It will be interesting to see whether some tumor cells are more efficient at forming metastasis, whether this is linked to the cell types we have described, and which genetic or epigenetic factors contribute to this behavior,” said Kreso. TTN Kreso A, O’Brien CA, van Galen P, et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science. 2013;339(6119):543-548. doi: 10.1126/science. 1227670.

BRCA Patenting Case (continued from cover) Before any insurance coverage, the test costs approximately $3,340. In 2010, the American Civil Liberties Union (ACLU) filed a lawsuit against the US Patent and Trademark Office, as well as Myriad Genetics and the University of Utah Research Foundation. The lawsuit charged that human gene patents are invalid as they are “products of nature.” The US Patent and Trademark Office has been awarding patents on genes for about 30 years. According to a study published earlier this year in the journal Genome Medicine by Jeffrey A. Rosenfeld and Christopher E. Mason, there are patents on approximately 41% of the genes that have been identified in the human genome. This patent, which will expire in approximately two years, has prevented

said that there have not been arbitrary price increases on the test. In 2012, the US Court of Appeals for the Federal Circuit declared the isolated DNA of the BRCA1 and BRCA2 genes falls under the category of patent-eligible material. “This case has potentially broad implications for the biotech, animal health and agricultural industries and the development of products and services of enormous benefit to society,” said Peter Meldrum, president and CEO of Myriad. “Countless companies and investors have risked billions of dollars to research and develop scientific advances under the promise of strong patent protection.” A ruling from the Supreme Court is expected this summer. TTN

Targeted Therapy News • 5.13

Feature Feature Colorectal Cancer (continued from cover)

CRC is approximately 50%, but for stage IV it is only 6%, according to the American Cancer Society. It is estimated that nearly 52,000 men and women died of colorectal cancer in the United States in 2012, according to the National Cancer Institute. Regorafenib was approved based on the results of the phase III CORRECT trial, which demonstrated an improved median overall survival (OS) of 1.4 months versus placebo in patients with mCRC that had progressed on previous therapy. The results were initially presented at the annual American Society of Clinical Oncology (ASCO) meeting in June 2012,1 and updated survival data were subsequently presented at the annual European Society for Medical Oncology (ESMO) meeting in September/October 2012.2 The full trial results have been published in The Lancet.3 The CORRECT trial randomized 760 patients in a 2:1 ratio to receive either 160 mg of once-daily regorafenib plus best supportive care or placebo plus best supportive care. Patients all were previously treated for mCRC with either oxaliplatin-, irinotecan-, or fluoropyrimidine-based chemotherapy or with bevacizumab. Median OS was 6.4 months in the regorafenib arm compared with 5.0 months in the placebo arm (P =.0052). The OS rate at 12 months was 24.1% in the regorafenib arm compared with 17% in the placebo arm. The median progressionfree survival (PFS) was 2.0 months in the experimental arm compared with 1.7 months in the placebo arm (P <.0001). Regorafenib reduced the risk of progression by 51%. “I think many oncologists are adopting the use of regorafenib,” said Randall F. Holcombe, MD, professor of Medicine, Hematology and Oncology at Mount Sinai Hospital and deputy director of the Tisch Cancer Institute in New York City. “We have many patients who have progressed on all standard therapies. [The drug is a good option], especially for those whose tumors harbor a KRAS mutation, who are not candidates for EGFR antibody therapy, but who still have a good performance status and are looking for additional treatment options.” “Regorafenib is not a drug without toxicities,” said Holcombe. “Patients can have fatigue, fever, rash, including a hand-foot syndrome, mucositis, diarrhea, fluid retention and anorexia.” Treatment-related toxicities occurred in the vast majority, 93%, of patients on regorafenib therapy. Serious side effects included hepatotoxicity, hemorrhage, and gastrointestinal perforation. According to Axel Grothey, MD, of

Targeted Therapy News • 5.13

the division of Medical Oncology at the Mayo Clinic in Rochester, Minnesota, and lead author of the CORRECT trial, it is sometimes difficult to decide if the symptoms experienced on therapy are truly drug- or tumor-related. Grothey noted that side effects on regorafenib tend to occur within the first two weeks of treatment, when patients should be closely monitored. Regorafenib is a multikinase inhibitor that targets various intracellular and membrane-associated kinases involved in angiogenic, stromal, and oncogenic signaling. Its targets include VEGFR1 and 2, KIT, FGFR1 and 2, BRAF, and the Abl kinase.

New Targets, New Drugs in Development As data on the genetic basis of CRC accumulate, new treatment targets are emerging. For example, the BRAF kinase is mutated in 5% to 10% of mCRC. An extensive analysis of 276 colon and rectal tumors by The Cancer Genome Atlas Network confirmed genetic targets and identified novel genes frequently mutated, as well as chromosomal rearrangements and amplifications.4 KRAS and PIK3CA, the phosphatidylinositide 3-kinase catalytic subunit of the PI3 kinase, were both identified among the eight most frequently mutated genes in either colon or rectal tumors. Such detailed analyses continue to lead to a better understanding of the important genes and pathways involved in CRC development and progression. This knowledge is facilitating not only the development of new targeted agents, but also allowing for risk stratification based on molecular subtypes and molecular predictors of response to therapies.

Oral Kinase Inhibitors in Development Several oral tyrosine kinase inhibitors (TKIs) are currently in development for advanced CRC. Cediranib, an oral inhibitor of VEGF kinase, has been tested in a phase III trial in combination with chemotherapy for first-line mCRC in comparison with bevacizumab plus chemotherapy. The HORIZON III trial5 demonstrated that cediranib was similar to bevacizumab in terms of OS and PFS. Unfortunately, the study also found that cediranib was associated with worse patient-reported outcomes, resulting in interruption of treatment, noted Holcombe. Trials with other TKIs are still awaiting results. Tivozanib, also an oral VEGF inhibitor, is currently in a phase II trial in combination with chemotherapy versus bevacizumab in patients with

treatment-naïve mCRC. Apatinib, an oral, selective inhibitor of the VEGF receptor-2 is being tested as a monotherapy for advanced CRC. “Any of these oral tyrosine kinase inhibitors may have an advantage over bevacizumab, although it is not clear which if any will prove to be superior to bevacizumab yet,” said Holcombe. “The oral mode of administration is appealing if the toxicity profile is not worse than that of bevacizumab.” Regorafenib is being tested both in the first- and second-line CRC setting in combination with chemotherapy. Grothey sees regorafenib moving into these earlier treatment settings. Currently, bevacizumab is the most frequently used biologic agent in advanced CRC. These TKIs are promising, but not as add-on therapies to standard firstline chemotherapy FOLFOX, which is “a graveyard for many interesting agents,” Grothey said. Instead, he believes that regorafenib should be tested as a maintenance monotherapy after first-line induction with chemotherapy.

Other Targeted Agents Several oral agents that target the PI3K pathway are in phase I development for cancers that include advanced CRC. These include BKM120, a specific class I PI3K inhibitor, and DS-7423, a dual inhibitor of PI3K and mammalian target of rapamycin (mTOR) kinase. “Combinations of inhibitors targeting the MAP kinase pathway, including BRAF and MEK along with PI3K inhibitors, are promising,” said Grothey. Holcombe agrees. “I think agents targeting the PI3K/AKT signaling pathway are potentially especially promising,” he said. “These agents will likely need to be combined with either traditional chemotherapy or other biologics for maximal effectiveness because of redundancy in signaling pathways,” Holcombe added.

Prognostic and Predictive Biomarkers Many clinical trials for CRC now include biomarker analyses as part of the drug development. For example, it has been known for some time that those patients whose CRC tumor harbors a mutation in the KRAS gene do not respond to treatment with cetuximab, an anti-EGFR antibody. About 30% to 50% of patients with CRC have a KRAS mutation. The FDA has recently approved a polymerase chain reaction (PCR)based screening test to determine the KRAS mutation status of a CRC tumor. The test recognizes seven frequent mutations in the KRAS gene.

Mutations in the BRAF gene also are a likely predictor of nonresponse to anti-EGFR therapy. Many other molecular biomarkers are still in early development awaiting clinical validation testing. For antiangiogenesis therapy, there is not likely to be a single marker that can predict response to treatment, Grothey said. If any biomarkers are identified, they will likely be quantitative, generating a predictive value score on a continuous scale. “Angiogenesis is a very complicated process involving signals from the tumor cells, but also from the stromal cells in the tumor microenvironment,” said Holcombe. “The process also involves the ability of endothelial cells in this tumor environment to respond to a variety of signals.” This is one reason that simple biomarkers, particularly molecular biomarkers, are not likely for antiangiogenesis therapy. Many more studies are needed to understand how molecular mutations can dictate either response or resistance to a targeted therapy. A molecular mutation or genotype is not always associated with a particular treatment response or phenotype because of the complexity of the genetics of CRC. Datasets such as that created by The Cancer Genome Atlas Network will continue to serve as tools for both the creation of new therapies and for predictive and prognostic biomarker approaches. Furthermore, analyses of epigenetic alterations and other layers of complexity will need to be integrated for a full understanding of what drives colorectal cancer. TTN 1. Van Cutsem E, Sobrero AF, Siena S, et al. Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC). J Clin Oncol. 2012;30 (suppl; abstr 3502). 2. Van Cutsem EJD, Grothey A, Laeuven BE. Phase 3 CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC): overall survival update. Presented at: 38th European Society for Medical Oncology (ESMO) Congress; September 28-October 2, 2012; Vienna Austria. Ann Oncol. 2012;23(suppl 9; abstr LBA18). 3. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. The Lancet. 2013;381(9863): 303-312. 4. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407): 330-337. 5. Schmoll HJ, Cunningham D, Sobrero A, et al. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a doubleblind, randomized phase III study (HORIZON III). J Clin Oncol. 2012;30(29):3588-3595.

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

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

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

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

Randomization Randomization Randomization Randomization Randomization Randomization Randomization

1 11 1 BELLE-3 BELLE-3 BELLE-3 BELLE-3 1 1 1 BELLE-3 BELLE-3 BELLE-3

Evidence of Evidence Evidence Evidence of progression ofprogression progression of progression Evidence Evidence Evidence of progression of progression ofmTOR progression mTOR onon or onor after or onafter after ormTOR after mTOR on or on after or on after or mTOR after mTOR mTOR inhibitor-based inhibitor-based inhibitor-based inhibitor-based inhibitor-based inhibitor-based inhibitor-based treatment treatment treatment treatment treatment treatment treatment

Buparlisib Buparlisib Buparlisib Buparlisib + fulvestrant ++fulvestrant +fulvestrant fulvestrant Buparlisib Buparlisib Buparlisib + fulvestrant + fulvestrant + fulvestrant

Placebo Placebo Placebo Placebo + fulvestrant ++ fulvestrant +fulvestrant fulvestrant Placebo Placebo Placebo + fulvestrant + fulvestrant + fulvestrant

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

Buparlisib Buparlisib (BKM120) Buparlisib (BKM120) is(BKM120) an investigational is an investigational is an investigational new drug. new drug. Efficacy new drug. Efficacy andEfficacy safety and safety have and safety not have been not have established. been not established. been established. Buparlisib (BKM120) new drug. Efficacy andavailable. safety have notestablished. been established. There There is no(BKM120) There guarantee is no guarantee is no that guarantee buparlisib that buparlisib buparlisib become willdrug. become will commercially become commercially commercially available. Buparlisib Buparlisib Buparlisib (BKM120) is(BKM120) anisinvestigational isan aninvestigational investigational isthat anwill investigational new new drug. Efficacy new drug. Efficacy and Efficacy safety and safety have andavailable. safety not have been not have been not established. been established. There that will commercially available. There There is nois1There guarantee isnonoguarantee guarantee is nothat guarantee buparlisib thatbuparlisib buparlisib thatwill buparlisib become will become become will commercially become commercially commercially available. available. available. 1 1 Additional Additional inclusion/exclusion Additional inclusion/exclusion inclusion/exclusion criteriacriteria apply. criteria apply.apply. 1 Additional inclusion/exclusion criteria apply. 1 1 1 Additional Additional inclusion/exclusion Additional inclusion/exclusion inclusion/exclusion criteria criteria apply. criteria apply.apply. Abbreviations: Abbreviations: Abbreviations: ECOG, ECOG, Eastern ECOG, Eastern Cooperative Eastern Cooperative Cooperative Oncology Oncology Group; Oncology Group; HER2–, Group; HER2–, human HER2–, human epidermal human epidermal growth epidermal growth factor growth factorfactor Abbreviations: ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor receptor 2-negative; receptor 2-negative; 2-negative; HR+, hormone HR+, hormone HR+, receptor-positive; hormone receptor-positive; receptor-positive; mTOR, mTOR, mammalian mTOR, mammalian mammalian target target of rapamycin; target ofgrowth rapamycin; ofgrowth rapamycin; Abbreviations: Abbreviations: Abbreviations: ECOG, ECOG, Eastern ECOG, Eastern Cooperative Eastern Cooperative Cooperative Oncology Oncology Group; Oncology Group; HER2–, Group; HER2–, human HER2–, human epidermal human epidermal epidermal factor growth factor factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; PI3K, receptor PI3K, phosphatidylinositol PI3K, phosphatidylinositol phosphatidylinositol 3-kinase. 3-kinase. 3-kinase. receptor 2-negative; receptor 2-negative; 2-negative; HR+, hormone HR+, hormone HR+, receptor-positive; hormone receptor-positive; receptor-positive; mTOR, mTOR, mammalian mTOR, mammalian mammalian targettarget of rapamycin; target of rapamycin; of rapamycin; PI3K, phosphatidylinositol 3-kinase. PI3K, PI3K, phosphatidylinositol PI3K, phosphatidylinositol phosphatidylinositol 3-kinase. 3-kinase. 3-kinase.

Pioneering Pioneering Research ofPioneering Research PI3K inhibitors ofResearch PI3Kininhibitors Malignancies of PI3Kininhibitors Malignancies in Malignancies Pioneering Pioneering Research ofPioneering Research PI3K inhibitors ofResearch PI3K ininhibitors Malignancies of PI3Kininhibitors Malignancies in Malignancies Pioneering Research of PI3K inhibitors in Malignancies

Novartis Novartis Pharmaceuticals Novartis Pharmaceuticals Pharmaceuticals Corporation Corporation Corporation EastNovartis Hanover, East Hanover, East NJ Hanover, 07936 NJ 07936 NJ 07936 Novartis Novartis Pharmaceuticals Novartis Pharmaceuticals Pharmaceuticals Corporation Corporation Corporation Pharmaceuticals Corporation EastEast Hanover, EastHanover, Hanover, East NJHanover, 07936 NJ07936 07936 NJ 07936 NJ

August August 2012 August 2012 2012 August August 2012 August 2012 2012 August 2012

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

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Integrating Novel Agents Into the Treatment of Prostate Cancer Case-Based Discussion By Beth Fand Incollingo

n the wake of the approval of several novel treatments for prostate cancer—including antiandrogens enzalutamide and abiraterone and immunotherapy sipuleucel-T, physicians must now focus on how best to integrate new therapies into the treatment of patients with prostate cancer. At the 2013 Annual Interdisciplinary Prostate Cancer Congress (IPCC), in New York City, researchers reviewed the latest strategies and therapeutic agents available for patients, and held a case-based discussion to build consensus about best treatments. The cases were presented by IPCC Co-Chair Leonard Gomella, MD, and discussed by a panel that included Co-Chair Daniel P. Petrylak, MD; Robert Dreicer, MD, MS; E. David Crawford, MD; and Susan Slovin, MD.

Case 1 Gomella: The patient is a 55-year-old white male. His father died of prostate cancer at 65 years of age, and no other family members have any history of prostate cancer. The patient is worried and wants to be checked, although he’s done some reading and is doubtful about the value of the prostate-specific antigen (PSA) test. What do you tell him? Dreicer: The patient is at risk, since he had a first-degree relative who was impacted. Screening is reasonable for him. Petrylak: I’d tell him that PSA has its implications. If it’s elevated, he’ll need a biopsy, and then he’ll have to choose either local therapy or observation. I would do it if I were him. But he needs to know what the studies say. Slovin: I would explain the pros and cons and then leave it up to him, although I probably would give him the strong arm because his risk is at least two-fold higher than Joe Blow’s next door as a result of his family history. I’d also make sure he’s had a screening colonoscopy. Crawford: One family member probably doesn’t increase risk a lot. You’ve got to have two or three to be at a higher risk. Gomella: The patient has his PSA tested and it’s deemed normal at 1.1 His digital rectal exam is normal. Can you tell him he doesn’t have prostate cancer? Crawford: No. Based on the results of the Prostate Cancer Prevention Trial [in which 15% of men with PSAs of <4 ng/ mL were found to have prostate cancer], he still faces a risk.1 I’d do a Prostate Cancer Gene 3 (PCA3) test on him.

Targeted Therapy News • 5.13

Gomella: Even though he hasn’t had a biopsy yet, you would jump the fence on the PCA3 and use it sort of off-label? The labeled indication is to see if a second biopsy is needed. Crawford: Yes. Gomella: What I tell my residents—and my patients—is that we’re finding our way with PCA3, but that we have a lot of questions. Still, I’d rather have a PCA3 in the bank in case some breakthrough comes up over the next couple of years.

Petrylak: He needs a repeat biopsy. I would do a saturation biopsy. Gomella: How about PCA3, if he didn’t have it before? Petrylak: It probably would be appropriate, but I still think he’s going to need a biopsy. Gomella: What about freeto-total PSA? Is anyone using that anymore? We asked this question two years ago and just about everybody put their hands up, and now, as I look around, there seems to be a lot of cooled enthusiasm.

What would the audience do in this setting? The So, you can’t tell the pachoices are: (1) perform a tient he doesn’t have prosbiopsy; (2) repeat the PSA tate cancer. What would Leonard Gomella, MD test; (3) check free-to-total you do next? PSA; or (4) check PCA3. Slovin: I would ask him to Okay, 61% said biopsy, 22% repeat PSA, 7% repeat a PSA in a short period of time to free-to-total PSA, and 9% PCA3. get a sense of how rapidly it’s going up. Dreicer: I’d do a PCA3 first, though. Gomella: I agree, although it does scare me a little bit that his PSA had had such a rapid rise. Crawford: The PCA3 would make me feel better about doing another biopsy.

“What I tell my residents—and my patients—is that we’re finding our way with PCA3, but that we have a lot of questions. Still, I’d rather have a PCA3 in the bank in case some breakthrough comes up over the next couple of years.”

—Leonard Gomella, MD Gomella: Let’s assume he had a biopsy a year ago that was completely normal. Now he comes in and his PSA has gone up to 5. He still has a normal digital rectal exam. What would you do next?

Crawford: A lawyer told me the other day that he’s defending a urologist for that very thinking. The patient was just like this one: negative biopsy, negative biopsy, negative biopsy, PSA not even up this high, and so he didn’t do anything. A couple of years later he’s got metastatic disease, and they’re saying he should have had a TUR biopsy. But to me, what takes the place of the TUR biopsy are the staging and mapping biopsies. We’ve actually shown that if you take those biopsies and you correlate them to whole mount radical prostatectomy specimens, they’re just as accurate, if not more accurate, at predicting what’s there. Audience member: I have a question about PSA leaks in people who’ve had multiple biopsies. I’ve certainly done three or four biopsies on people, but I worry that I have created the [elevated] PSA with all the [needle] sticks. Gomella: Dave, with all those needle sticks in the prostate, are you making a leaky prostate, making neovascular channels when it heals, and sending more PSA out to the bloodstream? Crawford: I don’t buy it.

Gomella: There’s some data out there Gomella: The patient comes back three years now saying that the more biopsies you later and his PSA is up to 8. He’s had at least have, the more difficult it may be to spare three sets of 12-core biopsies, and they’ve all nerves when you get treated definitively been negative. Now where with a radical prostatectare we? omy. What do you think Crawford: This is a guy about that, Dave? that I would get the MRI Crawford: Well, I’ve had on, and the mapping bia lot of experience in opsies. I’d also consider going in after mapping. the fact that, every time Since the mapping is you have one negative done transperineally, biopsy, your risk goes it’s not much more diffidown. If the guy is tired cult to do. In the people of biopsies or his insurthat have had a couple ance company won’t of what you described pay for more, I’d also as saturation biopthink about putting sies, which are tranhim on dutasteride to srectal, that has been see what his PSA does, difficult. Daniel P. Petrylak, MD because I’ve seen people like this go from 8 to Gomella: So what can a pa1 again, or at least cut their PSA in half. tient like this do to prevent prostate cancer, and what should you recommend? Gomella: Dave, what about transurethral Slovin: There are data that there is some (TUR) biopsy? We used to do that in the ’90s benefit to changing the diet, limiting the when we ran into this situation. It was sort of amount of red meat. And while I recoman anterior biopsy. Is this a dead issue now mend that for some patients who are because of MRIs? on the heavier side, I don’t know that

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it’s something we would do for everybody. The question is, do I put him on dutasteride or finasteride? I’d be a little worried, but you can make an argument that if the prostate shrinks down a little bit more, it’s going to be easier to find a Gleason 8 or 9 cancer sitting there waiting for us. Gomella: It’s kind of disappointing that we don’t have this as an approved prevention strategy, since we have two large clinical trials that show a 20% to 25% relative risk reduction with 5 alphareductase inhibitors, and data from trials such as CombAT demonstrating no increased risk of high-grade cancer.2 Dr. Dreicer, you’ve been involved in some drug discussions at the FDA level. Do you think there’s any chance that this thing could get resurrected?

“In my opinion, chemo prevention trials in prostate cancer are dead, because it’s too risky.” —E. David Crawford

Dreicer: None. Crawford: Less than none. We’ve been through so many things on the prevention of prostate cancer: vitamin E, and selenium, and saw palmetto, and the 5-alpha reductase inhibitors, and Vioxx. I think the benefit of 5-alpha reductase inhibitors is real, but we also need to document the risk of high-grade cancer, which is probably volume-related. In my opinion, chemo prevention trials in prostate cancer are dead, because it’s too risky. Gomella: You may also be familiar with the data that came out a few years ago that patients with advanced prostate cancer who went on hyper-vitamin therapy actually had a worse outcome. They progressed more rapidly. So we have to convince our patients that more is not necessarily better. Petrylak: That was demonstrated in the SELECT trial, too.3 The trial took all comers, and you wonder what giving these vitamins at high dosages to somebody who has a normal level is going to do to their prostate tissue. A lot of these agents are yin-yang: In low doses they may be inhibitory, in high doses they may be stimulatory. So when designing these studies in the future, you’re going

to have to look at levels and see whether you’re supplementing something that doesn’t need to be supplemented. Gomella: And despite this data, we still find all our patients taking vitamin E

and selenium to prevent prostate cancer, which is really sad.

Case 2 Gomella: The patient is a 62-year-old who de-

velops urinary frequency. His primary care doctor detects a nodule on rectal exam and a PSA of 82. A urologist does a biopsy and finds Gleason 7 cancer. A bone scan shows four lesions in the lumbar sacral spine, and

B:8.25” T:7.5” S:6.75”

INVESTIGATIONAL PHASE 3 TRIALS CURRENTLY ACCRUING

Cabozantinib phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases 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

Randomized, double-blind, controlled trial

Mitoxantrone + Prednisone

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a CT scan of the abdomen shows retroperiI could make the argument that if he toneal lymphadenopathy. The patient underwent into a complete biochemical ragoes combined androgen blockade. His PSA diographic remission, I would have rabottoms out at less than 0.1 seven months diated his prostate for local control and after the blockade is started, and he remains maybe used adjuvant hormones for an on continuous androgen blockade for about extra year, and then gotten him off evthree years. His PSA then begins to slowly erything. He’s a young guy, and the law rise from 0.2 to 0.8 to 1.0 over a six-month does not say one should stay on horperiod. On bone scan, progression is noted mones for ever and ever. with two more spots in the ribs. A CT scan of Dreicer: Clearly we’re going to stop his the abdomen and pelvis shows resolution of bicalutamide—that’s a no brainer—and retroperitoneal adenopathy, and the patient if you’re going to think about immufeels pretty good. He’s not in any pain, and he nomodulatory therapy, this might be has a good appetite and a good performance a very good patient to use it in. Even if status. At this point, what would you do? he has an antiandrogen withdrawal reAudience choices are: (1) discontinue bicalusponse, you could argue that that’s okay, tamide and monitor for and may make him antiandrogen withdrawal even a better candidate. syndrome; (2) start second-line hormonal therapy Gomella: The patient’s teswith ketoconazole and tosterone is 55 and he’s hydrocortisone; (3) give been getting leuprolide. him sipuleucel-T; (4) do What would you do at that numbers 1 and 2; or (5) do point? numbers 1 and 3. Petrylak: One option The results are pretty would be to put him even. Twenty-eight percent on abiraterone, which would stop the bicaluwould reduce his testamide and monitor for tosterone even further. antiandrogen withdrawal, A second would be to 24% would give him sipuput him on degarelix, leucel-T, 12% would do 1 which could also lower Robert Dreicer, MD and 2, and 30% would do his testosterone. Of antiandrogen withdrawal course, the final option and sipuleucel-T. At 6 %, it looks like ketoconis simply to do an orchiectomy. azole and hydrocortisone do not have a lot of Gomella: An important point, and one traction right now. that Dr. Crawford has been out in the Petrylak: The only times I’ve used kelead on, is that our LHRH analog theratoconazole in a patient who’s castratepies are one-size-fits-all. If you have a resistant is when the patient has non98-pound gentleman and a 300-pound metastatic disease. Except in that situgentleman, they get the same dose of ation, abiraterone has superseded ketothe LHRH analog, and there are some conazole in this clinical state. issues now to suggest that the mode of Slovin: I’ve gone back to ketoconazole, administration and obesity can actually affect absorption and utility. So, at our shop, we’ve flipped people from goserelin to triptorelin, or triptorelin to leuprolide, and I have to say that we’ve always gotten their testosterone to come down. Crawford: In a study, we looked at patients with T (testosterone) less than 50 who went on sipuleucel-T, and then [investigational] GTx-758 and a couple of other agents, and watched T levels. Twenty-one percent of participants had T levels above about 20. Orchiectomy gets you to 14 to 17. And so, theoreti—Susan Slovin, MD cally, these patients aren’t castrate. And maybe the reason 20% to 30% of people because abiraterone is not always covrespond to secondary androgen ablaered by insurance. Ketoconazole is not tion is because they weren’t totally supas effective, and it has more toxicity, but pressed to begin with. if you’re in a dither it’s the best one to Slovin: While we’re getting serum tesuse. On this particular patient, though, tosterone levels down, we still are never

“I’ve gone back to ketoconazole, because abiraterone is not always covered by insurance.”

Targeted Therapy News • 5.13

100% sure of intratumoral testosterone levels. That’s always sitting in the background. Dreicer: And the testosterone assays most of us use in the hospitals are not very sensitive, especially at the low level. Crawford: You’ve got to also measure the free T level. Gomella: The patient gets sipuleucel-T and, at one month post-therapy, his PSA continues to rise to 20 and then to 30. His bone scan is stable with no new lesions. He has no complaints and feels well. Six months later, his bone scan stays stable and his PSA goes up to 50. What would you tell him now about the sipuleucel-T? Slovin: I would tell him that we don’t know how long it takes to see a propitious antitumor response, and as long as his cancer is stable, it’s fine. Gomella: In this case, the patient was put on abiraterone and prednisone. Do you think he needed to be there, Rob? Dreicer: I would have been concerned that, in a relatively short period of time, he was going to become symptomatic, and I’d want to obviate that, so I think it’s eminently reasonable to have treated him.

abiraterone. Also, at this point, it’s not approved for that indication.

Case 3 Gomella: The patient is 69 years old and has Gleason 4+3 prostate cancer. His PSA is 9, and his rectal exam shows a T2a nodule. He is staged negative on bone scan and CAT scan, has good GU function, and is sexually active without PDE-5 inhibitors. He has had no previous pelvic radiation or irritable bowel disease, and his prostate size is about 40 ccs on transrectal ultrasound. Since he prefers radiation therapy, his options are brachytherapy, external-beam radiation, brachytherapy plus external-beam, protons, or all of the above. The audience selected all of the above (48%), external-beam (24%), brachytherapy plus external-beam (18%), brachytherapy (8%), and protons (2%). Dr. Crawford, what are your thoughts on this gentleman? Crawford: I think he has all of those things available. The current “sexy treatment” seems to be focusing on brachytherapy and how high the dose can go. So that’s what a lot of people are doing. Gomella: Probably mixing brachytherapy with external-beam would be a top option for him. But it’s almost dealer’s choice.

Gomella: So the next quesGomella: So the patient is tion is: What’s the benefit put on the abiraterone/ of adding hormonal therprednisone regimen, and apy in this patient who’s his PSA goes down. Eight getting radiation therapy? months after treatment, Would people do that? it’s down to 3. However, it Eighty percent of you say then goes up to 5 and then, yes, 20% say no. four weeks later, to 9. He We’re going to assume this has new or recurring retman is intermediate or roperitoneal adenopathy. higher-intermediate risk, His bone scan shows more Susan Slovin, MD and that’s probably a realesions, and he has lumsonable choice. Dave, do bosacral spine pain. He’s you have any thoughts about using an LHRH failed hormonal therapy, sipuleucel-T, and agonist or antagonist in these settings? Are abiraterone. What would the audience do for you still using combined androgen blockade? this gentleman? Crawford: I still believe in combined anThe choices are to give (1) enzalutamide, (2) drogen blockade. If you give an agonist, docetaxel/prednisone, or (3) cabazitaxel. you get a flare, testosterone goes up, Okay, 12% of you said enzalutamide, 72% the tumor gets bigger, and the prostate said docetaxel and prednisone, and 16% said gets bigger. If you’re trying to downsize, cabazitaxel. you’re wasting time. So combined anIt looks like the clear winner here is standard drogen blockade makes sense. There’s docetaxel and prednisone. Dan, any compretty good evidence about using an anments about using it in the setting of having tagonist where you don’t get that, and pain? some other advantages. So, we tend to Petrylak: The right situation to use it is use more antagonist activity. when the patient is symptomatic. As The other trend that’s interesting is far as your alternatives, there’s no data that the hormone therapy is kind of for using cabazitaxel in the frontline going away, except in really high-risk setting. With enzalutamide, we don’t patients, and that it’s being continued know what the response rate is after

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for less than two years, while the radiation dose is going up. The claim is that there’s less local failure because we’re able to get the gray up so high. But I don’t buy that. My argument is that a lot of these people who are getting hormones and radiation with intermediate and advanced disease are actually benefiting from treatment of micrometastatic disease with hormone therapy. Gomella: The other question that has been unanswered is: How many of these patients actually recover their testosterone level to some reasonableness? That’s something that the radiation/oncology community has not been enthusiastic about studying, because they think it’s not an important issue. Crawford: Another thing that never gets talked about is that when you radiate the prostate, you have radiation scatter that hits the testes and lowers testosterone. If you look at a few studies that have been done, the bump in testosterone down is not huge. It’s 10%, 20%, maybe even more. What effect does that have?

focal therapy there, but it’s just another way of getting the radiation into the gland.

Case 4

Gomella: Here’s another high-risk patient, an 83-year-old gentlemen with urinary retention and an inability to walk. His PSA is over 1000. An MRI of the spine shows a T12 epidural spinal cord compression. He undergoes a decompressive laminectomy that shows metastatic carcinoma of the prostate. His bone scan is extensively positive, with lesions in the left femur, axial and appendicular skeleton, the T12 vertebra, and the ribs. A CAT scan of the abdomen and pelvis shows no evidence of any visceral metastases. The patient is treated with androgen blockade, and seven months after therapy, his PSA is 12. Three months later he has pain in his back. A bone scan shows new lesions. His PSA has bounced up to 80 and he’s put on abiraterone, and now is also given denosumab. The bone scan continues to progress six months after treatment, and his pain worsens. He then goes on docetaxel and prednisone. He gets a good response after eight cycles. His pain improves. Gomella: Here’s a question However, after two more for the audience. If you cycles, his PSA goes up to were going to treat this 10 and then to 20. He gets man with external-beam very bad pain. He has a reradiation monotherapy, peat bone scan and now he what is the optimum dose has a lot of problems in his he should receive for localthoracic spine, but no epiized prostate cancer? The dural lesions. choices are (1) 66.6 gray What would you do for this (Gy) at 1.8 Gy/fraction; gentleman who’s wracked (2) 72 Gy at 1.8 Gy/fracE. David Crawford, MD with pain and has failed tion; (3) 79.2 Gy at 1.8 Gy/ multiple therapies? The fraction; or (4) 80 Gy at 2.0 choices are to give (1) isotope therapy with Gy/fraction. samarium; (2) isotope therapy with radiThirty percent of you say 80 Gy, 23% say 72 um-223; (3) palliative focal radiation to the Gy, and 6% say 66.6 Gy. Forty percent say thoracic spine; (4) abiraterone; or (5) enzalu79.2 Gy, and that’s about right. Once you tamide. start getting to 80 Gy with external-beam Okay, 60% of the group says radium-223. radiation, the toxicity goes up dramatically. Twenty-three percent went with palliaAudience member: What’s your opinion tive care, 11% with samarium, and 6% with about local radiation at this point? Not enzalutamide. No one chose abiraterone. the complete gland, but focal radiation? Radium-223 is only available on compassionCrawford: I think it’s a good idea to do ate release at a few centers around the US. extra loading of the seeds in the area Susan, what are your thoughts? that is involved, and then not as much Slovin: I could probably make an arguto cover the rest of the gland. ment for any of these. The only reason I Gomella: It might make theoretic sense would be reluctant to use enzalutamide from a standard-of-care standpoint, but is because he is symptomatic and you it’s nowhere in any kind of guidelines. want to get him out of his misery. If Crawford: They’re actually doing it at Meone were to assume radium-223 was morial Sloan-Kettering. And we’re going FDA-approved, I probably would be usto be joining them in a trial that will ining that, either alone or in concert with volve targeting, loading it to the lesion. another chemotherapy, if we had it, in a Gomella: High-dose radiation therapy is clinical trial. Cabazitaxel would be very being reconsidered in localized prostate reasonable, as well. cancer as well. We’re not talking about

Petrylak: There is a clinical trial available for this patient in the early stages of his disease. For those patients who do not normalize their PSA to less than 4, SWOG is looking at early abiraterone prior to progression. Second, Susan’s right: You can make an argument for anything here. I wouldn’t be so sure about using enzalutamide, though, because you’ve had already a short initial response to hormones, and you’ve seen abiraterone, so I don’t think he’s going to respond to that. I would agree with going with radium-223. Gomella: Are there any questions from the audience? Audience member: We never really talked about intermittent androgen therapy. What do the panelists think about that? Dreicer: The intermittent therapy question has been addressed by two randomized trials. If a patient has nonmetastatic disease, had radiation, and is deemed appropriate for hormones, I think there’s reasonable data from the Canadian trial, which suggests that it’s equivalent.4 The US intergroup trial led by SWOG addressed the question of intermittent therapy versus continuous in metastatic patients.5 I think the data are

“The other trend that’s interesting is that the hormone therapy is kind of going away, except in really high-risk patients, and that it’s being continued for less than two years, while the radiation dose is going up.” —E. David Crawford, MD

reasonably obvious that intermittent therapy is likely to be inferior to continuous therapy in a majority of those patients. And I think, for the majority of patients, continuous therapy should be

the standard of care. Audience member: What are your thoughts on the role of the sodium fluoride PET/CT bone scan? Dreicer: The problem with these new technologies is that they’re beginning to define what we’ve always known was happening. For example, we know that many patients with rapidly shortening PSA doubling time have systemic disease. We have clinically managed these patients for a long time using the technology that we have. So, if you have a positive bone scan or CT, you say you have radiographic evidence of metastases. So the question is: As we have better tests that resolve things earlier, have we gotten smart enough to intervene and use that information meaningfully? And I would argue right now we’re in a sort of in-between, and it’s going to screw things up for a while. We do trials for nonmetastatic disease based on bone scans. But Mr. X who’s on a trial could go over to the neighborhood mobile PET imaging store and learn that he has metastases—even though he was on the trial because we thought he didn’t have metastases. The larger issue that will play out is that, if we are in a value-based care environment and the test helps us take care of people and they do better, it’ll likely get used. If it doesn’t, and it’s a lot more expensive, I think we’ll have to make a choice. TTN 1. National Cancer Institute. The Prostate Cancer Prevention Trial. National Cancer Institute at the National Institutes of Health. http://www.cancer. gov/clinicaltrials/noteworthy-trials/pcpt/Page1. Accessed March 27, 2013. 2. Roehrborn CG, Barkin J, Siami P, et al. Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial. BJU Int. 2011;107(6): 946-954. 3. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009; 301(1):39-51. 4. Crook JM, O’Callaghan CJ, Graeme D, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012;367: 895-903. 5. Hussain M, Tangen CM, Higano CS, et al. Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): results of S9346 (INT-0162), an international phase III trial. J Clin Oncol. 2012;30 (suppl; abstr 4).

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A Guide to ASCO 2013: Key Targeted Trials An Interview with Douglas Yee, MD, Scientific Program Chair By Anna Azvolinsky, PhD

n advance of the 2013 American Society of Clinical Oncology (ASCO) annual meeting, Targeted Therapy News spoke with this year’s chair of the Scientific Program Committee, Douglas Yee, MD, about key presentations and sessions that attendees can expect.

TTN: What do you see as a challenge in coordinating and planning the meeting? Yee: The general challenge of ASCO has to do with the size and scope of the science. On one hand, it is an incredible meeting because there is such a broad representation of the latest that is going on in every facet of oncology clinical research and the science of oncology. But at the same time, it is such a big meeting that you don’t necessarily get to attend all of the venues you would like and interact with everyone you want to interact with. I think the program committee has been particularly conscious of this. We need big sessions to present the important data, but we also need smaller sessions to foster better interactions. At the same time, we also want to have sessions where experts in their field can really discuss what they think of new developments in clinical and basic science research.

TTN: As the chair of the scientific committee for this year’s meeting, what are the new types of sessions for this upcoming year or new ways for clinicians and researchers to interact at the meeting? Yee: The one concept we tried last year at the meeting and expanded this year is post-plenary sessions. The plenary session is meant to highlight the highestimpact science submitted to ASCO, but to have a discussion with the presenter about what the results actually mean is difficult because of the thousands of people that attend the session. The post-plenary session is a way for the presenter and several discussants to really put a TTN: Translational medispotlight on the plecine has been a major Douglas Yee, MD nary session data. This theme of the meeting and is an opportunity for continues to be so for this a presentation that is year. Could you highlight nonscripted and for viewers of the prehow scientists and clinical researchers are sentation to engage with the presenter collaborating and transferring information and discussants. These sessions take from the laboratory bench to the clinical place immediately after the plenary setting and vice versa? Are there any sespresentations. sions that will particularly highlight this communication? TTN: Could you highlight the role of the preYee: I think that is actually a challenge meeting session? This is a new addition to of the state of oncology in general. We the annual meeting that started in 2012. now understand that there are speYee: The premeeting has a few imporcific molecular targets that are critical tant sessions. There is a session on for tumor biology, and these molecuclinical trials with molecular selection lar targets exist across broad types of of molecular biomarkers that is partumors. We have drugs that have subticularly relevant in this day and age. stantial activity in targeting specific As targeted agents move forward in tumor types, the HER2 targeted theradevelopment, they likely work only in pies in breast cancer, for example. At a select number of patients within a the same time, there are other drugs particular cancer type. In the context of available with activity across many molecular analysis, how do we design cancer types. New therapies that target trials and develop therapies? The sesthe mTOR/PI3K pathway, for example, sion is useful for anyone who wants a need to be discussed and understood deep-dive into how to design biomarkin a deeper way. I think the educational er-driven trials. sessions are particularly important

Targeted Therapy News • 5.13

Trial Data to Be Presented at ASCO 2013 1. Colorectal cancer: KRAS/NRAS and BRAF mutation status biomarker analysis in the phase 3 PRIME trial. Abstract #3511. A new, prospective biomarker analysis will be presented from the PRIME ‘203 trial of panitumumab plus FOLFOX versus FOLFOX as first-line treatment for wild-type KRAS metastatic colorectal cancer (mCRC). Patient tumor samples were assessed for additional RAS mutations. The additional mutations in RAS were associated with an inferior progression-free survival and overall survival in the trial, according to the abstract. 2. Breast cancer: A phase II randomized trial of lapatinib with either vinorelbine or capecitabine as first- and second-line therapy for HER2 overexpressing metastatic breast cancer (MBC). Abstract #516. 3. Melanoma: OPTiM: a randomized phase 3 trial of talimogene laherparepvec (T-VEC) vs subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. Abstract #LBA9008. 4. Melanoma: Phase I combination results of nivolumab plus ipilimumab doseescalation study in metastatic melanoma patients (NCT01024231). Abstract # pending. 5. Ovarian cancer: Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AOC): Results of an international Intergroup trial (AGO-OVAR16). Abstract #LBA5503. 6. Cervical cancer: Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group. Abstract #3. Results were made public in February 2013 when an interim analysis demonstrated that patients with advanced, recurrent, or persistent cervical cancer not curable with standard treatment who received bevacizumab lived 3.7 months longer than patients treated with chemotherapy alone. This is the first study to demonstrate that a targeted agent significantly improved overall survival in gynecologic cancer. 7. Glioblastoma: Final results of the phase III CENTRIC Trial: cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Abstract #LBA2009. 8. Peripheral T-cell lymphoma: Results of the BELIEF registrational phase 2 trial: Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL). Abstract #8507. for both of these scenarios. One of the [sessions] I think that members may not attend as much compared to other sessions are the developmental therapeutics sessions. In these sessions you can really begin to discuss ‘if we have an EGFR inhibitor and a PI3K inhibitor, how do we begin to put those together across different cancer types?’ I think for me that is the aspect of the meeting program that is particularly interesting; how do we use the infor-

mation obtained from model systems to develop new therapeutics for cancer treatment? At the same time, anyone interested in a particular cancer type can stay on top of their specific field by attending the right sessions. This is what makes the meeting worthwhile— it is an opportunity for people to catch up on what they need to know.

(continued on page 26)

NOW ENROLLING

A phase II, multicenter, single-arm study of oral LDK378 in adult patients with ALK-positive non-small cell lung cancer previously treated with chemotherapy and crizotinib

Patients who have had prior chemotherapy and crizotinib

LDK378 750 mg po qd

Inclusion criteria:

Exclusion criteria:

• Histologically or cytologically conﬁrmed diagnosis of locally advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive • Age ≥18 years • Progression of disease during or within 30 days of last dose of crizotinib • Prior 1-3 lines of cytotoxic chemotherapy, 1 of which must have been a platinum doublet • Crizotinib must be the most recent therapy • Archival tissue sample available

• Systemic anticancer therapy given after the last dose of crizotinib and prior to starting study drug • Symptomatic central nervous system metastases that are neurologically unstable or required an increase in steroid dose within 2 weeks prior to study entry • History of carcinomatous meningitis • Clinically signiﬁcant, uncontrolled heart disease • Presence or history of a malignant disease other than non-small cell lung cancer that has been diagnosed and/or required therapy within the past 3 years

End Points Primary: ORR by RECIST v1.1 Secondary: DOR, DCR, TTR, ORR by BIRC assessment, Safety, PFS, OS

ORR, indicates overall response rate; RECIST, Response Evaluation Criteria In Solid Tumors; DOR, duration of response; DCR, disease control rate; TTR, time to response; BIRC, blinded independent review committee; PFS, progression-free survival; OS, overall survival.

LDK378 is an investigational compound. Efficacy and safety has not been established. There is no guarantee that LDK378 will become commercially available.

For more information, please visit www.novartis.com or www.clinicaltrials.gov (NCT01685060)

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

5/13

ONC-1064101

Feature

(continued from page 24) TTN: As a breast cancer clinician and researcher, are there any clinical trial sessions or data that you are particularly looking forward to? Yee: For someone trying to stay up to date on the breast cancer field, it is challenging to think about the HER2positive subset of breast cancer because there are a lot of choices and it is not entirely clear how to best sequence the use of these new drugs. Therapies that target the estrogen receptor are also challenging because there are new therapies that can be used to target the estrogen receptor and other signaling pathways, like the mTOR inhibitors and the new investigational CDK4/6 antagonists, for example. The chal-

coming from someone who is a laboratory-based researcher who is interested in the mechanisms of action of growth factor receptors and what they do biologically and how you target them. In many ways, T-DM1 represents something different. T-DM1 has shown us that without fully understanding how a target works biologically, we can use an antibody to bind to the target so that it internalizes a toxin attached to the antibody. So now we have to understand the linker chemistry, the linker between the toxin and the antibody, which is likely the key to how the molecule works or doesn’t work. This concept has been around for some time, but

the successful use of this strategy on the scale of HER2-positive breast cancer is a very important advance. It represents another way to treat HER2positive breast cancer that almost has nothing to do with the mechanism of action of HER2 in the tumor.

Once we understand this—which tumors benefit from T-DM1 or pertuzumab or trastuzumab or any combination—we will be better able to individualize care for our patients. —Douglas Yee, MD

How T-DM1 fits into the treatment landscape is not certain and will require further investigation. I am part of the I-SPY 2 clinical trial [NCT01042379], which is bringing certain drugs into the neoadjuvant setting to treat breast lenge is how to bring these new drugs into clinical practice, and, in meaningful clinical trials for women with advanced disease, how to control their disease with a goal of prolonging their overall survival and also impacting their quality of life in a positive way. At the same time, how do we take these strategies to the adjuvant setting to optimize their use when we know that not all patients will benefit from an mTOR inhibitor or the CDK4/6 inhibitor? New trials will begin to address this. TTN: How will T-DM1, which has recently been approved for HER2-positive metastatic breast cancer, fit into the current treatment paradigm for HER2-positive cancer? Yee: I think T-DM1 is an incredibly interesting development, and this is

Targeted Therapy News • 5.13

cancer. We will be offering both pertuzumab and T-DM1 in the neoadjuvant setting for HER2-breast cancer. The advantage of the trial is that we take and analyze samples to develop biomarkers to predict response and resistance. Once we understand this—which tumors benefit from T-DM1 or pertuzumab or trastuzumab or any combination—we will be better able to individualize care for our patients. Right now, the correct sequence of therapies and for which patients with advanced cancer is not known. Since we don’t know this information, it will be a challenge to use these drugs in the adjuvant setting. TTN: What are the sessions that you will be attending at the annual meeting this year? Yee: One of the best parts of ASCO is attending sessions on topics you know very little about. I am very interested in the educational session on comparative effectiveness research in oncology. The idea is that we can learn from patients that are not enrolled in clinical trials to provide better care. I will also attend sessions on how preclinical research can best guide clinical trial design. I am very interested in the new immunotherapy developments. I am not an immunotherapist, but one thing that I have learned from attending many ASCO meetings is that you can learn quite a lot about a topic you may not know very well, and then think about how to apply the knowledge to your own clinical practice or research. TTN

NOW ENROLLING

A phase II, multicenter, single-arm study of oral LDK378 in crizotinib-naive adult patients with ALK-positive non-small cell lung cancer

Patients who have had prior chemotherapy

LDK378 750 mg po qd

Inclusion criteria:

Exclusion criteria:

• Histologically or cytologically conﬁrmed diagnosis of locally advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive • Age ≥18 years • 1-3 lines of prior chemotherapy (1 of which must have been a platinum doublet) and progression of disease after last chemotherapy • Archival tissue sample available

• Prior treatment with an ALK inhibitor • Symptomatic central nervous system metastases that are neurologically unstable or required an increase in steroid dose within 2 weeks prior to study entry • History of carcinomatous meningitis • Clinically signiﬁcant, uncontrolled heart disease • Presence or history of a malignant disease other than non-small cell lung cancer that has been diagnosed and/or required therapy within the past 3 years

End Points Primary: ORR by RECIST v1.1 Secondary: DOR, DCR, TTR, ORR by BIRC assessment, Safety, PFS, OS

LDK378 is an investigational compound. Efficacy and safety has not been established. There is no guarantee that LDK378 will become commercially available.

For more information, please visit www.novartis.com or www.clinicaltrials.gov (NCT01685138)

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

5/13

ONC-1064102

Research Profile

Notch Holds Promise, but Presents Obstacles as Cancer Target Working in a laboratory at the National Institutes of Health, Benjamin W. Purow, MD, became the first researcher to demonstrate that the Notch pathway plays a role in gliomas. Today, he is pursuing the pathway at the University of Virginia School of Medicine in Charlottesville. He spends the majority of his time in the lab, where his research focuses on glioblastomas, the most common and most lethal primary brain tumors, with the ultimate goal of developing new therapies for this deadly disease. The remainder of his time is spent in the clinic and with patients in whom these treatments may one day be applied.

Benjamin W. Purow, MD Associate Professor Clinical Neurology University of Virginia School of Medicine Charlottesville, VA

How does the research in your laboratory relate to Notch signaling and cancer? Our primary focus is on glioblastoma brain tumors, and we are interested in a number of novel therapeutic approaches to these and other kinds of cancer. One of the foci of the lab is targeting the Notch pathway in these tumors. But we are also interested in other novel targets such as microRNAs, which we transitioned into through some of our Notch studies several years ago. We are interested in microRNAs both upstream and downstream of Notch (in other words, those that could regulate Notch or that are themselves being regulated by Notch). We have found some microRNAs that suppress the Notch pathway and offer a potential therapeutic angle in these tumors, though we face the significant challenge of efficient delivery to brain tumors. Why does Notch make a promising target for cancer therapy? Notch has been attracting increasing interest in oncology in recent years, although the first evidence came from some much older studies that showed that if you engineered a constitutively active form of the Notch protein into mice it could lead to T-cell leukemia. That was a beautiful indication that Notch activity could be causal or at least tumor−promoting in certain cancers. Since then, Notch has actually been found to play opposing roles in different kinds of cancer. In certain cancers, such as gliomas/glioblastomas, Notch seems to play a pro-tumor role. Interestingly though, in some cancers (such as T-cell leukemia) it plays a “classic” oncogenic role; in others it displays tumor-promoting activity without common mutations or amplifications in the gene. Then there are other cancers where it plays more of a tumor−suppressive role, such as skin and lung cancers and possibly B-cell malignancies, in which the Notch pathway is suppressed to foster tumorigenic activity. Another reason that interest in the Notch pathway has been enhanced is that we had small-molecule inhibitors ready and waiting in the wings that had originally been developed for use in Alzheimer patients: the gamma secretase inhibitors (or GSIs), which block the enzymatic processing of a number of different proteins, including Notch. A lot of clinical research thus far has focused on testing these inhibitors in various cancers. Finally, we tend to think of cancers as very primitive kinds of cells, stem cells gone awry, or mature cells that have reverted to a more primitive state, and, since Notch has a key role in maintaining the stem-cell state, it makes sense that it may have a role in fostering the development of cancers. Furthermore, in recent years

Targeted Therapy News • 5.13

we have realized that not all cancer cells are the same, and in a lot of cancers there seems to be a subset called cancer stem cells, which may be the original cells that got the tumor going and replenish the tumor after treatment with traditional therapies. By targeting Notch, we may be able to get leverage against these cells and sensitize cancers to chemotherapy or radiation treatment. What is the most significant recent development relating to Notch signaling in cancer? There have been a lot of really fascinating developments in recent years. With respect to the end goal of getting agents approved for use in patients, the trials in T-cell leukemia were actually somewhat disappointing. There were some serious toxicity issues with the GSIs. Researchers are now finding ways to get around this— with weekly dosing, for example—and there are ongoing clinical trials in a number of different cancers. Some of the pharmaceutical companies have been somewhat discouraged by the results of trials with a Notch inhibitor as a single agent, but it seems there may be increasing enthusiasm for combining Notch with other agents to sensitize cancer cells to chemotherapy or other anticancer agents. Also, Notch (specifically the delta-like ligand 4 [DLL4]) has been found to play an important role in angiogenesis (new blood vessel development). Monoclonal antibodies directed against DLL4 have been shown to significantly disrupt the tumor vasculature. One caveat of this is that it may lead to a certain kind of blood vessel tumor, so further work is clearly needed. In your opinion, which of the Notch-targeted agents holds the most promise? The gamma-secretase inhibitors are very nonspecific. They block processing of a number of proteins and affect a whole range of cellular processes, as well as being very nonspecific within the pathway itself, inhibiting all of the different Notch receptors. There have been hints that we might gain benefits from more selective and targeted inhibition of a single Notch receptor or ligand, and a number of pharmaceutical companies are working on developing antibodies to block these proteins. Interestingly, antibodies that activate certain Notch family members are also being looked at, and these may have interesting applications in tumors where Notch has a tumor-suppressive role. I think these more specific agents probably hold the most promise at the moment. What are the major hurdles to the development of Notch-targeted anticancer agents? Notch is not an enzyme, so developing drugs to block it has been a challenge. Enzymes, like kinases, are much more easily druggable. It was a bit of luck really that there is a druggable protein that processes Notch, namely gamma-secretase. Another issue has been the diversity and sheer level of complexity within the pathway; there are four Notch receptors and several different ligands as well, and it’s starting to become clear that they can have different functions within the cell. A third issue is the toxicity I mentioned. It is not harmless to block Notch, with side effects like severe diarrhea. All of these present significant challenges in the pursuit of Notch-targeting agents. TTN

Targeted Therapy

Evidence-Based Oncology

Bundled Payment: Practice Savior or Killer? By Kurt Ullman

he new “in” term among those Episode of care a better fit? The model that may be the best paylooking to lower the cost of healthment fit for oncologists is episode of care is “bundled payment” (BP). care (EOC). As currently evolving, this Although there is still disagreement model transfers a specific part of the about what it means, the bundling of risk to the oncologists, but one that is payments revolves around oncologists easier to manage. being paid a set fee for managing their Gould’s group is patients’ care. participating in an “Five or ten years early pilot study in ago, the oncology cooperation with spend was not high United Healthcare. on the payer’s priThe participants ority list,” said Matdefined 19 catthew Farber, direcegories for lung, tor of Provider Ecobreast, and colon nomics and Public cancers. Policy at the Asso“They have takciation of Commuen our margins nity Cancer Centers for chemotherapy in Rockville, Marymedications, addland. “As the numed extra money for ber of patients goes hospitalizations, up, the number of and that is what those who survive Matthew Farber we get when a paincreases, and as tient is registered the general demoas an EOC fee,” said Gould. “We are still graphic shifts, the cost of cancer care paid a fee for service when we see the goes up. In addition, the recent run of patients in our offices and to adminisnew (and expensive) drug approvals ter the medications. The drugs are rehas caused payer’s focus to turn toward imbursed at Average Sales Price.” oncology.” The insurance company knows what Concerns about BP in cancer its medicine costs will be and the most treatment it has to spend for physician services True bundled payments would give onshould its enrollees need hospital cologists a set amount of money per treatment. It hopes to save money by patient to cover all costs from initial giving oncologists incentives to treat visit through to discharge from care patients in the office (where they get or to hospice. There are concerns that paid) and not in the hospital. Hospital a BP system would not work in cancer in-patient costs are still paid by the intreatment, and could cause disruptions surance company. The oncologists are in practices. only assuming the risk for their in-hosOne reason is that cancers are a very pital services. individualized and diverse group of Shifts in how practices make diseases. To say that a payer will offer money a set amount of money for two lines How practices make their money is of treatment does not address who is shifting, and getting the bulk of inresponsible should a third be needed. come from drug charges is past. Other There is enough variability in oncolresponses by oncologists such as pay ogy that true BP is likely to be probfor administering medications and inlematic. creasing in-office diagnostic radiology “Oncologists do not take care of large have come under greater scrutiny. populations of patients, where you can “This gradual reduction in payment mitigate the risk of outliers who utilize is a long-term trend that practices have a lot of costs, time, and energy,” said to recognize to stay afloat,” said Farber. Bruce J. Gould, MD, medical director “I think eventually fee for service for of Northwest Georgia Oncology Cenboth Medicare and private insurers is ters in Marietta, Georgia. “Any payment going down. Instead they will pay for system has to reflect this so that one better, more efficient, and less duplicaor two expensive patients don’t break tive care.” a practice.”

Because of this, it is important for practices to take a long and close look at their processes and find ways to

“I think eventually fee-for-service for both Medicare and private insurers is going down. Instead, they will pay for better, more efficient, and less duplicative care.” —Matthew Farber streamline them. Physicians, according to both experts, should look to implement established clinical guidelines as a first step. But they will also need to update information-gathering abilities through use of electronic medical record (EMR) programs tracking both what they are doing well and where they need to improve.

What practices should consider

These systems help analyze costs, an important part of the process when negotiating fees and managing costs. Business management may play as big a role in a practice’s profitability as the medical management side. For example, the efficiency and accuracy of coding and billing staff will impact cash flow. “The investment in a strong management team is not cheap, but will pay dividends and keep practices strong and independent,” said Gould. “Over the last few years, all of the fat has been removed from the system. If you don’t have a lean, mean practice that is collecting every penny due you on the first try, the chances the practice will fold increase.”

How long to get ready? There is some disagreement on how long practices have to get ready for whichever system wins out. Gould thinks the “ability to worry about tomorrow is gone,” with an immediate need to get the office in order. On the other hand, Farber thinks there is still time for practices to watch the early adopters work out the kinks. Both agree that keeping track of the various models as they mature is important so that practices are “leaning” the right way when approached. They also concur that things like establishing EMRs and familiarizing physicians with guidelines should begin immediately. TTN

Compare current treatment modalities with guidelines from the National Comprehensive Bruce J. Gould, MD Author Affiliation: Cancer Network From KVU Commu(NCCN) or other nication, Inc, Carmel, IN. professional sources. Getting a physiFunding Source: None. cian to buy in is important, as just one Author Disclosure: Mr Ullman reports no rephysician opting out of the predeterlationship or financial interest with any mined treatment regimens could harm entity that would pose a conflict of interthe program for all. This also highlights est with the subject matter of this article. the need for ways to monitor compliAuthorship Information: Drafting of the ance. manuscript; critical revision of the manuFull commitment to EMR technology script for important intellectual content; is another important part of this puzand administrative, technical, or logistic zle. Both BP and EOC require practices support; and supervision. to have the ability to monitor, document, and report treatment regimens.

Targeted Therapy News • 5.13

B:17.5” T:15.5” S:6.875”

Injection for intravenous use Initial U.S. Approval: 2013 This is a brief summary of information about KADCYLA. Before prescribing, please see full Prescribing Information. Do Not Substitute KADCYLA for or with Trastuzumab WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action. If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of KADCYLA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. (2.2, 5.1) • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. (2.2, 5.2) • Embryo-Fetal Toxicity: Exposure to KADCYLA can result 5.4 Pulmonary Toxicity in embryo-fetal death or birth defects. Advise patients Cases of interstitial lung disease (ILD), including pneumonitis, of these risks and the need for effective contraception. some leading to acute respiratory distress syndrome or fatal (5.3, 8.1, 8.6) outcome have been reported in clinical trials with KADCYLA. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) 1 INDICATIONS AND USAGE has been reported, with one case of grade 3 pneumonitis. Signs KADCYLA™, as a single agent, is indicated for the treatment and symptoms include dyspnea, cough, fatigue, and pulmonary of patients with HER2-positive, metastatic breast cancer who infiltrates. These events may or may not occur as sequelae of previously received trastuzumab and a taxane, separately or in infusion reactions. In the randomized trial (Study 1), the overall combination. Patients should have either: frequency of pneumonitis was 1.2% [see Adverse Reactions (6.1)]. • Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. completing adjuvant therapy. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies (14.1)]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2)]. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment. In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension but with normal transaminases and no manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued. 5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution’s normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2)]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies (14.1)].

and 13.5% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2)].

All gr (%

Blood and Lymphatic Syste Neutropenia

Anemia

Thrombocytopenia

Lacrimation increased

Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

Dry eye

Vision blurred

Conjunctivitis

5.9 Extravasation In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, One case of a serious, allergic/anaphylactic-like reaction has been musculoskeletal pain, thrombocytopenia, headache, increased observed in clinical trials of single-agent KADCYLA. Medications to transaminases, and constipation. treat such reactions, as well as emergency equipment, should be The ADRs described in Table 6 were identified in patients with HER2positive metastatic breast cancer treated in a randomized trial available for immediate use. (Study 1) [see Clinical Studies (14.1)]. Patients were randomized 5.6 Thrombocytopenia to receive KADCYLA or lapatinib plus capecitabine. The median Thrombocytopenia, or decreased platelet count, was reported in duration of study treatment was 7.6 months for patients in the clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade KADCYLA-treated group and 5.5 months and 5.3 months for patients 3; 283 of 884 treated patients with any Grade). The majority of these treated with lapatinib and capecitabine, respectively. Two hundred patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the and eleven (43.1%) patients experienced ≥ Grade 3 adverse events nadir occurring by day 8 and generally improving to Grade 0 or in the KADCYLA-treated group compared with 289 (59.2%) patients 1 (≥ 75,000 /mm3) by the next scheduled dose. In clinical trials of in the lapatinib plus capecitabine-treated group. Dose adjustments KADCYLA, the incidence and severity of thrombocytopenia were for KADCYLA were permitted [see Dosage and Administration higher in Asian patients. Independent of race, the incidence of (2.2)]. Thirty-two patients (6.5%) discontinued KADCYLA due to an severe hemorrhagic events in patients treated with KADCYLA was adverse event, compared with 41 patients (8.4%) who discontinued low. lapatinib, and 51 patients (10.5%) who discontinued capecitabine In the randomized trial (Study 1), the overall frequency of due to an adverse event. The most common adverse events leading thrombocytopenia was 31.2% in the KADCYLA-treated group and to KADCYLA withdrawal were thrombocytopenia and increased 3.3% in the lapatinib plus capecitabine-treated group [see Adverse transaminases. Eighty patients (16.3%) treated with KADCYLA had Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was adverse events leading to dose reductions. The most frequent 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus adverse events leading to dose reduction of KADCYLA (in ≥ 1% of capecitabine-treated group. In Asian patients, the incidence of patients) included thrombocytopenia, increased transaminases, ≥ Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated and peripheral neuropathy. Adverse events that led to dose delays occurred in 116 (23.7%) of KADCYLA treated patients. The most group and 1.3% in the lapatinib plus capecitabine-treated group. Monitor platelet counts prior to initiation of KADCYLA and prior frequent adverse events leading to a dose delay of KADCYLA (in to each KADCYLA dose [see Dosage and Administration (2.2)]. ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, KADCYLA has not been studied in patients with platelet counts fatigue, increased transaminases and pyrexia. interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR [see Dosage and Administration (2.2)]. Patients should be observed closely for IRR reactions, especially during the first infusion.

5.7 Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any 5.3 Embryo-Fetal Toxicity Grade). In the randomized trial (Study 1), the overall frequency of KADCYLA can cause fetal harm when administered to a pregnant peripheral neuropathy was 21.2% in the KADCYLA-treated group

Adverse Drug Reactions (MedDRA) System Organ Class

5.8 HER2 Testing Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC.

Patients with dyspnea at rest due to complications of advanced 6 ADVERSE REACTIONS malignancy and co-morbidities may be at increased risk of The following adverse reactions are discussed in greater detail in other sections of the label: pulmonary toxicity. • Hepatotoxicity [See Warnings and Precautions (5.1)] 5.5 Infusion-Related Reactions, Hypersensitivity Reactions • Left Ventricular Dysfunction [See Warnings and Precautions (5.2)] Treatment with KADCYLA has not been studied in patients who • Embryo-Fetal Toxicity [See Warnings and Precautions (5.3)] had trastuzumab permanently discontinued due to infusion-related • Pulmonary Toxicity [See Warnings and Precautions (5.4)] reactions (IRR) and/or hypersensitivity; treatment with KADCYLA is • Infusion-Related Reactions, Hypersensitivity Reactions [See not recommended for these patients. Warnings and Precautions (5.5)] Infusion-related reactions, characterized by one or more of • Thrombocytopenia [See Warnings and Precautions (5.6)] the following symptoms − flushing, chills, pyrexia, dyspnea, • Neurotoxicity [See Warnings and Precautions (5.7)] hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In the randomized 6.1 Clinical Trials Experience trial (Study 1), the overall frequency of IRRs in patients treated with Because clinical trials are conducted under widely varying KADCYLA was 1.4% [see Adverse Reactions (6.1)]. In most patients, conditions, adverse reaction rates observed in the clinical trials of these reactions resolved over the course of several hours to a day a drug cannot be directly compared to rates in the clinical trials of after the infusion was terminated. KADCYLA treatment should be another drug and may not reflect the rates observed in practice.

<100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm3) [see Dosage and Administration (2.2)]. Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

Table 6 Summary of Advers KADCYLA Treatment Arm in

Table 6 reports the ADRs that occurred in patients in the KADCYLAtreated group (n=490) of the randomized trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

Cardiac Disorders Left ventricular dysfunction

Eye Disorders

Gastrointestinal Disorders Dyspepsia

Stomatitis

Dry Mouth

Abdominal pain

Vomiting

Diarrhea

Constipation

Nausea

General Disorders and Adm Peripheral edema

Chills

Pyrexia

Asthenia

Fatigue

Hepatobiliary Disorders Nodular regenerative hyperplasia*

Portal hypertension*

Immune System Disorders Drug hypersensitivity

Injury, Poisoning, and Proc Infusion-related reaction

Infections and Infestations Urinary tract infection

Investigations Blood alkaline phosphatase increased

Increased transaminases

Metabolism and Nutrition Hypokalemia

Musculoskeletal and Conn Myalgia

Arthralgia

Musculoskeletal pain

Nervous System Disorders Dysgeusia

Dizziness

Peripheral neuropathy

Headache

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and M Pneumonitis

Dyspnea

Cough

Epistaxis

Skin and Subcutaneous Ti Pruritus

Rash

Vascular Disorders Hypertension

* Nodular Regenerative Hy in the same patient. ND = Not determined

KADCYLA™ (ado-trastuzumab emtansine)

PharmaGrap

discontinued in patients europathy until resolution to ly monitored on an ongoing rotoxicity [see Nonclinical

ion or gene amplification is opriate for KADCYLA therapy udied for whom benefit has e (1), Clinical Studies (14.1)]. nts with breast cancer were erexpression defined as 3+ of overexpression defined as ER2 FISH PharmDx™ test kit. tients whose breast cancer .

e performed by laboratories specific technology being ce, including use of subpecified reagents, deviation ailure to include appropriate o unreliable results.

secondary to extravasation s, observed more frequently sually mild and comprised pain, or swelling at the KADCYLA extravasation is osely monitored for possible dministration.

scussed in greater detail in

ecautions (5.1)] nings and Precautions (5.2)] and Precautions (5.3)] d Precautions (5.4)] sitivity Reactions [See

d Precautions (5.6)] cautions (5.7)]

in patients in the KADCYLAed trial (Study 1). Selected Table 7. The most common mized trial (frequency > 25%) al pain, thrombocytopenia, , and constipation. The ≥ Grade 3 ADRs (frequency ed transaminases, anemia, d fatigue.

Adverse Drug Reactions (MedDRA) System Organ Class

KADCYLA (3.6 mg/kg) n=490 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) n=488 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Blood and Lymphatic System Disorders Neutropenia

6.7

2.0

9.0

4.3

Anemia

14.3

4.1

10.5

2.5

Thrombocytopenia

31.2

14.5

3.3

0.4

1.8

0.2

3.3

0.4

Lacrimation increased

3.3

2.5

Dry eye

3.9

3.1

Vision blurred

4.5

0.8

Conjunctivitis

3.9

2.3

Cardiac Disorders Left ventricular dysfunction Eye Disorders

Gastrointestinal Disorders Dyspepsia

9.2

11.5

0.4

Stomatitis

14.1

0.2

32.6

2.5

Dry Mouth

16.7

4.9

0.2

Abdominal pain

18.6

0.8

17.6

1.6

Vomiting

19.2

0.8

29.9

4.5

Diarrhea

24.1

1.6

79.7

20.7

Constipation

26.5

0.4

11.1

Nausea

39.8

0.8

45.1

2.5 0.2

General Disorders and Administration Peripheral edema

7.1

8.2

Chills

7.6

3.1

Pyrexia

18.6

0.2

8.4

0.4

Asthenia

17.8

0.4

17.6

1.6

Fatigue

36.3

2.5

28.3

3.5

Nodular regenerative hyperplasia*

0.4

Portal hypertension*

0.4

0.2

0.8

0.2

9.4

0.6

3.9

Blood alkaline phosphatase increased

4.7

0.4

3.7

0.4

Increased transaminases

28.8

8.0

14.3

2.5

2.7

9.4

4.7 0

Hepatobiliary Disorders

Immune System Disorders Drug hypersensitivity

2.2

Injury, Poisoning, and Procedural Infusion-related reaction

1.4

Infections and Infestations Urinary tract infection Investigations

Metabolism and Nutrition Disorders Hypokalemia

10.2

Musculoskeletal and Connective Tissue Disorders Myalgia

14.1

0.6

3.7

Arthralgia

19.2

0.6

8.4

Musculoskeletal pain

36.1

1.8

30.5

1.4

Nervous System Disorders Dysgeusia

8.0

4.1

0.2

Dizziness

10.2

0.4

10.7

0.2

Peripheral neuropathy

21.2

2.2

13.5

0.2

Headache

28.2

0.8

14.5

0.8

12.0

0.4

8.6

0.2

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and Mediastinal Disorders Pneumonitis

1.2

Dyspnea

12.0

0.8

8.0

0.4

Cough

18.2

0.2

13.1

0.2

Epistaxis

22.5

0.2

8.4

Skin and Subcutaneous Tissue Disorders Pruritus

5.5

0.2

9.2

Rash

11.6

27.5

1.8

5.1

1.2

2.3

0.4

Vascular Disorders Hypertension

* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient. ND = Not determined

PharmaGraphics

Table 7 Selected Laboratory Abnormalities Lapatinib (1250 mg) + Capecitabine (2000 mg/m2)

KADCYLA (3.6 mg/kg)

Parameter

All Grade %

Grade 3 %

Increased bilirubin

Increased AST

Increased ALT

Grade 4 %

All Grade %

Grade 3 %

Grade 4 %

component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant monkeys at doses up to 25 mg/kg (about 7 times the clinical dose), trastuzumab crossed the placental barrier during the early and late phases of gestation. The resulting concentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings.

8.3 Nursing Mothers It is not known whether KADCYLA, specifically, is excreted in human milk, but IgG is known to be excreted in human milk. In 83 14 3 21 <1 <1 lactating monkeys, trastuzumab was excreted in small amounts Decreased (about 0.3% of maternal serum concentrations) in breast milk after 60 4 1 64 3 <1 hemoglobin post-partum doses of 25 mg/kg (about 7 times the clinical dose of Decreased KADCYLA). Because many drugs are excreted in human milk and 39 3 <1 38 6 2 neutrophils because of the potential for serious adverse reactions in nursing Decreased 33 3 0 31 6 <1 infants from KADCYLA, a decision should be made whether to potassium discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see Warnings and 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune Precautions (5.3)]. response to KADCYLA. 8.4 Pediatric Use A total of 836 patients from six clinical studies were tested at Safety and effectiveness of KADCYLA have not been established in multiple time points for anti-therapeutic antibody (ATA) responses pediatric patients. to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients 8.5 Geriatric Use tested positive for anti-KADCYLA antibodies at one or more post- Of 495 patients who were randomized to KADCYLA in the randomized dose time points. The presence of KADCYLA in patient serum at trial (Study 1) [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 the time of ATA sampling may interfere with the ability of this assay years of age and 11 patients (2%) were ≥ 75 years of age. In patients to detect anti-KADCYLA antibodies. As a result, data may not ≥ 65 years old (n=138 across both treatment arms) the hazard ratios accurately reflect the true incidence of anti-KADCYLA antibody for progression-free survival (PFS) and Overall Survival (OS) were development. In addition, neutralizing activity of anti-KADCYLA 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. antibodies has not been assessed. Population pharmacokinetic analysis indicates that age does not Immunogenicity data are highly dependent on the sensitivity and have a clinically meaningful effect on the pharmacokinetics of specificity of the test methods used. Additionally, the observed ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)]. incidence of a positive result in a test method may be influenced 8.6 Females of Reproductive Potential by several factors, including sample handling, timing of sample KADCYLA can cause embryo-fetal harm when administered during collection, drug interference, concomitant medication and the pregnancy. Counsel patients regarding pregnancy prevention and underlying disease. Therefore, comparison of the incidence of planning. Advise females of reproductive potential to use effective antibodies to KADCYLA with the incidence of antibodies to other contraception while receiving KADCYLA and for 6 months following products may be misleading. Clinical significance of anti-KADCYLA the last dose of KADCYLA. antibodies is not yet known. If KADCYLA is administered during pregnancy or if the patient 7 DRUG INTERACTIONS becomes pregnant while receiving KADCYLA, immediately report No formal drug-drug interaction studies with KADCYLA have exposure to the Genentech Adverse Event Line at 1-888-835-2555. been conducted. In vitro studies indicate that DM1, the cytotoxic Encourage women who may be exposed during pregnancy to enroll component of KADCYLA, is metabolized mainly by CYP3A4 and to in the MotHER Pregnancy Registry by contacting 1-800-690-6720 a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 [see Patient Counseling Information (17)]. inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 8.7 Renal Impairment telithromycin, and voriconazole) with KADCYLA should be avoided No dedicated renal impairment trial for KADCYLA has been due to the potential for an increase in DM1 exposure and toxicity. conducted. Based on the population pharmacokinetics, as well Consider an alternate medication with no or minimal potential to as analysis of Grade 3 or greater adverse drug reactions and dose inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is modifications, dose adjustments of KADCYLA are not needed in unavoidable, consider delaying KADCYLA treatment until the strong patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) CYP3A4 inhibitors have cleared from the circulation (approximately or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose 3 elimination half-lives of the inhibitors) when possible. If a strong adjustment can be recommended for patients with severe renal CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot impairment (CLcr less than 30 mL/min) because of the limited data be delayed, patients should be closely monitored for adverse available [see Clinical Pharmacology (12.3)]. reactions. 8.8 Hepatic Impairment In vitro studies in human liver microsomes indicates that DM1 is 8 USE IN SPECIFIC POPULATIONS metabolized by CYP3A4/5. The influence of hepatic impairment on 8.1 Pregnancy the pharmacokinetics of ado-trastuzumab emtansine conjugate has Pregnancy Category D [see Warnings and Precautions (5.3)] not been determined. Risk Summary 10 OVERDOSAGE KADCYLA can cause fetal harm when administered to a pregnant There is no known antidote for overdose of KADCYLA. In clinical woman. There are no adequate and well-controlled studies of trials, overdose of KADCYLA has been reported at approximately KADCYLA in pregnant women. No reproductive and developmental two times the recommended dose which resulted in Grade 2 toxicology studies have been conducted with ado-trastuzumab thrombocytopenia (resolved 4 days later) and one death. In the fatal emtansine. Nevertheless, two components of KADCYLA case, the patient incorrectly received KADCYLA at 6 mg/kg and died (trastuzumab and DM1) are known or suspected to cause fetal harm approximately 3 weeks following the overdose; a cause of death and or death when administered to a pregnant woman. If KADCYLA is a causal relationship to KADCYLA were not established. administered during pregnancy, or if a patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus. Patients should be advised to use effective contraception during treatment with KADCYLA and for 6 months following the last dose of KADCYLA. Decreased platelet count

If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Human Data In the post-marketing setting, treatment with trastuzumab during pregnancy has resulted in cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped. In one case, trastuzumab therapy resumed after the amniotic fluid index improved, and oligohydramnios recurred.

KADCYLA™ (ado-trastuzumab emtansine)

Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way Animal Data South San Francisco, CA There were no reproductive and developmental toxicology studies 94080-4990 conducted with ado-trastuzumab emtansine. DM1, the cytotoxic U.S. License No: 1048

AE/AS

PROD

T:10.5”

ntified in patients with HER2ated in a randomized trial Patients were randomized capecitabine. The median months for patients in the s and 5.3 months for patients e, respectively. Two hundred ed ≥ Grade 3 adverse events ed with 289 (59.2%) patients ed group. Dose adjustments Dosage and Administration ntinued KADCYLA due to an nts (8.4%) who discontinued discontinued capecitabine mon adverse events leading bocytopenia and increased treated with KADCYLA had ctions. The most frequent ion of KADCYLA (in ≥ 1% of increased transaminases, vents that led to dose delays treated patients. The most dose delay of KADCYLA (in ombocytopenia, leukopenia, pyrexia.

Table 6 Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA Treatment Arm in the Randomized Trial (Study 1)

B:11.5”

evaluated as single-agent astatic breast cancer. The erse drug reactions (ADRs) CYLA were fatigue, nausea, enia, headache, increased

S:6.875”

S:9.875”

ted under widely varying erved in the clinical trials of rates in the clinical trials of tes observed in practice.

T:15.5”

citabine-treated group [see nce of ≥ Grade 3 peripheral reated group and 0.2% in the up.

B:17.5”

NOW APPROVED Additional Important Safety Information Pulmonary Toxicity • Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in clinical trials with KADCYLA. In EMILIA the overall frequency of pneumonitis was 1.2% • Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis Infusion-Related Reactions, Hypersensitivity Reactions • Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the overall frequency of IRRs in patients treated with KADCYLA was 1.4% • KADCYLA treatment should be interrupted in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR

HER2 Testing • Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA approved tests by laboratories with demonstrated proficiency Extravasation • In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration Nursing Mothers • Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother Pregnancy Registry • Encourage women who may be exposed to KADCYLA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720

• Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate

Adverse Reactions • The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue

Neurotoxicity • In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group

You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/ medwatch or calling 1-800-FDA-1088.

Thrombocytopenia • In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group

• Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2

In the Phase III EMILIA trial (N=991) versus lapatinib + capecitabine:

Single-agent KADCYLA significantly improved survival1 PRIMARY ENDPOINT: OVERALL SURVIVAL (OS) 100

30.9 months

Proportion surviving (%)

HR=0.682 95% CI: 0.55, 0.85 P=0.0006

70 60 50

25.1 months

40 30 20

KADCYLA (n=495) No. of events: 149 lapatinib + capecitabine (n=496) No. of events: 182

10 0 0

164 133

136 110

111 86

86 63

62 45

38 27

28 17

13 7

5 4

Months No. at risk: 495 KADCYLA lapatinib + 496 capecitabine

485 471

474 453

457 435

439 403

418 368

349 297

293 240

242 204

197 159

Patients received KADCYLA (3.6 mg/kg IV, q3w) or lapatinib (1250 mg po qd, Days 1-21) + capecitabine (1000 mg/m2 po bid, Days 1-14) until disease progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) assessed by independent review committee, OS, and safety.1,2

• KADCYLA increased median OS by 5.8 months vs lapatinib + capecitabine1 • 50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.55, 0.77; P<0.0001)1 • The most common NCI-CTCAE (version 3) adverse reactions (ARs) Grades ≥3 (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

References: 1. KADCYLA Prescribing Information. Genentech, Inc. February 2013. 2. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.

Please see brief summary of full Prescribing Information on following pages for additional important safety information, including Boxed WARNINGS. For more information on KADCYLA, please visit KADCYLA.com

NOW APPROVED

The first antibody-drug conjugate (ADC) for HER2-positive (HER2+) metastatic breast cancer

Indication KADCYLA™ (ado-trastuzumab emtansine) injection, for intravenous use, as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

Important Safety Information Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY • Do Not Substitute KADCYLA for or with Trastuzumab • Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function • Embryo- Fetal Toxicity: Exposure to KADCYLA can result in embryo- fetal death or birth defects. Advise patients of these risks and the need for effective contraception Please see brief summary of full Prescribing Information on following pages for additional important safety information, including Boxed WARNINGS.