Targeted Therapy News January 2013 by Intellisphere, LLC

The Personalized Oncology Pipeline:

Solid tumors and hematologic malignancies: Phase III trials

Targeted TherapyNews (see page 35)

For the Practicing Oncology Professional

Bevacizumab

01.13

In this issue... Melanoma • Nab-paclitaxel extends PFS vs standard chemotherapy Prostate Cancer • Enzalutamide delays first SRE, improves pain and QoL • FDA approves earlier use of abiraterone acetate

Feature

Innovations in Precision Medicine

s 2012 drew to a close, several key oncology conferences highlighted the most important innovations in targeted oncology therapy—an area often termed “precision medicine” based on our increasing ability to precisely target and treat specific oncogeneic mutations and pathways. The Chemotherapy Foundation Symposium, held November 7 to 9, and the 35th Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS), held December 4 to 8, were two such conferences, both focusing on recent rapid developments in targeted therapies. In this issue, we highlight key data and presentations from the two conferences.

Lung Cancer • EGFR mutation status and sorafenib in NSCLC

Thyroid Cancer • FDA approves cabozantinib to treat medullary thyroid cancer

(continued on page 18)

Targeted Oncology Therapy in 2012 and 2013: Where Have We Been, Where Are We Going? By Anna Azvolinsky, PhD

T © SABCS/Todd Buchanan 2012

Feature

Researchers Determine How PARP Inhibitors Work By Ben Leach

Hematologic Malignancies • Ponatinib approved for CML and ALL

Colorectal Cancer • Biomarker may predict response to bevacizumab in mCRC

™

wenty new cancer drugs were approved in 2012, and thousands of new targeted and immunotherapeutic oncology agents, including some that will emerge in 2013, are in development. Here we look back at the most important advances in oncology targeted therapy in 2012, and ahead to what to expect for 2013 in key therapeutic areas.

Breast Cancer It has been a productive year for breast cancer trial results and approvals. Two new drugs were

Sara Hurvitz, MD

(continued on page 30)

esearchers from the National Institutes of Health Yves Pommier, MD, PhD (NIH) have discovered a new mechanism of action utilized by poly (ADP-ribose) polymerase (PARP) inhibitors in an effort to promote antitumor activity, suggesting that existing and in-development PARP inhibitors differ in how they are able to treat cancer. The results of the study were published in the journal Cancer Research. PARP1 and PARP2 belong to a family of proteins associated with cellular processes such as chromosome stability, regulation of apoptosis, cell division, and transcriptional regulation and differentiation. PARP enzymes are responsible for repairing DNA damage caused by environmental stresses and DNA replication errors, including single-strand breaks, by enlisting other proteins to actually repair the damage. These single-strand breaks can become double-strand breaks that are then repaired by a complex that contains BRCA1 and BRCA2, mutations closely linked to breast cancer and ovarian cancer. Prior to the study, researchers understood that PARP inhibitors—including drugs such as olaparib and veliparib—worked by blocking PARP enzyme activity, thus preventing the repair of DNA damage and ultimately initiating apoptosis, or cell death, by selectively killing cells with genetic abnormalities.

(continued on page 24)

In advanced prostate cancer

TREAT FIRST LINE WITH PROVENGE TO PROVENGE

Activate PROVENGEactivated T cells

Resting T cell

T-cell activation

Amplify Activated T cell attacks prostate cancer

Attack Prostate cancer cell cell Prostate cancer

EXTEND SURVIVAL

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

100

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

100

Control (n=171)

22.5%

25.8

75 Survival (%)

Survival (%)

RISK REDUCTION

months 25.8

months

21.7

months 21.7 21.7 months

months21.7

months

HR=0.775 HR=0.775

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

0 0

12 24

012

24 36 36

4848

60 60

72 72

Time From Randomization (Months)

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

2 1 1

Extends median survival beyond 2 years1 years

and only

line

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

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

www.PROVENGE.com

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. DOSAGE AND ADMINISTRATION • For Autologous Use Only. • The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals. • Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine. • Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag. • Do Not Initiate Infusion of Expired Product. • Infuse PROVENGE intravenously over a period of approximately 60 minutes. Do Not Use a Cell Filter. • Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction. (See Dosage and Administration [2] of full Prescribing Information.) CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use. • Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction. I n controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed. • Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed. • Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination. (See Warnings and Precautions [5] of full Prescribing Information.) ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells. The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group. Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare. PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended. Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%). Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian. Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

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

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

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

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

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

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

(Table 1 continued on next page.)

Table 1 Incidence of Adverse Events Occurring in â&#x2030;Ľ5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

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

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

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

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

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

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

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

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

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

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

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

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

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group. (See Adverse Reactions [6] of full Prescribing Information.) To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. PROVENGE [package insert]. Dendreon Corporation; June 2011. 3. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. V.3.2012. National Comprehensive Cancer Network Web site. www.nccn.org. Accessed April 26, 2012.

In This Issue...

Features

News

18 Innovations in Precision Medicine

MELANOMA

Highlights of the most important developments in targeted therapies from key conferences.

Targeted

Healthcare Communications

11 N ab-Paclitaxel Extends PFS Versus Standard Chemotherapy in Metastatic Melanoma

Peter Ciszewski pciszewski@TargetedHC.com

By Ben Leach Evan M. Hersh, MD

PROSTATE CANCER

11 E nzalutamide Delays First SRE, Improves Pain and QoL in Patients With Metastatic Prostate Cancer

President

By Bonnie Gillis

Editorial & Production Karim Fizazi, MD

Senior Editors Anita T. Shaffer Jason M. Broderick Beth Fand Incollingo

15 F DA Approves Earlier Use of Abiraterone Acetate

By Jason M. Broderick

HEMATOLOGIC MALIGNANCIES

24 Researchers Determine How PARP Inhibitors Work

By Ben Leach ARP inhibitors may differ P in how they are able to treat cancer.

Yves Pommier, MD, PhD

30 Targeted Oncology Therapy in 2012 and 2013: Where Have We Been, Where Are We Going? Sara Hurvitz, MD

By Anna Azvolinsky, PhD wenty cancer drugs were T approved in 2012, and more are in development in 2013.

Charles J. Ryan, MD

15 P onatinib Approved for CML and ALL

LUNG CANCER

17 Biomarker May Predict Response to Bevacizumab in mCRC

Jorge E. Cortes, MD

Tony S. Mok, MD

Solid Tumors and Hematologic Malignancies

Phase III trials

Web Editor Silas Inman

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

Directors of Sales Scott Harwood sharwood@TargetedHC.com

Vice President, Digital Media Jung Kim

Director, Digital Content Sean Johnson

Operations & Finance David O. Bates, PhD

17 FDA Approves Cabozantinib to Treat Medullary Thyroid Cancer By Ben Leach Richard Pazdur, MD

35 The Targeted Oncology Pipeline:

Design Director Jennifer Rittmann

Digital Media

By Ben Leach

THYROID CANCER

Oncology Special Projects Editor Devera Pine dpine@onclive.com

By Bonnie Gillis

COLORECTAL CANCER

Associate Editor Lauren M. Green Ben Leach

Assistant Web Editors Andrew Roth

Sales & Marketing

16 EGFR Mutation Status and Sorafenib in NSCLC

Vice President, Oncology and Managed Markets Lyn Beamesderfer lbeamesderfer@onclive.com

Departments 38 R esearch Profile: Exploring the Breast Cancer Genome

Key trials for 2013.

Evidence-Based Oncology

Director of Operations Thomas J. Kanzler

Controller Jonathan Fisher, CPA

Group Director, Circulation & Production John Burke jburke@mdng.com

Assistant Controller Leah Babitz, CPA

Corporate Chairman/Chief Executive Officer Mike Hennessy Chief Operating Officer Tighe Blazier Chief Financial Officer Neil Glasser, CPA / CFE Vice President/Executive Director of Education Judy V. Lum, MPA Vice President/Group Creative Director Jeff Brown

40 P recision Medicine and the Rapidly Approaching Future of Cancer Management

By Maurie Markman, MD

Office Center at Princeton Meadows, Bldg. 300 Plainsboro, NJ 08536 â&#x20AC;˘ (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.

Targeted Therapy News â&#x20AC;˘ 1.13

From the Publisher Emerging Personalized Therapies Offer Hope in Multiple Myeloma

Delivering More Targeted News

Researchers are working to turn multiple myeloma into a chronic disease. (See page 30)

Targeted TherapyNews Kenneth C. Anderson, MD

For the Practicing Oncology Professional

T-DM1

11.12

In this issue...

Breast Cancer • Everolimus plus tamoxifen in hormone-resistant mBC • One year of adjuvant trastuzumab remains standard of care • Subcutaneous trastuzumab vs standard IV infusion • Research identifies four distinct subtypes of breast cancer Lung Cancer • Positive results with first ALK inhibitor • Dacomitinib improves PFS in NSCLC Melanoma • Pathway that causes chemotherapy resistance in melanoma cells identified • Long-term data show significant survival improvement for ipilimumab Renal Cell Carcinoma • Phase III safety data for tivozanib • Pazopanib shows better tolerance in advanced RCC Hematologic Malignancies • Current and emerging strategies for managing relapsed/ refractory Hodgkin lymphoma • Switching therapy following suboptimal response in chronic myleogenous leukemia

Feature

™

Feature

N ORT H AME R I CAN E D I T I ON Targeted Multikinase Inhibitors Pazopanib Molecular Challenges and Cabozantinib Explored in Thyroid in Lung Cancer Journal of The and International Other Cancers By Ben Leach By Ben Leach

TargetedHC.com Healthcare Communications

Part of the Onclive Network

I TargetedTherapies

n less than a decade, lung cancer wo targeted agents—pazopanib and cabozantinib—are under investigation has been transformed from a disfor different types of thyroid cancer, and while the therapies have not yet ease broadly characterized by tumor been approved for these indications, researchers are already trying to deterhistology to an intricate molecular momine the best way to integrate them into existing treatment regimens. saic in which at least 10 genetic driver Several trials are investigating pazopanib (Votrient)—a small-molecule mutations or abnormalities have been multikinase inhibitor that is already approved to treat advanced renal cell identified in adenocarcinomas alone. A P E E R R E V I E W E P U BCamidge, L I C A T MD, I O NPhD, , N direcOVEMBER carcinoma and soft-tissue sarcoma—for use in advanced thyroid cancer. A phase D.D Ross II trial is under way to assess the use of pazopanib in combination with the tor of the Thoracic Oncology Clinical chemotherapy agent paclitaxel and radiation therapy in patients with anaplastic Program at the University of Colorado thyroid cancer, a very rare and aggressive form that accountswww.TargetedHC.com for about 1% of all Denver, has been at the forefront of efcases of thyroid cancer. forts to identify driver mutations and (continued on page 48) develop therapies that target those abnormalities. In 2009, Camidge helped define the Feature impact of rearrangements in the anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) (J Thorac Oncol. 2009;4[12]:1450-1454). He then played a leading role in the clini-

2 012

in Cancer

Clinical Articles The Evolving Role of

T-DM1 Improves Overall SurvivalBrentuximab in HER2- Vedotin in Positive Breast Cancer the Management of CD30Positive Lymphoma

By Bonnie Gillis

Francisco J. Hernandez-Ilizaliturri, MD

n updated analysis of the phase III EMILIA trial showed that the antibodydrug conjugate T-DM1 significantly extended survival compared with the combination of lapatinib/capecitabine in women with HER2-positive, unresectable, locally advanced or metastatic breast cancer. The data were presented at the European Society for Medical Oncology (ESMO) 2012 Congress. At a median follow-up of about 20 months, T-DM1 reduced the mortality risk by 32% (hazard ratio [HR] = 0.68; 95% CI, 0.55-0.85; P <.001), with a 6-month differHolly L. Geyer, MD, and ence favoring T-DM1. Median overall survival (OS; death from any cause) was 30.9 D. Ross Camidge, MD, PhD Ruben A. Mesa, MD months for T-DM1 versus 25.1 months for lapatinib/capecitabine, which experts called “unprecedented” in metastatic breast cancer. “The significant improvement in progression-free survival and overall survival cal trial that led to the FDA’s approval as well as the favorable safety suggest that T-DM1 should be an important theralast year of crizotinib (Xalkori), the first peutic option in the treatment of metastatic HER2-positive breast cancer,” said ALK inhibitor for advanced NSCLC. lead author Sunil Verma, MD, Sunnybrook Odette Cancer Center, Toronto, Ontario, This year, the Bonnie J. Addario Lung Canada. The results of the EMILIA trial were simultaneously published online in Cancer Foundation honored Camidge The New England Journal of Medicine to coincide with Verma’s presentation. with its fifth annual lectureship award The OS data presented at ESMO were from the second EMILIA interim analyduring the 13th International Lung sis, with a data cutoff of July 31, 2012, when more than 50% of targeted survival Cancer Congress. In announcing the Jiali Li, MD, Alexa Glencer, andthe foundation leadership said events had occurred. Final OS data are expected in 2014. award, Rugo, cheMD T-DM1 is an antibody-drug conjugate linking trastuzumabHope to theS.potent Camidge is “a relentless advocate of motherapy DM1, allowing intracellular delivery of chemotherapy that is said to molecular testing, redefining the stan-

Prepare to Attack JAK: Managing Myeloproliferative Neoplasm Constitutional Symptoms

Trastuzumab Emtansine (T-DM 1): A Novel and Effective Immunoconjugate for the Treatment of HER2+ Breast Cancer

(continued on page 48)

(continued on page 42)

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

TTN_11'12.2.indd 1

Antibody-Drug Conjugates Target Drug Delivery 11/16/12 3:29 PM

IJTT_Cover_11'12.indd 1

11/15/12 5:45 PM

s we enter into our second year of publication, we are delighted to announce that Targeted Therapy News will now be published six times a year. The decision to increase our frequency was spurred both by the extremely positive feedback from our readers and by the rapid pace of developments in oncology. Also with this issue, Targeted Therapy News reaches a broader circulation of physicians, nurses, and pathologists. In each issue we will focus additional attention on clinical trial updates, conference highlights, and exclusive interviews with leading physicians. Along with our sister publication, the peer-reviewed The International Journal of Targeted Therapies in Cancer, and our website, TargetedHC.com, our aim is to keep the oncology community up to date on the newest developments in targeted, personalized medicine in oncology. TargetedHC.com provides tailored content focused on next-generation therapeutics and their molecular targets. Our website provides information on the latest news in targeted therapies while creating a clinical and peer-to-peer platform for our visitors. As always, we welcome your feedback and suggestions for our targeted therapy publications. Please contact our editorial staff with your comments at dpine@onclive.com. Thank you for reading.

Peter Ciszewski

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Targeted Therapy News • 1.13

INDICATIONS • DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy • DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy IMPORTANT SAFETY INFORMATION BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution • The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 – Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose – Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy • Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate – Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use – The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions

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

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

Janssen Products, LP Distributed by: Janssen Products, LP, Horsham, Pennsylvania 19044-3607 © Janssen Products, LP 2012 10/12 KO8D121011C

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

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

K08D121023

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DOXIL®

DOXIL® (doxorubicin HCl liposome injection)

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

DOXIL (n=250) 10 0 10 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of ≥ 15% over baseline or a ≥ 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDSrelated Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Full Prescribing Information]. Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions].

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described in Dosage and Administration section [see Full Prescribing Information]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy. Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Full Prescribing Information]. Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [see Warnings and Precautions]. ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [see Warnings and Precautions] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma. Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma. Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Patients Topotecan Patients (n = 239) (n = 235) Neutropenia 500 - <1000/mm3 19 (7.9%) 33 (14.0%) <500/mm3 10 (4.2%) 146 (62.1%) Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) <6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 10,000 - <50,000/mm3 3 (1.3%) 40 (17.0%) <10,000/mm3 0 (0.0%) 40 (17.0%) Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 3: Ovarian Cancer Randomized Study Non-Hematologic Adverse Reaction 10% or Greater Body as a Whole Asthenia Fever Mucous Membrane Disorder Back Pain Infection Headache

DOXIL (%) treated (n = 239) All Grades grades 3-4

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

40.2 21.3 14.2

7.1 0.8 3.8

51.5 30.6 3.4

8.1 5.5 0

11.7 11.7 10.5

1.7 2.1 0.8

10.2 6.4 14.9

0.9 0.9 0

Digestive Nausea Stomatitis Vomiting Diarrhea Anorexia Dyspepsia

46.0 41.4 32.6 20.9 20.1 12.1

5.4 8.3 7.9 2.5 2.5 0.8

63.0 15.3 43.8 34.9 21.7 14.0

8.1 0.4 9.8 4.2 1.3 0

Nervous Dizziness

4.2

10.2

Respiratory Pharyngitis Dyspnea Cough increased

15.9 15.1 9.6

0 4.1 0

17.9 23.4 11.5

0.4 4.3 0

Skin and Appendages Hand-foot syndrome Rash Alopecia

50.6 28.5 19.2

23.8 4.2 N/A

0.9 12.3 52.3

0 0.4 N/A

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks. Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis.

DOXIL® (doxorubicin HCl liposome injection) Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 4 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma. Table 4: Frequency of treatment emergent adverse reactions reported in ≥ 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. Adverse Reaction DOXIL + bortezomib Bortezomib (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0 Infections and infestations Herpes zoster 11 2 0 9 2 0 Herpes simplex 10 0 0 6 1 0 Investigations 12 0 0 4 0 0 Weight decreased Metabolism and Nutritional disorders Anorexia 19 2 0 14 <1 0 Nervous system disorders Peripheral Neuropathy* 42 7 <1 45 10 1 Neuralgia 17 3 0 20 4 1 Paresthesia/dysesthesia 13 <1 0 10 0 0 Respiratory, thoracic and mediastinal disorders Cough 18 0 0 12 0 0 Skin and subcutaneous tissue disorders Rash** 22 1 0 18 1 0 Hand-foot syndrome 19 6 0 <1 0 0 *Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category D [see Warnings and Precautions].: DOXIL is embryotoxic at doses of 1 mg/kg/day in rats and is embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about one-eighth the 50 mg/m2 human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DOXIL, discontinue nursing during treatment with DOXIL. Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established. Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Hepatic Impairment: The pharmacokinetics of DOXIL has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Thus, DOXIL dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. Prior to DOXIL administration, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as SGOT, SGPT, alkaline phosphatase, and bilirubin [see Full Prescribing Information]. OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Manufactured for: Janssen Products, LP Horsham, PA 19044 © Janssen Products, LP 2010 Revised September 2012 TM

An ALZA STEALTH® Technology Product

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

Targeted

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 • 1.13

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: Melanoma

Nab-Paclitaxel Extends PFS Versus Standard Chemotherapy in Metastatic Melanoma The baseline characteristics of patients in both arms were well balanced. The majority of patients were male (66%), had an ECOG performance status phase III trial that compared nabof 0 (71%), and had M1c classified disease paclitaxel (nab-P; Abraxane) with (65%), meaning either the melanoma dacarbazine (DTIC) in patients had metastasized to other organs or had with metastatic malignant melanoma spread to any distant site with elevated (MMM) found that nab-P nearly doubled levels of serum lactate dehydrogenase the median time to progression-free (LDH). survival (PFS), suggestIn the intent-to-treat ing that it might be a population, the study superior treatment opfound that the median tion when compared PFS among patients who with the standard chereceived nab-P was 4.8 motherapy regimen months compared with currently offered to pa2.5 months in the DTIC tients. arm (HR = 0.792; 95.1% The international ranCI, 0.631-0.992; P = .044). domized, open-label An interim analysis CA033 trial enrolled showed that the median chemotherapy-naïve OS in the nab-P arm was patients with stage IV 12.8 months compared MMM who had no brain with 10.7 months with metastases. Patients DTIC, although those rewere randomized to results did not achieve staEvan M. Hersh, MD ceive either 150 mg/m2 tistical significance (HR of nab-P on days 1, 8, and = 0.831; 99.9% CI, 0.57815 every 4 weeks (n = 264) or 1000 mg/m2 1.196; P = .094). of DTIC every 3 weeks (n = 265). PFS was The authors reported that 73% of pathe primary endpoint, with overall surtients received subsequent therapies. vival (OS) serving as the secondary endAn independent analysis found that the point. Other endpoints included objecORR was 15% in patients who received tive response rate (ORR), disease control nab-P compared with 11% in the DTIC rate (DCR), and safety and tolerability. arm (P = .239), and the DCR was 39% ver-

By Ben Leach

Table. Phase III Results Comparing Nab-Paclitaxel With Dacarbazine Treatment

Median OS

Median PFS

ORR

Nab-paclitaxel

12.8 mo

4.8 mo

15%

Dacarbazine

10.7 mo

2.5 mo

11%

P value

.094

.044

.239

mo = months; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

sus 27%, respectively (P = .004). In the CA033 study, the most common grade >3 treatment-related adverse events that were reported in >10% of patients were neuropathy, which was reported in 25% of nab-P patients and 0% of DTIC patients (P < .001), with a median time to improvement of 28 days, and neutropenia, which was reported in 20% of nab-P patients versus 10% of DTIC patients (P = .004). “Metastatic melanoma presents significant treatment challenges due in part to limited therapies, low survival rates at diagnosis, and no advances in chemotherapy in 37 years,” said Evan M. Hersh, MD, lead principal investigator and professor of Medicine at the University of Arizona College of Medicine and Arizona Cancer Center in Tucson, and lead author of the CA033 study, in a statement. “Despite advances with targeted treatment and immunotherapies, there is still a need for new agents including chemotherapy treatments for

patients with metastatic melanoma.” The results of the trial were presented at the Society for Melanoma Research 2012 Congress in Hollywood, California. Nab-paclitaxel is a nanoparticle-sized anticancer compound delivered as an injection that uses human albumin, a water-soluble protein, as a shell to house the active drug. The shell binds to the tumor, and the therapeutic agent is released in a targeted dose, initiating apoptosis. The agent is already approved by the FDA to treat metastatic breast cancer after failure on combination chemotherapy and untreated locally advanced non–small cell lung cancer in patients who are not candidates for radiation or surgery. TTN Hersh E, Del Vecchio M, Brown M, et al. Phase 3, randomized, open-label, multicenter trial of nabpaclitaxel (nab-P) versus dacarbazine (DTIC) in previously untreated patients with metastatic malignant melanoma (MMM). Pigment Cell Melanoma Res. 2012;25(6): 863.

Targeted Therapies: Prostate Cancer

Enzalutamide Delays First SRE, Improves Pain and QoL in Patients With Metastatic Prostate Cancer By Bonnie Gillis

n analysis of the phase III AFFIRM trial showed that enzalutamide (Xtandi) significantly delayed the time to first skeletal-related event (SRE) and significantly improved pain and quality of life (QoL) compared with placebo in men with metastatic castrationresistant prostate cancer (mCRPC) who had received prior docetaxel. Enzalutamide is an oral androgen receptor inhibitor that targets multiple steps on the androgen receptor pathway. Based on the results of the AFFIRM trial, the FDA recently approved enzalu-

tamide to treat patients with mCRPC who were previously treated with docetaxel. The AFFIRM trial included 1199 patients with progressive mCRPC who had received ≤2 regimens of docetaxel. Participants were randomized 1:1 to enzalutamide or placebo. Demographic characteristics were well balanced between the two treatment arms. Median age was 69 years. Medi-

Karim Fizazi, MD

an pain score was >4 in 28% of patients. Ninety percent had bone metastasis, and 43% had received bisphosphonates. Overall results of the AFFIRM study showed that enzalutamide prolonged survival and risk of death versus placebo. Median survival was 18.4 months with enzalutamide versus 13.6 months with placebo, representing a 37% reduction in risk of death.

At the 2012 ESMO Congress, Karim Fizazi, MD, Institut Gustav Roussy, Villejuif, France, reported a subanalysis of AFFIRM focused on the effect of enzalutamide versus placebo on SRE, pain, and QoL. The subanalysis showed that enzalutamide significantly delayed time to first SRE: a median of 16.7 months with enzalutamide versus 13.3 months with placebo, representing a 31% reduction in risk of SRE (P = .0001). The distribution of first SRE showed a generally favorable effect of enzalutamide, with fewer patients experiencing radiation to the bone (20% for

(continued on page 15)

Targeted Therapy News • 1.13

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

News

Targeted Therapies: Prostate Cancer (continued from page 11) enzalutamide versus 25% for placebo) and spinal cord compression (6% vs 8%), but about 4% in each group experiencing pathological fracture. Pain was assessed by three methods: Brief Pain Inventory Short Form (BPI-SF, baseline and week 13); self-reported pain diaries at baseline and weekly, including analgesic use and worst pain for 7-day period; and Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire at baseline and week 13. On the BPI-SF, enzalutamide reduced pain severity; patients taking enzalutamide improved pain scores by 7.5%, while those on placebo had worsening pain by 23% (P <.001). Pain diaries showed pain progression in 28% taking enzalutamide versus 39% of placebo patients (P = .0018). Palliation

(ie, >30% reduction in mean pain score at week 13 vs baseline without a >30% increase in analgesic use) was achieved in 45% of the enzalutamide arm versus 7% of the placebo arm (P = .0079). On the FACT-P, the median for time to pain progression had not yet been reached in the enzalutamide arm versus 13.8 months in the placebo arm, representing a risk reduction of 44% (P = .0004). The total QoL score on the FACT-P showed that QoL was dramatically improved in patients taking enzalutamide: 43% had improvement in QoL versus 18% in the placebo arm. Significant improvements were seen in all QoL domains for enzalutamide compared with placebo (P <.001 for all except social/family, which was significant at P = .006).

symptomatic men with Formal discussant of CRPC. However, we canthis trial, Eleni Efstathiou, not declare victory, given MD, PhD, MD Anderson that severe pain-related Cancer Center, Houston, events may not be alTexas, commended the tered,” Efstathiou said. authors for including QoL She added that better unand pain alleviation in derstanding of the mechtheir analysis of AFFIRM. anisms involved in bone However, she urged caumetastasis could move tion when considering the field forward. TTN the positive results of the subanalysis. Fizazi K, Scher HI, Saad F, et “Although enzalual. Impact of enzalutamide, an tamide clearly reduced Eleni Efstathiou, MD, PhD androgen receptor signaling inthe risk of SRE, improved hibitor, on time to first skeletal QoL and functionality, related event (SRE) and pain in the phase 3 AFFIRM and relieved pain and delayed pain prostudy. Presented at: 37th European Society for gression, there is no evidence in this Medical Oncology Congress; September 28-Octotrial that severe pain is reduced. Enzaluber 2, 2012; Vienna, Austria. Abstract 896O. tamide ameliorated bone metastasis in

FDA Approves Earlier Use of Abiraterone Acetate By Jason M. Broderick

he FDA has authorized the use of abiraterone acetate (Zytiga) prior to chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). The oral agent was originally approved in April 2011 to be used in combination with prednisone in patients with mCRPC following the failure of chemotherapy with docetaxel. “This expanded indication for Zytiga helps fill a critical medical need, providing physicians an important tool for treating men with metastatic castration-resistant prostate cancer who have not received chemotherapy,” Charles J. Ryan, MD, University of California, San

Francisco, Helen Diller Family Comprehensive Cancer Center, said in a press release. Ryan is the lead author of the phase III COU-AA-302 trial that was the basis for the FDA’s decision. Coinciding with the FDA’s approval, results from the COUAA-302 study were published online in The New England Journal of Medicine. In the trial, 1088 chemotherapy-naïve patients with mCRPC were randomized 1:1 to either abiraterone or placebo plus prednisone. The trial was unblinded earlier this year, with patients in the placebo arm being offered the option to receive abiraterone. At 22.2 months’ median follow-up, radiographic progression-free survival

tigue, joint swelling or was 16.5 months with discomfort, swelling abiraterone versus 8.3 caused by fluid retenmonths with placebo tion, hot flush, diarrhea, (hazard ratio [HR] = vomiting, cough, high 0.53; 95% CI, 0.45-0.62; P blood pressure, short<.001). Overall survival ness of breath, urinary (OS) was 27.2 months in tract infection, and the control arm, and had bruising. TTN not yet been reached in the abiraterone arm (HR Ryan CJ, Smith MR, de Bono = 0.75; 95% CI, 0.61-0.93; JS, et al. Abiraterone in metaP = 0.01). The researchstatic prostate cancer without ers noted that the OS previous chemotherapy [pubdata did not cross the efCharles J. Ryan, MD lished online ahead of print ficacy boundary. December 10, 2012]. N Engl J According to the FDA, Med. doi:10.1056/NEJMoa1209096. the most frequently reported side effects in the abiraterone arm were fa-

Targeted Therapies: Hematologic Malignancies

Ponatinib Approved for CML and ALL

he FDA has approved ponatinib (Iclusig) for the treatment of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant (R/I) to prior tyrosine kinase inhibitors (TKIs). Ponatinib was approved three months earlier than expected, under the FDA’s accelerated approval program. It is a third-generation TKI that has demonstrated potent activity against native and mutated BCR-ABL and other kinas-

es, as well as in subtypes with a T315I gene mutation. “The availability of Iclusig will improve the outcome of many patients with CML and Philadelphia-positive ALL who are resistant or intolerant to prior TKI therapy. It is an effective therapy that meets an unmet medical need and has to date overcome all known resistant mutations in preclinical studies,” said Jorge Cortes, MD, professor and deputy chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. “Clinical responses to

Iclusig have been observed in patients regardless of their mutation status or stage of disease. It is a valuable new treatment option for leukemia patients.” Ponatinib, an oral multikinase inhibitor, generated significant responses in more than 50% of patients with certain chronic myeloid leukemia (CML) subtypes, in the phase II PACE trial that was the basis for its approval. The benefit reached 70% for some patients with CML who also harbored a T315I gene mutation. The PACE trial examined 449 pa-

tients with CML who were R/I to dasatinib (Sprycel) or nilotinib (Tasigna), or for those with the T315I mutation. Patients were divided into cohorts based on whether they were diagnosed with refractory CML in chronic-phase (CP), acute-phase (AP), or blast-phase (BP) CML, and Ph+ALL. Each group was further categorized according to whether the participants were R/I to prior treatment, or whether they exhibited a T315I mutation. The primary endpoint for the patients with CP-CML was a major cytogenic re-

Targeted Therapy News • 1.13

News

Targeted Therapies: Hematologic Malignancies sponse (MCyR), while the outcome was a major hematologic response (MaHR) in the other subtypes. All patients received 45 mg of ponatinib once daily. In the CP-CML group, 54% of patients (144 of 267) achieved MCyR, which included 70% of patients with the T315I mutation (45 of 64). For the AP-CML group, 58% of patients (48 of 83)

Jorge E. Cortes, MD

reached MaHR; patients in the R/I group achieved a higher response of 60% (39 of 65) than those wih the mutation. In the BP-CML and Ph+ALL groups, 34% of patients achieved MaHR (32 of 94), with a slight advantage for those without the T315I mutation (35% vs 33%, respectively). In a further breakdown for patients in the

chronic CP-CML phase, 44% of patients overall (118 of 267) exhibited a complete cytogenic response (CCyR), a figure that includes a 66% CCyR for those with the T315I mutation (42 of 64). Ponatinib’s label will contain a boxed warning about a possible risk that the drug can cause blood clots and liver toxicity. The most common side effects reported in the PACE trial included high blood pressure, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. “For patients with CML and Philadelphia-positive ALL who become resistant

or intolerant to TKI treatments, the approval of Iclusig is very positive news,” said Rosalie Canosa, program division director at CancerCare. “The addition of Iclusig to the arsenal of anti-leukemia medicines is a significant development and one that offers hope for patients coping with CML and Philadelphiapositive ALL.” Approximately 5000 new cases of CML are diagnosed each year in the US. CML patients treated with TKIs can develop resistance or intolerance over time to these therapies. TTN

Targeted Therapies: Lung Cancer

EGFR Mutation Status and Sorafenib in NSCLC By Bonnie Gillis

cally significant improvements with (HR = .62; 95% CI, Table. EGFR Mutational Subanalysis of Phase III sorafenib were demonstrated with sev.48-.82; P <.001). Mission Trial esults of the phase III MISSION eral secondary endpoints, including However, meTreatment Median PFS (mo) Median OS (mo) trial presented at the 2012 ESMO median progression-free survival (PFS; dian OS was sigEGFR-mutant tumors Congress showed that third- or P <.0001), time to disease progression nificantly better fourth-line treatment with sorafenib did (P <.0001), overall response rate (P <.001), in EGFR-positive Sorafenib (n = 44) 2.7 13.9 not improve overall survival (OS) in paand disease control rate (P <.0001). patients who re Placebo (n = 45) 1.4 6.5 tients with advanced non–small cell lung Although the primary results were ceived sorafenib, P value <.001 <.002 cancer (NSCLC). A post-hoc biomarker negative, the researchers conducted a but no difference analysis of MISSION sugmutational analysis inwas found between EGFR wild-type tumors gested that patients with volving 347 patients to the study arms Sorafenib (n = 122) 2.7 8.3 EGFR-mutant tumors determine if some pain the wild-type Placebo (n = 136) 1.5 8.4 may benefit from treattients might benefit from group. Median OS ment with sorafenib, but sorafenib. In the analysis was 13.9 months P value <.001 <.559 KRAS mutation status subgroup, EGFR mutawith sorafenib mo = months; OS = overall survival; PFS = progression-free survival. was not predictive of retions were detected in versus 6.5 months sponse. 26% and KRAS mutations with placebo for sponse to sorafenib. A negative interac“Mutated EGFR is a in 20%, and were well EGFR-positive patients (HR = .48; 95% CI, tion was observed for both PFS and OS. potent predictor for gefibalanced between the .30-.76; P <.002). In patients with wildSorafenib resulted in more favorable tinib. There was a hint in two study arms. type EGFR, median OS was 8.3 months PFS outcomes than placebo in patients the biomarker analysis The EGFR mutation in the treatment arm versus 8.4 months with both KRAS-mutant and wild-type that it may be predictive analysis included 44 pawith placebo (HR = .92; 95% CI, .70-1.21; tumors,” Mok said. for sorafenib, but intertients from the sorafenib P <.559). Tony S. Mok, MD In a press conference at ESMO 2012, pret these data with caugroup and 45 from the The lack of benefit in the wild-type Luis Paz-Ares, MD, Hospital Virgen tion,” said lead author placebo group who had EGFR group suggests a potential benefit del Roc, Seville, Spain, commented on Tony S. Mok, MD, Chinese University of mutated EGFR in tumor of EGFR mutational stathe next step for researchers. “There Hong Kong. “The sample size is small, it or plasma, and 122 in tus as a biomarker, Mok is no clear explanation for the benefit was a subgroup analysis, and an explorthe sorafenib group and noted. of sorafenib in the EGFR-mutated subatory analysis only.” 136 in the placebo group With KRAS-mutated or group. We need to perform the rest of MISSION was a multinational, doublewith wild-type EGFR. KRAS wild-type NSCLC, the biomarker analysis before doing a blind, placebo-controlled, randomized A significant PFS benhowever, no significant larger trial. This study is hypothesisphase III trial comparing sorafenib plus efit was observed for PFS or OS benefit was obgathering.” TTN best supportive care versus best supsorafenib in patients served for sorafenib. portive care alone as third- or fourthwith mutated EGFR: me“Based on current Mok TSK, Paz-Ares L, Wu Y-L, et al. Association line therapy in an unselected populadian PFS was 2.7 months data, we hypothesize between tumor EGFR and KRAS mutation status tion with NSCLC. The study enrolled with sorafenib versus that EGFR mutation is a and clinical outcomes in NSCLC patients ran703 patients who were randomized 1:1 1.4 months with placebo predictive biomarker for domized to sorafenib plus best supportive care to either 400 mg of oral sorafenib twice (hazard ratio [HR] = .27; sorafenib in treatment of (BSC) or BSC alone: subanalysis of the phase III daily or placebo. 95% CI, .16-.46; P <.001). patients with advanced Luis Paz-Ares, MD MISSION trial. Presented at: 37th European SociMedian overall survival was comPFS was also significantNSCLC. It is possible that ety for Medical Oncology Congress; September parable between the sorafenib and ly better with sorafenib the OS outcome was 28-October 2, 2012; Vienna, Austria. Abstract placebo arms (248 vs 253 days; in wild-type EGFR patients versus biased by the unbalanced use of postLBA9. P = .4687), and thus the trial failed to the placebo group: median PFS of 2.7 study tyrosine kinase inhibitor. KRAS reach its primary endpoint. Statistimonths versus 1.5 months, respectively mutation did not appear to influence re-

Targeted Therapy News • 1.13

News

Targeted Therapies: Colorectal Cancer

Biomarker May Predict Response to Bevacizumab in mCRC been identified to determine which patients may experience a greater survival benefit when given the therapy. esearchers have identified a poThe drug works by targeting and tential predictive marker for blocking VEGF-A, a protein associated survival in cases of metastatic with angiogenesis. Since VEGF-A is the colorectal cancer (mCRC) treated with product of one gene encoding multiple bevacizumab (Avastin), suggesting that isoforms, researchers decided to focus patients who have the on one splice variant of appropriate biomarkVEGF-A called VEGF165b er could experience a that was shown to have greater benefit when antiangiogenesis propgiven the drug, whereas erties. The hypothesis others who do not exfor the study was that press the biomarker patients with relatively could be spared from low levels of VEGF165b receiving unnecessary would respond bettherapy. ter—measured by proBevacizumab is apgression-free survival proved by the FDA to (PFS)—when treated treat mCRC when given with bevacizumab. Rein combination with a searchers posited that in David O. Bates, PhD standard chemotherapy patients with lower levregimen of ironotecan, els of VEGF165b, more 5-fluorouracil, and leucovorin as a firstof the drug might be able to block the or second-line therapy. Although cliniangiogenesis-promoting form of procal trials in patients with mCRC have tein VEGF165. shown an improvement in survival, Researchers at the University of Brisno proven predictive markers have yet tol used 97 blinded tumor samples from

By Ben Leach

a phase III trial in which patients with mCRC received the FOLFOX4 (oxaliplatin, leucovorin, and 5-fluorouracil) chemotherapy regimen with or without bevacizumab. Those tissue samples were assessed for VEGF165b and total VEGF by immunohistochemistry, and the ratio of the two levels was scored relative to normal tissue samples. An unadjusted analysis of PFS showed that patients with lower VEGF165b:total VEGF ratios treated with the FOLFOX4 and bevacizumab regimen (n = 24) had a longer median PFS than those who received FOLFOX4 alone (n = 26; median, 8.0 months vs 5.2 months; P <.02). However, no beneficial effect on PFS was observed in patients with higher VEGF165b:total VEGF ratios when the combination regimen (n = 20) was compared with FOLFOX4 alone (n = 27; median, 5.9 months vs 6.3 months). Although patients with a lower VEGF165b ratio achieved a higher median overall survival (OS) when given FOLFOX4 and bevacizumab (median, 13.6 months) compared with patients who received FOLFOX4 alone (median, 10.6 months), the results did not reach

statistical significance. No difference in OS was observed in the higher VEGF165b ratio group when comparing the FOLFOX4 and bevacizumab regimen (median, 10.8 months) with FOLFOX4 alone (11.3 months). “Avastin has shown great potential for a minority of people with bowel cancer, but it’s been impossible to predict who will benefit from the drug,” said David O. Bates, PhD, lead researcher from the University of Bristol School of Physiology and Pharmacology and lead author of the study. “We now need to look at cancer samples from a larger group of patients about to start taking Avastin and determine if the amount of VEGF165b can accurately identify those patients that will benefit, and so potentially open a new treatment option for some people with advanced bowel cancer.” TTN Bates DO, Catalano PJ, Symonds KE, et al. Association between VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with bevacizumab [published online ahead of print October 25, 2012]. Clin Cancer Res. doi:10.1158/1078-0432.CCR-12-2223.

Targeted Therapies: Thyroid Cancer

FDA Approves Cabozantinib to Treat Medullary Thyroid Cancer By Ben Leach

he US Food and Drug Administration today approved cabozantinib to treat medullary thyroid cancer that has metastasized to other parts of the body. Medullary thyroid cancer develops in cells in the thyroid gland that make the hormone calcitonin, which helps maintain a healthy level of calcium in the blood. This type of cancer may occur spontaneously or in families with certain genetic mutations that result in one or more cancers of the endocrine system, including the thyroid gland. The National Cancer Institute estimates that 56,460 Americans will be diagnosed with thyroid cancer and 1780 will die from the disease in 2012. About 4% of thyroid cancers are medullary thyroid cancer, making it one of the rarer types of thyroid cancers. “Cometriq is the second drug approved to treat medullary thyroid can-

intended to treat a rare disease or concer in the past two years and reflects dition. FDA’s commitment to the development Cabozantinib is a kinase inhibiand approval of drugs for treating rare tor that blocks abnormal kinase prodiseases,” said Richard Pazdur, MD, diteins involved in the development rector of the Office of Hematology and and growth of medullary cancer cells. Oncology Products in the FDA’s Center Patients should not eat for at least 2 for Drug Evaluation and Research. “Prihours before and 1 hour or to today’s approval after taking cabozanand the approval of Catinib. prelsa in April 2011, paThe safety and eftients with this rare and fectiveness of cabozandifficult to treat disease tinib were established had limited therapeutic in a clinical study intreatment options.” volving 330 patients The FDA completed with medullary thyroid review of cabozancancer. Treatment with tinib’s application in cabozantinib increased six months under the the length of time a agency’s priority review patient lived without program. This program the cancer progressing provides for an expe(progression-free surdited six-month review Richard Pazdur, MD vival) and, in some pafor drugs that may offer tients, reduced the size major advances in treatof tumors (response rate). ment or that provide a treatment when Patients who were given cabozanno adequate therapy exists. Cabozantinib lived an average of 11.2 months tinib also received orphan-product without tumor growth compared with designation by the FDA because it is

an average of four months in patients receiving a sugar pill (placebo). Results also showed that 27 percent of patients treated with cabozantinib had reductions in tumor size lasting an average of nearly 15 months, while patients who received a placebo saw no reductions. Treatment with cabozantinib did not extend patients’ lives. The prescribing information for cabozantinib includes a boxed warning alerting patients and healthcare professionals that severe and fatal bleeding and holes (perforations and fistula) in the colon occurred in some patients. The most common side effects were diarrhea; inflammation or sores of the mouth; redness, pain, or swelling of the digits (hand-foot syndrome); weight loss; loss of appetite; nausea; fatigue; oral pain; graying or loss of hair color; bad taste; new or worsening high blood pressure; abdominal pain and constipation. The most common laboratory abnormalities included increases in liver enzymes, low calcium and phosphorus, and decreased white blood cells and platelets.TTN

Targeted Therapy News • 1.13

Chemotherapy Feature Foundation Symposium Conference Coverage Conference Updates (continued from cover)

Novel Formulations and Molecular Characterization of AML Offer Hope and Complexity By Devera Pine

espite advances in the treattrial development [to determine] how ment of acute myeloid leuketo make the therapeutic outcomes mia (AML) over the last few more than just anecdotal for two peoyears, survival of patients with the ple with a particular set of mutations. disease remains poor. Recent rapid It has to be quite carefully considered, advances in the characterization of and the construction of these personthe molecular genetic defects underalized trials is not easy.” lying AML, as well as in novel formuThe current treatment paradigm lations of therapies, for AML is a very old are offering hope for one, Roboz said, and improved outcomes, comprises remission however. In a preinduction followed by sentation at the 2012 consolidation (with 1 Chemotherapy Founto 4 cycles of chemodation Symposium, therapy or autologous Gail J. Roboz, MD, asor allogeneic stem sociate professor of cell transplant). Roboz Medicine and director highlighted a number of the Leukemia Proof studies now under gram at Weill Mediway that are aimed at cal College of Cornell improving the current University, New York, treatment paradigm, NY, reviewed some of including methods for the AML therapies in Gail J. Roboz, MD optimizing “7 + 3” (cylater-stage developtarabine [ara-C] comment. bined with an anthraAML is the most common form of cycline or anthracenedione). acute leukemia in adults, with apIn a multicenter, phase III trial, 652 proximately 13,000 new cases diagpatients with untreated AML were nosed each year. Long-term survival is randomized to one of three inducpoor, particularly in patients over the age of 60 years, and AML results in approximately 10,000 deaths annually, according to Roboz. Traditionally, patient-specific factors—age, performance status, and comorbid illnesses—were used to determine disease prognosis, but those are giving way to leukemia-specific factors, including cytogenetics, singlegene mutations, antecedent hematologic disorders, and secondary AML as prognostic indicators. “Cytogenetics and mutational analyses are driving how we look at the disease,” Roboz said. AML is now recognized as a genetically highly heterogeneous disease, and although that diversity presents the opportunity to categorize AML by distinct molecular subgroups—possibly with personalized treatments for the various mutations—it also presents a challenge in terms of drug development and clinical trials. “This is a disease of one name, but it’s many different diseases,” Roboz said. “When tion regimens: DA (daunorubicin plus you’re thinking ahead about personalcytarabine), DAC (DA plus cladribine), izing therapy…it’s going to be an awor DAF (DA plus fludarabine). Comful lot of personalization and clinical pared with patients in the DA arm,

patients who received cladribine had a higher rate of complete remission (67.5% vs 56%; P = .01) and overall survival (45% ± 4% at 3 years in the DAC arm vs 33% ± 4% in the DA arm; P = .02).1 Despite these encouraging results, Roboz said that few clinicians add cladribine to the treatment regimen. “This is one of the most perplexing things going on in AML—[this is] a big, randomized study with a clear benefit for cladribine, yet nobody does it.” The addition of cladribine, she added, might be something to consider down the road. Other approaches seek to improve 7 + 3 with the use of novel formulations. CPX-351, for instance, is a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio. Elacytarabine conjugates cytarabine with elaidic acid (a naturally occurring fatty acid). Elacytarabine is thought to bypass the transporter protein hENT1 in the leukemic cell membrane, thereby allowing for increased cellular uptake. Novel agents are also under development, including vosaroxin, a

“When you’re thinking ahead about personalizing therapy…it’s going to be an awful lot of personalization and clinical trial development [to determine] how to make the therapeutic outcomes more than just anecdotal for two people with a particular set of mutations. It has to be quite carefully considered, and the construction of these personalized trials is not easy.”

Targeted Therapy News • 1.13

—Gail J. Roboz, MD

first-in-class, anticancer quinolone derivative being studied in the phase III VALOR trial. Patients with first relapsed or refractory acute AML will be

Key Points: • Cytogenetics, single gene mutations, antecedent hematologic disorders, secondary AML are key prognostic indicators • Cladribine added to daunorubicin and cytarabine during induction prolonged survival • Novel agents in trials include vosroxin, decitabineSGI-110, azacitidine

randomized to vosaroxin plus cytarabine versus placebo plus cytarabine. The primary endpoint is overall survival; the secondary endpoints are the complete remission rate and safety and tolerability. Another late-stage trial is investigating the use of decitabine, a DNA demethylating agent, as an induction strategy for patients age 60 years and older with acute AML. The phase II CALGB (Alliance) 11002 trial will look at “real-world” older AML patients, Roboz said. The study’s primary endpoint is overall survival, not the complete remission rate, which may indicate whether overall survival for this group of patients depends upon a complete remission. Finally, two other novel therapies are in development: SGI-110, a dinucleotide of decitabine and deoxyguanosine that increases in vivo exposure/ efficacy of decitabine by protecting it from elimination by cytidine deaminase; and oral azacitidine (AZA-008), now being studied in a phase III trial in AML post-remission and for use post-transplant, Roboz said. (Azacitidine is approved as Vidaza for the treatment of all five French-AmericanBritish subtypes of myelodysplastic syndromes.) TTN Holowiecki J, Grosicki S, Giebel S, et al. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012;30:2441-2448.

Chemotherapy Foundation Symposium Conference Coverage

Choosing a Tyrosine Kinase Inhibitor in CML By Devera Pine

he introduction of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myelogenous leukemia (CML) has dramatically changed the course of the disease, so that today there is an 85% chance of a 10-year survival rate for patients treated with imatinib. Now, with five TKIs potentially available for CML, clinicians must weigh the relative advantages and toxicities of each when selecting a course of treatment. In a presentation at the 2012 Chemotherapy Foundation Symposium, Hagop Kantarjian, MD, professor of Medicine, and chairman and professor, Leukemia Department, MD Anderson Cancer Center in Houston, Texas, detailed key considerations for selecting TKI therapy. Three TKIs are approved for frontline therapy in CML—imatinib, nilo-

least controversial of those factors, he “For all of these reasons, there is no said, is cost: If a patient is paying out doubt that second [the newer] TKIs are of pocket, imatinib is likely to be the going to get increasing utilization as least expensive therapy. frontline therapy for chronic myeloid Disease status leukemia,” Kantarjian should play a role in said. “What we have therapy selection: Alto keep in mind is so though TKIs have also far, there is no survival improved survival benefit. Many patients in accelerated- and who fail imatinib can blast-phase CML, that be salvaged effectively improvement is by no with second TKIs.” But means ideal, KantarKantarjian said that jian said. For patients the choice of whethin transformation, er to use imatinib as TKIs should be used in frontline therapy vercombination and not sus one of the newer as single-agent theraTKIs may come down py, he said. to cost considerations. Hagop Kantarjian, MD Kantarjian comOne question that pared the use of imaremains to be antinib versus newer TKIs as frontline swered in this area is what price should be paid for what difference in survival or transformation at 5 or 10 years, Kantarjian said. The question will be particularly relevant when

Although TKIs have also improved survival in accelerated- and blast-phase CML, that improvement is by no means ideal. tinib, and dasatinib—and a total of five TKIs are available for use in different sequences and circumstances in patients with CML (Table). In addition, omacetaxine, although not a TKI, may have potential for use in combination therapy, Kantarjian said. Efficacy, toxicities, disease status, salvage status, comorbidities, and cost all should factor into the choice of TKI in CML, Kantarjian said. The

therapy in CML. In this setting, the newer TKIs have been shown to result in improved complete cytogenic response (CCyR), major molecular response (MMR), complete molecular response (CMR), event-free survival (EFS), and transformation rates. On average, the newer TKIs cause less chronic toxicity compared with imatinib; the newer therapies also have a cost similar to imatinib.

Table. TKIs for CML TKI

Frontline

Salvage

Imatinib

Approved

Nilotinib

Approved

Dasatinib

Approved

Bosutinib

Approved

Ponatinib

Approved

CML = chronic myelogenous leukemia; TKI = tyrosine kinase inhibitor.

Key Points: • Generally, second TKIs cause less chronic toxicity vs imatinib • Choice of imatinib vs second TKIs as frontline therapy may come down to cost • Long-term data on survival or transformation advantages for second TKIs needed

imatinib goes off-patent in the next few years and the price will presumably decrease. In three randomized trials of TKIs as frontline therapy (the ENEST-nd, DASISION, and BELA trials), on average, the second TKIs reduced the cumulative incidence of transformation to accelerated phase/ blast phase in the first 2 to 3 years from about 5% to approximately 1.5%. The incidence of transformation on study (intent-to-treat population) was reduced by half, from 6% to approximately 3%. “If second TKIs are effective in reducing the incidence of transformation in the first 2 to 3 years, but not later on, what you would expect is at 10 years, a difference in the survival of 3% to 5%,” Kantarjian said. “If second TKIs reduce the incidence of transformation consistently across the years, then you will see a marked difference in the 10-year survival, which will justify their use in frontline therapy regardless of the cost.” TTN

Study Identifies Potential New Pathways for HNSCC Treatment By Lauren M. Green

cientists now know much more about the genetic landscape of head and neck cancer and hope that eventually this knowledge will lead the way to new therapies, according to Aaron D. Tward, MD, PhD, of the Broad Institute of MIT and Harvard. Tward described findings of recent collaborative research on the topic at the 2012 Chemotherapy Foundation Symposium. Head and neck squamous cell carcinoma (HNSCC) is the sixth most com-

mon non-skin cancer in the world, with approximately 600,000 cases reported each year and a mortality rate of 50%. The National Cancer Institute estimates that 52,000 new cases will be diagnosed in the US in 2012, accounting for 3% of all cancers. For this research, Tward, also with the Department of Otology and Laryngology at Harvard Medical School and a clinical fellow in those specialties at the Massachusetts Eye & Ear Infirmary in Boston, and colleagues analyzed tu-

mor samples provided by the University of Pittsburgh from 92 HNSCC patients. The samples were chosen to be reflective of the normal distribution of patients with these cancers, that is, mostly men and mostly smokers. Of these patients, 89% reported a history of tobacco use and 79% alcohol use; 14% of all tumors and 53% of oropharyngeal tumors were found to be positive for human papillomavirus. Tumor sites also were selected so as to be roughly representative of the

Key Points: • Mutations implicated in HNSCC include TP53, CD-KN2A, PTEN, PIK3CA, and HRAS • Trials of PI3K inhibitors may be fruitful in patients with PI3KCA mutations in HNSCC

(continued on page 22)

Targeted Therapy News • 1.13

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

Oncolytic Immunotherapy

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Oncolytic Immunotherapy References: 1.

Varghese S, Rabkin SD. Oncolytic herpes simplex virus vectors for cancer virotherapy. Cancer Gene Ther. 2002;9(12):967-978.

Dranoff G. GM-CSF-secreting melanoma vaccines. Oncogene. 2003;22(20):3188-3192.

Hawkins LK, Lemoine NR, Kim D. Oncolytic biotherapy: a novel therapeutic platform. Lancet Oncol. 2002;3(1):17-26.

Fukuhara H, Todo T. Oncolytic herpes simplex virus type 1 and host immune responses. Curr Cancer Drug Target. 2007;7(2):149-155.

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Chemotherapy Foundation Symposium Conference Coverage

(continued from page 19) general HNSCC patient population; thus, most were oral cavity cancers, followed by a substantial proportion of oropharynx cancer samples, and a few from patients with hypopharyngeal or laryngeal tumors. Investigators used hybrid capture sequencing to compare tumor tissue with nontumor tissue from the same individual. They also compared the total number of mutations in the HNSCC samples with samples from previous tumor studies done at Broad. Tward noted that HNSCC clusters with lung cancer, in that both possess a relatively high number of mutations, sometimes referred to as “the smoking cluster.” The analysis yielded a very large number of mutations; for example, 5000 genes had at least one mutation, and 1300 had at least two. Tward emphasized, however, that most of these are not implicated either in promoting or maintaining the cancer. “The vast majority,” he said, “are what we call ‘passengers,’ that is, mutations alongside another mutation that is acting as a driver.” His colleagues at Broad have developed an algorithm to help

“When we add all this up, we come up with wiring patterns in head and neck cancer.” —Aaron D. Tward, MD, PhD

researchers distinguish the two, using indicators such as the presence of a mutation in a larger number of tumors and filtering out larger genes, which are more likely to have random mutations. Tward said their studies confirmed earlier findings implicating TP53, CDKN2A, PTEN, PIK3CA, and HRAS in head and neck malignancies. Of particular interest, however, are mutations they discovered that have not previously been implicated in these cancers: TP63, IRF6, MED1, and, notably, NOTCH. Depending on what cell it resides in, NOTCH can act either as an oncogene

(as is the case with acute lymphoblas- ate syndromes. “We think this is all retic leukemia) or as a tumor suppres- lated,” said Tward. “When we add all this up, we come sor gene in HNSCC and skin cancer. In these latter two, NOTCH is “a critical up with wiring patterns in head and player in the decision to stop proliferat- neck cancer,” which can be used to ing,” Tward said. When mutations inac- inform further studies. He added that researchers did not tivate NOTCH, terminal find many oncogenes differentiation ceases, in these tumor samcausing unrestrained ples, an exception beproliferation. To iling PI3KCA. Tward said lustrate the challenge that trials with PI3K posed by NOTCH’s dual inhibitors are likely to mechanisms, Tward be fruitful in HNSCC noted a clinical trial patients, but “only for testing a gamma secrethose who have the tase inhibitor predicted mutation.” He also notto inhibit NOTCH in paed that investigators tients with Alzheimer’s did not find EGFR mudisease. The trial was tations, a finding constopped because the sistent with the much drug was causing an Aaron D. Tward, MD, PhD larger Cancer Genome increase in squamous Atlas (TCGA) data set. cell cancers in the TTN treatment arm. The researchers also found that mutations in genes at the “top of our rank Stransky N, Egloff AM, Tward AD, et al. The mulist” for head and neck cancers and de- tational landscape of head and neck squamous fects in squamous differentiation are cell carcinoma. Science. 2011;333(6046):1157also present in patients with cleft pal- 1160.

Next-Generation Therapy for Multiple Myeloma By Ben Leach

mmunomodulatory drugs and protewere observed when pomalidomide asome inhibitors have revolutionized was given with dexamethasone. the treatment of multiple myeloIn the phase II trial, patients refracma by improving patient response and tory to lenalidomide, bortezomib, survival. Now, newer and more potent or both were randomized to receive versions of existing pomalidomide with therapies are under delow-dose dexamethavelopment and showsone or pomalidomide ing considerable promalone. The overall reise in early clinical trisponse rate in the als. At the 2012 Checombination arm was motherapy Foundation 29% versus 15% with Symposium, Sundar Japomalidomide alone. gannath, MD, presentMedian progressioned a comprehensive refree survival was 3.8 view of several emergmonths in patients reing multiple myeloma ceiving pomalidomide drugs.1 plus dexamethasone, In terms of immuas compared with 2.5 nomodulatory agents, months with pomalidSundar Jagannath, MD pomalidomide appears omide alone (hazard to be building upon ratio = 0.73; P = .037). the success of its predecessors, inAdditionally, pomalidomide appears cluding lenalidomide. Several clinical to work better when given in a 3-weekstrials have confirmed the activity of on/1-week-off regimen, according to pomalidomide in patients with multhe results of a study presented at the tiple myeloma. For example, a study 2011 American Society of Hematolpresented at the 2012 American Sociogy (ASH) Annual Meeting.2 Results of the IFM 2009-02 study showed that ety of Clinical Oncology (ASCO) Annual median time to first response, median Meeting showed that good responses

Targeted Therapy News • 1.13

duration of response, and the proportion of patients who were alive at least 1 year into the study were all higher in patients who received 3 weeks of pomalidomide followed by 1 week off with weekly dexamethasone compared with patients who received continuous pomalidomide with dexamethasone. “These responses are durable and meaningful,” said Jagannath, who is director of the Multiple Myeloma Program at the Tisch Cancer Institute at Mount Sinai Medical Center in New York City. The FDA has set an action date for pomalidomide of February 10, 2013. In addition to the next generation of immunomodulatory therapy, new proteasome inhibitors poised to improve upon bortezomib and carfilzomib are also in development. Jagannath highlighted two agents—ixazomib (MLN9708) and marizomib (NPI-0052)— that have yielded promising early data, and clinical trials continuing to assess their efficacy are currently enrolling patients. Small studies of ixazomib, the first orally available proteasome inhibitor to enter clinical trials, were presented at ASH 2011 and ASCO 2012. These stud-

Key Points: • Pomalidomide produced durable and meaningful results in refractory disease • Ixazomib, first oral proteasome inhibitor showed activity in heavily pretreated patients

ies showed activity in heavily pretreated patients with multiple myeloma and suggested that the drug produced durable responses and disease control. The study presented at ASH showed that six patients had achieved minimal response or better among 36 evaluable patients.3 Additionally, two of those patients achieved a partial response (PR) with duration of disease control of up to 11.3 months. Another 22 patients achieved stable disease. The study presented at ASCO further confirmed these positive ixazomib results. Of 53 evaluable relapsed and/ or refractory patients, six achieved at least PR. Additionally, a duration of disease control of up to 21.1 months was observed.4

Chemotherapy Foundation Symposium Conference Coverage Feature

“There is reason to believe that this drug may be better than bortezomib and could be given orally,” Jagannath said. Data on marizomib were also presented at ASH 2011. An interim analysis of 22 patients who received marizomib, the majority of whom were refractory to bortezomib, found that three had achieved PR. Those patients were evaluable in the active dose range of 0.4 to 0.6 mg/m2, and all were refractory to prior bortezomib. The median time on treatment was 1.5 months, and 16 patients (73%) achieved stable disease or better. The authors suggested further investigation of the drug in combination with lenalidomide and dexamethasone. Perhaps most significant, Jagannath noted,

“There is reason to believe that [ixazomib] may be better than bortezomib and could be given orally.” —Sundar Jagannath, MD

is the fact that peripheral neuropathy did not appear to be a side effect, since it is a significant adverse event associated with bortezomib.5 TTN 1. Vij R, Richardson PG, Jagannath S, et al. Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): outcomes in pts refractory to lenalidomide (LEN) and/or bortezomib (BORT). J Clin Oncol. 2012;30(suppl; abstr 8016). 2. Leleu X, Attal M, Arnulf B, et al. High response rates to pomalidomide and dexamethasone in patients with refractory myeloma, final analysis of IFM 2009-02. Blood. 2011;118(21):812. 3. Richardson PG, Baz R, Wang L, et al. Investigational agent MLN9708, an oral proteasome

inhibitor, in patients (pts) with relapsed and/or refractory multiple myeloma (MM): results from the expansion cohorts of a phase 1 dose-escalation study. Blood. 2011;118(21):301. 4. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM). J Clin Oncol. 2012;30(suppl; abstr 8017). 5. Richardson PG, Spencer A, Cannell P, et al. Phase I clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (MM). Blood. 2011;118(21):302.

Personalized Therapy and Companion Diagnostics for Lung Cancer By Devera Pine

he era of personalized therapy lecular targets were identified in lung in lung cancer is here, but as cancer—ROS1, RET, and HER2. “They’re technology for all actionable—there genetic sequencing are drugs in the clinic continues to improve, right now; there are the use of companion things you can do,” diagnostics to identify he said. For example, mutations is likely to cabozantinib is bebe replaced by nexting investigated for generation sequencthe treatment of RETing, according to Mark positive lung cancer; G. Kris, MD, chief, Thosunitinib, sorafenib, racic Oncology Service and vandetanib also at Memorial Sloantarget RET. “So these Kettering Cancer in are not theoretical, New York, NY. they’re not maybe it Kris, speaking at the will work in ten years. 2012 Chemotherapy It’s an amazing story,” Mark G. Kris, MD Foundation SympoKris said. sium, noted that 60% At Memorial Sloanof lung cancers are adenocarcinomas. Kettering, genetic sequencing idenA good histologic diagnosis is absotifies driver mutations in 65% of adlutely critical for treatment of these enocarcinoma specimens, with most cancers, he said. mutations in EGFR or KRAS, Kris Testing generally identifies many said. That information helps oncolomutations, but not every mutation is gists select the appropriate treatan active driver (Table 1), Kris said. In ments, and it also sets the stage for 2012 alone, however, three new moresearch—there are 18 open studies just for non-small-cell lung cancer alone at the center. Table 1. Driver Oncogenes For oncologists in community pracCurrently Identified in Lung tice, the molecular characteristics of lung cancers can be used to select Adenocarcinomas targeted therapies (Table 2). Routine KRAS ROS1 genotyping at diagnosis for lung canEGFR RET cer should include EGFR and ALK testing as standard for all lung cancers ALK PI3KCA except small cell and squamous cell HER2 MET carcinomas in smokers and large biDouble Mt MEK1 opsy specimens, Kris said. He recommended up-front, parallel, multiplex BRAF NRAS

testing for all mutation drivers, and strongly emphasized that there is no clinical selection or patient profile for adenocarcinoma that can substitute for testing. “I spend a lot of time trying to find it—it’s not there,” he said.

“So these are not theoretical, they’re not maybe it will work in ten years. It’s an amazing story.” —Mark G. Kris, MD

“Test, don’t guess.” In the next five years, Kris expects that next-generation sequencing of all lung cancers for all cancer genes will become commonplace, replac-

Key Points: • Test for EGFR and ALK at diagnosis for all lung cancers except small cell and squamous cell carcinomas in smokers and large biopsy specimens • No clinical selection or patient profile for adenocarcinoma can substitute for testing

ing companion diagnostics, which he says will have limited use. Molecular testing of lung cancers—“It’s cancers, not cancer,” Kris said—has evolved from direct sequencing to identify one gene, to identification of eight genes using systems such as Sequenom genotyping today, to, in the near future, high-throughput sequencing that can identify more than 200 genes. “Personalized care for lung cancers is here,” Kris said. “The ‘one size fits all’ treatment era is over.” TTN

Table 2. Lung Cancer Molecular Characteristics and Initial Therapies Molecular Characteristic

Targeted Therapy

EGFR mutation

erlotinib

ALK rearrangement

crizotinib

KRAS mutation

do not treat with erlotinib

HER2 mutation or amplification

trastuzumab or lapatinib

MET amplification

crizotinib

ROS1 rearrangement

crizotinib

RET fusion

vandetanib, sunitinib

BRAF

vemurafenib

V600E

Targeted Therapy News • 1.13

Chemotherapy Feature Foundation Symposium Conference Coverage

Beyond Bevacizumab: Potential Agents for the Treatment of Ovarian Cancer By Ben Leach

lthough the association between ogy Group (GOG) 9923 phase I study, carvascular endothelial growth fac- boplatin and paclitaxel chemotherapy tor (VEGF) and ovarian cancer has were given in combination with bevabeen known for quite some time, re- cizumab along with escalating doses of searchers are still struggling to use drugs veliparib. Additional trials are currently that inhibit VEGF and angiogenesis in recruiting patients to assess the efficacy ovarian cancer patients. Bevacizumab of veliparib in combination with other appeared promising in clinical trials but agents such as topotecan. has yet to receive FDA approval for treat“The problem with veliparib is we still ment of the disease, so other agents are don’t know its single-agent efficacy,” Konbeing looked at as promner said. “A recent singleising novel therapies. agent phase II study was At the 2012 Chemocompleted by the GOG. It therapy Foundation Symaccrued very quickly, and posium, Jason A. Konner, we’re waiting for efficacy MD, a medical oncologist data on that.” at Memorial Sloan-KetOther agents have also tering Cancer Center in shown promising data. New York City, reviewed Cabozantinib, an oral some of the promising tyrosine kinase inhibinewer agents that may tor, is being investigated provide a benefit to this in a number of different difficult-to-treat group of tumor types, including patients. ovarian cancer. “That’s PARP, poly(adenosine probably the most promdiphosphate [ADP]–riising oral TKI for ovarian Jason A. Konner, MD bose) polymerase, plays cancer, having shown an important role in the the most pronounced rerepair of single-strand DNA breaks. Sin- sponse rates in early trials,” Konner said. gle-strand breaks can become doubleThe results of a phase II randomized strand breaks that are, in turn, repaired discontinuation trial were presented at by a complex that contains BRCA1 and the American Society of Clinical OncoloBRCA2, two genes that have deleteri- gy (ASCO) meeting in 2011. The study was ous mutations associated with ovarian halted because a high rate of clinical accancer. Researchers have theorized that tivity was observed. The overall response inhibiting the PARP enzyme should se- rate among patients with progressive lectively kill cells with those genetic ab- measurable disease at 12 weeks was normalities, so PARP inhibitors are being 24%, and clinical activity was observed explored as a treatment option for ovar- regardless of whether patients had previian cancer. ously been treated with platinum-based One investigational PARP inhibitor, ve- therapy.1 A randomized phase II trial has liparib, is being assessed in a number of been designed to compare cabozantinib clinical trials. In the Gynecologic Oncol- with paclitaxel in patients with persis-

tent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cavity cancer. Another agent under investigation for the treatment of ovarian cancer is aflibercept. Aflibercept is a dual inhibitor of VEGF-A and placental growth factor (PlGF), proteins that promote angiogenesis. Recently approved for the treatment of metastatic colorectal cancer, studies have shown promising data for the treatment of ovarian cancer.

“[Cabozantinib is] probably the most promising oral TKI for ovarian cancer, having shown the most pronounced response rates in early trials.” —Jason A. Konner, MD

At the 2011 ASCO meeting, results of a phase II multi-institutional study combining aflibercept with docetaxel in patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer found that the combination of agents was generally effective. An objective response rate was confirmed in 25 of 46 (54%; 95% CI, 39%–69%) patients in the trial, with 11 patients achieving a com-

Key Points: • Cabozantinib showed pronounced response rates in early trials • Aflibercept being tested but may not have advantages over bevacizumab • Single-agent efficacy trial of veliparib under way

plete response and 4 patients whose disease did not recur for a median of 18.4 months (95% CI, 5.2–31.1) once off treatment. The median progression-free survival was 6.43 months and the median overall survival was 26.6 months.2 Konner said that aflibercept mimics bevacizumab in several ways. However, Konner said that the outlook for aflibercept may be similar to bevacizumab, in that it may struggle to find FDA approval for ovarian cancer. “It’s unclear what role, if any, aflibercept will have in the future, since it’s not clear that there are any advantages over bevacizumab,” Konner said. TTN 1. Buckanovich RJ, Berger R, Sella A, et al. Activity of cabozantinib (XL184) in advanced ovarian cancer patients (pts): results from a phase II randomized discontinuation trial (RDT). J Clin Oncol. 2011;29(suppl; abstr 5008). 2. Coleman RL, Duska LR, Ramirez PT, et al. Phase II multi-institutional study of docetaxel plus aflibercept (AVE0005, NSC# 724770) in patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer. J Clin Oncol. 2011;29(suppl; abstr 5017).

PARP Inhibitors (continued from cover) However, this study established another mechanism of action for PARP inhibitors. Normally, PARP1 and PARP2 are released from DNA once other proteins begin the repair process. However, PARP inhibitors are able to trap PARP1 and PARP2 on sites of damaged DNA. These PARP-DNA complexes are more toxic to cells than unrepaired singlestrand breaks of DNA that accumulate in the absence of PARP activity, suggesting that PARP inhibitors work by “poisoning” these accumulations of PARP proteins. Additionally, the researchers determined that different PARP inhibitors have varying degrees of potency

Targeted Therapy News • 1.13

when it comes to trapping these complexes. “Critical to our research is that, while PARP inhibitors had been assumed to be of equivalent potency based on the degree to which they elicit PARP inhibition, we now know that they are not equivalent with respect to their potency to trap PARP,” said Yves Pommier, MD, PhD, head of the DNA Topoisomerase/Integrase Group at the National Cancer Institute Center for Cancer Research, in a statement. “Our findings suggest that PARP inhibitors should be categorized according to their potency to trap PARP, in addition to their enzyme inhibition abilities.”

The researchers used PARP assays to assess olaparib, veliparib, and niraparib. They determined that niraparib had the highest potency when it came to trapping PARP, followed by olaparib and veliparib. These findings suggest that these drugs could be classified in two ways: inhibitors that primarily inhibit PARP enzyme activity but do not trap PARP proteins on DNA; and inhibitors that have a dual mechanism of action and inhibitor PARP enzyme activity while also being able to trap PARP proteins. “Our findings suggest that clinicians who use PARP inhibitors in clinical trials

should carefully choose their drug, because we now suspect results may differ, depending upon the PARP inhibitor used,” said Junko Murai, MD, PhD, Laboratory of Molecular Pharmacology, NCI Center for Cancer Research, and lead author of the study, in a statement. “As a next step, we are working to categorize other leading PARP inhibitors based upon both PARP trapping and PARP inhibition.” TTN Murai J, Huang SN, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;71(21):5588-5599.

San Antonio Breast Cancer Symposium Conference Coverage Feature

One Year of Adjuvant Trastuzumab Confirmed as Standard of Care By Jason M. Broderick

ight-year follow-up data from or FISH-positive] prior to randomizathe phase III HERA trial has contion.” firmed that 1 year of adjuvant Following surgery and physiciantrastuzumab (Herceptin) should redetermined treatment with chemomain the treatment standard in womtherapy and/or radiotherapy, patients en with HER2-positive were randomized to 1 early-stage breast canyear of trastuzumab cer. In the HERA study, (n = 1703), 2 years of extending trastuzumtrastuzumab (1701), ab therapy to 2 years or observation (1698). did not produce an Trastuzumab theraadditional benefit. The py in both treatment long-term HERA rearms consisted of an sults were presented 8-mg/kg loading dose at the 2012 European followed by a 6-mg/kg Society for Medical dose every 3 weeks. Oncology (ESMO) ConAfter the initial gress and again at the HERA results were 35th Annual San Anpresented at the 2005 tonio Breast Cancer ASCO Annual Meeting, Symposium (SABCS). Brian Leyland-Jones, MBBS, PhD patients in the obser“You gain nothing vation arm were given from adding the additional year of the option to receive trastuzumab. “In Herceptin. One year of trastuzumab is 2005, after the release of the strikingly now a proven advantage from both a positive results in this trial and two disease-free survival and overall surother trials conducted in the United vival viewpoint,” said Brian LeylandStates, 52% of the women randomJones, MBBS, PhD, director of Edith ized to the observation arm selectively Sanford Breast Cancer Research, Sioux crossed over to receive trastuzumab,” Falls, South Dakota, and one of the auPiccart said. thors of the HERA study. At 8 years’ median follow-up, disHERA accrued 5102 women with ease-free survival (DFS) and overall locally determined HER2-positive insurvival (OS) were similar between vasive early breast cancer between the 1- and 2-year treatment arms. 2001 and 2005. In a press conference The unadjusted hazard ratio (HR) for a at SABCS, Martine J. Piccart, MD, PhD, DFS event in the longer versus shorter chief of the Medicine Department trastuzumab arms was 0.99 (95% CI, at the Jules Bordet Institute in Brus0.85-1.14; P = .86). With the OS comsels, Belgium, president of ESMO, parison, the HR was 1.05 (95% CI, 0.86and chair of the Breast International 1.28; P = .63). Group, said, “HER2 status had to be Piccart said hormone-receptor stacentrally confirmed [IHC 3-positive tus did not affect the efficacy of the

treatment. “Women with HER2-positive breast cancer benefited from Key Points: trastuzumab whether they had hormone receptor-positive tumors or hor• 1 year of trastuzumab provides mone receptor-negative tumors.” disease-free and overall survival The primary cardiac endpoint of advantage symptomatic congestive heart failure was rare and did not vary greatly be• 2 years offered no additional tween the two treatment arms. Howbenefit ever, rates of the secondary cardiac • Hormone-receptor status not a endpoint of asymptomatic cardiac factor dysfunction were higher with 2 versus 1 year of trastuzumab at 7.2% and • Asymptomatic cardiac dysfunction 4.1%, respectively. Importantly, Piccart higher with 2 years noted that treatment cessation mostly eliminated cardiotoxicity. “Very few women experienced any cardiac event after stopping adjuof the Dan L. Duncan vant trastuzumab,” Cancer Center and the Piccart said. “Most Lester and Sue Smith of the cardiac events Breast Center at Baylor in HERA, like in the College of Medicine in other adjuvant trials Houston, Texas. of trastuzumab, have Going forward, Lebeen reversible.” yland-Jones said the With the 1 year next challenge will be trastuzumab regidetermining the optimen now established, mal treatment duraKent Osborne, MD, tion of trastuzumab in commented at the combination regimens. SABCS press confer“We think that we’ve ence about the cost hit the gold standard implications of the in terms of [treatment Martine J. Piccart, MD, PhD HERA results. “I think length] of Herceptin as the HERA trial is an monotherapy. How this extremely important one. The reason could change is when you have comit’s so important is that you can imagbinations. So when you have trastuine the cost to healthcare if we had to zumab plus pertuzumab or when you give trastuzumab for two years rather start adding PI3 kinase inhibitors or than one. So I was really gratified to other drugs, then I think this whole see that one year seems to be just as duration question is going to come up good,” said Osborne, who is director again.” TTN

Adjuvant Bevacizumab Falls Short in Triple-Negative Breast Cancer By Ben Leach

atients with triple-negative breast cancer had no statistically significant improvement in disease-free survival when they received adjuvant treatment with chemotherapy plus 1 year of bevacizumab compared with patients who received chemotherapy alone, according to the results of the phase III BEATRICE trial presented at the 35th Annual San Antonio Breast Cancer Symposium. In the open-label, multinational trial, 2591 patients with resected triple-negative invasive early breast cancer were

randomized to receive the investigator’s choice of either standard chemotherapy for four to eight cycles followed by observation (n = 1290) or bevacizumab (5 mg/kg/ week equivalent) plus investigator’s choice of standard chemotherapy for four to eight cycles followed by bevacizumab monotherapy for a total of 1 year (n =

David Cameron, MD

1301). Researchers were allowed to use taxanebased chemotherapy (>4 cycles), anthracyclinebased chemotherapy (>4 cycles), or anthracycline and taxane chemotherapy (3-4 cycles each). Patients were recruited between December 2007 and March 2010. The primary endpoint of the trial was invasive diseasefree survival (IDFS).

“This endpoint includes other invasive cancers, just as a check to make sure that we’re not inducing cancer in another area,” said David Cameron, MD, professor of Oncology at Edinburgh University in Scotland and lead author of the study. After a median follow-up of 31.5 months in the chemotherapy-alone arm and 32 months in the bevacizumab arm, the 3-year IDFS rate in the bevacizumab arm was 83.7% (95% confidence interval [CI], 81.4-86.0) compared with 82.7% (95% CI, 80.5-85.0) in

Targeted Therapy News • 1.13

San Antonio Breast Cancer Symposium Conference Coverage

the chemotherapy arm (stratified hazard ratio [HR] = 0.87; 95% CI, 0.72-1.07; P = .1810). An interim analysis of overall survival (OS) was also performed, although only 59% of the required number of events had occurred, so the data were not considered mature. In the bevacizumab arm, 93 deaths had occurred during follow-up compared with 107 deaths in the chemotherapy arm (stratified HR = 0.84; 95% CI, 0.641.12; P = .2318). The adverse events observed in this trial are consistent with other trials of bevacizumab in metastatic breast cancer, Cameron said. Certain grade >3 adverse events appeared more frequently in the bevacizumab arm than the chemotherapy arm, including hypertension (88 [7%] versus 6 [<1%], respectively), a side effect that has been associated with bevacizumab use in past studies. Left ventricular dysfunction and clinical heart failure were

“The good news for women is that the outcome of 84% invasive diseasefree survival after three years was actually much better than we had originally planned.” —David Cameron, MD

also more common with bevacizumab, although these adverse events were resolved more quickly in the bevaci-

zumab arm compared with the chemotherapy arm. “The good news for women is that the outcome of 84% invasive diseasefree survival after three years was actually much better than we had originally planned,” Cameron said. “When women go onto the Web and look up what is a very negative image of triple-negative breast cancer, we can at least say [according to] a big worldwide phase III trial, actually the outcomes maybe are not as bad as the older literature suggests. But in terms of an improvement in outcome, one year of bevacizumab isn’t the answer.” Cameron noted that further followup is required to determine whether bevacizumab has any potential to improve OS. The prespecified OS analysis will be performed when 340 patients in the study have died or all patients have been followed for a median of 5 years, whichever comes first. Cameron said

Key Points: • 1 year adjuvant bevacizumab did not improve disease-free survival • Hypertension, left ventricular dysfunction, clinical heart failure more common in bevacizumab patients • Overall survival analysis still under wayy the results are estimated to become available in late 2013. TTN Cameron D, Brown J, Dent R, et al. Primary results of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative breast cancer. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract S6-5.

Genetic Alterations Targetable in Triple-Negative Breast Cancer By Ben Leach

atients with triple-negative respond to neoadjuvant chemotherabreast cancer who have residual py have residual disease that leads to disease after receiving neoadjuworse outcomes. vant chemotherapy have a series of “In treatment, those patients don’t genetic alterations that are clinically really have therapeutic options,” said targetable and may warrant further Justin M. Balko, PharmD, PhD, a restudy with various targeted therapies search faculty member who works in already available or in development, the lab of Carlos Arteaga, MD, at the according to research presented at the Vanderbilt-Ingram Cancer Center in 35th Annual San AntoNashville, Tennessee, nio Breast Cancer Symand lead author of the posium. study. “In particular, The research showed they have no targeted that triple-negative therapeutic options. breast cancer has treWe already know that mendous molecular their tumors were not heterogeneity, with completely responsome patients in the sive to chemotherapy, study having as many so using more chemoas 6 or 7 different altherapy down the road terations based on deep may or may not be efsequencing that looked fective. Our goal was for 182 different oncoto use state-of-the-art genes and tumor supmolecular techniques pressors known to be alto profile those residuJustin M. Balko, PharmD, PhD tered in human cancers. al tumor cells and see Approximately 30% if we could find some of patients with triple-negative breast clinically actionable alterations that cancer achieve a pathological comare present in that residual disease in plete response after receiving neoadtriple-negative breast cancer.” juvant chemotherapy, which leads to Of the 81 tumors that were evalua favorable diagnosis. However, the ated for oncogenes using next-genremaining 70% of patients who do not eration sequencing, 72 (89%) had

Targeted Therapy News • 1.13

mutations in TP53, 22 tumors were MCL1-amplified (27%), and 17 tumors were MYC-amplified (21%). At least 15 additional mutations among the 182 that were tested for were identified in the study. “This diversity states that we really need to not just look at single biomarkers alone but be able to organize these alterations into pathways,” Balko said. Using this information, the researchers identified clinically targetable pathways for which various targeted therapies are either already available or in development. These included alterations of the PI3K/mTOR pathway in 27 tumors (33%), alterations in cell cycle genes in 25 tumors (31%), DNA repair pathway alterations in 16 tumors (20%), Ras/MAPK pathway alterations in 10 tumors (12%), and sporadic growth factor receptor amplifications that occurred in EGFR, IGFR1, FGFR1, KIT, and others. Additionally, amplifications in the JAK2 locus were identified in 11% (8 of 72) of the patients in whom copy number aberrations were identified among the 81 original tumor samples. Balko said that the survival of patients with this particular amplification is very poor. Since pan-JAK and JAK2 in-

Key Points: • Genetic alterations have been found in PI3K/mTor, Ras/MAPK, EGFR, KIT and others • Targeted therapies are available or under development for many of the identified mutations hibitors are currently in clinical trials, Balko said that this is another potential therapeutic target that can be explored. “I think the timing would be right to not only identify the biomarker but also identify the drug and identify the patients, and hit that in an adjuvant study,” Balko said. “I would be very encouraged to do that based on our data.” TTN Balko JM, Wang K, Sanders ME, et al. Profiling of triple-negative breast cancers after neoadjuvant chemotherapy identifies targetable molecular alterations in the treatment-refractory residual disease. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract S3-6.

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 andand 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 advanced aromatase advanced oraromatase metastatic orinhibitor metastatic orinhibitor metastatic breast breast breast cancer cancer cancer pretreated pretreated pretreated withadvanced with aromatase with aromatase 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 No more than one prior line of No 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 ECOG ECOG ECOG Performance Performance Performance Status Status Status ≤2 ≤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 BELLE-3 BELLE-3 BELLE-3 1

Evidence of Evidence Evidence Evidence of progression ofprogression progression of progression Evidence Evidence Evidence of progression of progression ofmTOR progression on or after mTOR on or onafter or onafter ormTOR after mTOR oninhibitor-based or onafter or onafter ormTOR after mTOR mTOR 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 isThere nonoguarantee that buparlisib will become commercially available. There There is no guarantee is guarantee is no that guarantee buparlisib that buparlisib that will buparlisib become will become will commercially become commercially commercially available. available. available. 1 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; hormone receptor-positive; mTOR, mammalian target rapamycin; PI3K, PI3K, phosphatidylinositol PI3K, phosphatidylinositol phosphatidylinositol 3-kinase. 3-kinase. 3-kinase. receptor receptor 2-negative; receptor 2-negative; 2-negative; HR+,HR+, hormone HR+, hormone HR+, receptor-positive; hormone receptor-positive; receptor-positive; mTOR, mTOR, mammalian mTOR, mammalian mammalian targettarget of rapamycin; target ofofrapamycin; 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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Feature San Antonio Breast Cancer Symposium Conference Coverage

HDAC Inhibition May Sensitize Triple-Negative Breast Cancer Cells to Certain Treatments By Bonnie Gillis

reliminary research suggests that in-vitro exposure to a histone deacetylase (HDAC) inhibitor may sensitize triple-negative breast cancer cells to treatment with a PARP inhibitor and cisplatin, according to research presented at the 35th Annual San Antonio Breast Cancer Symposium. HDAC inhibitor exposure appears to indirectly cause DNA damage and impair the ability of breast cancer cells to repair damaged DNA, thus sensitizing the cells to these two treatments. These effects mimic those in BRCA1mutated breast cancer cells. “Triple-negative breast cancer is a particularly aggressive breast cancer that is not susceptible to traditional hormone therapies,” said Kapil N. Bhalla, MD, chief of Personalized Cancer Medicine at the University of Kansas Cancer Center in Kansas City. “That is why it is important to find new ways of killing triple-negative breast cancer cells.” DNA repair is essential for survival of certain tumor cells. Previous research has found that proteins such as ATR, CHK1, and BRCA1 are key elements of a cell’s response to DNA damage and subsequent repair of the damage. These three proteins are chaperoned

by heat shock protein 90 (Hsp90). said. “By using HDAC inhibitors, we Previous work by Bhalla and colwere targeting the cancer in two ways leagues showed that treatment with at once.” an HDAC inhibitor renders hsp90 inacBhalla and colleagues also analyzed tive, thus impeding the whether treatment with DNA damage response the HDAC inhibitors involving the three provorinostat or panobiteins. In this way, HDAC nostat would sensitize inhibition creates an intriple-negative breast tracellular environment cancer cells to PARP that mimics that seen inhibition. Combining in breast cancer with either of the HDAC inBRCA1 mutations. hibitors with the PARP “In simple terms, with inhibitor ABT888 resultHDAC inhibition, we are ed in the death of tripletrying to cause a ‘BRCAnegative breast cancer ness’ to confer on triplecells with or without negative breast cancer the BRCA1 mutation. cells the sensitivity to Additionally, vorinostat PARP inhibition or platitreatment made the Kapil N. Bhalla, MD num therapy seen in the triple-negative breast presence of BRCA1 mucancer cells more sustations,” Bhalla said. ceptible to treatment with cisplatin. Their studies showed that inhibition “These findings indicate that treatof HDAC3 specifically rendered Hsp90 ment with pan-HDAC inhibitors voriinactive, consequently inhibiting renostat or panibostat creates ‘BRCApair of damaged DNA. ness,’ and in combination with a PARP “The icing on the cake, so to speak, inhibitor or cisplatin synergistically inwas that in addition to inhibiting the duces apoptosis in human triple-negaDNA damage response through depletive breast cancer cells,” Bhalla said. tion of DNA repair proteins, HDAC inIf these findings are confirmed by hibitors induced DNA damage,” Bhalla further study, Bhalla said that they

Key Points: • HDAC inhibitors may restore sensitivity to PARP inhibition or platinum therapy • Inhibitors depleted DNA repair proteins and induced DNA damage could have treatment implications for women with triple-negative breast cancer and potentially for ovarian cancer, which has a similar genetic makeup to that of triple-negative breast cancer. “If you have a patient with triplenegative breast cancer who does not have a BRCA1 mutation, you could consider a clinical trial with an HDAC inhibitor in combination with a PARP inhibitor and cisplatin,” Bhalla said. TTN Bhalla KN, Rao R, Sharma P, et al. Treatment with histone deacetylase inhibitors creates ‘BRCAness’ and sensitizes human triple negative breast cancer cells to PARP inhibitors and cisplatin. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract S3-7.

PD 0332991 Significantly Improves PFS in Patients With Advanced ER+ Breast Cancer By Bonnie Gillis

ombining an investigational of cyclin-dependent kinase (CDK) 4/6, agent called PD 0332991 with which prevents cellular DNA synthesis letrozole as first-line therapy exby blocking tumor cell cycle progrestended progression-free sion. survival (PFS) in women “The dramatic imwith advanced estrogen provement in progresreceptor-positive (ER+) sion-free survival with breast cancer in a phase the combination is very II study presented at the encouraging and clini35th Annual San Antocally meaningful,” said nio Breast Cancer SymRichard S. Finn, MD, posium. associate professor of The combination Medicine at the Jonsson achieved median PFS of Comprehensive Cancer 26.1 months compared Center at the University with 7.5 months for leof California, Los Angetrozole alone (P=.006). les (UCLA) and lead auPD 0332991 is a novel thor of the study. “These Richard S. Finn, MD oral selective inhibitor data represent a poten-

Targeted Therapy News • 1.13

tial major advancement in our efforts to identify new medicines that target patients most likely to have an optimal response.” Finn said this study validates preclinical studies showing that the new compound has significant activity in breast cancer models and acts synergistically with hormonal therapy. The phase II study had two parts. In both parts, postmenopausal women with ER+/HER2- advanced breast cancer were randomized 1:1 to receive letrozole plus PD 0332991 or letrozole alone. Part 1 enrolled 66 patients, while part 2 enrolled 99 patients using the same eligibility criteria but also screened tumors for CCND1 amplification and/or loss of p16 by FISH analysis.

Key Points: • Letrozole and a novel CDK4/6 inhibitor resulted in 63% improvement in risk of progression • AEs: uncomplicated neutropenia, leucopenia, anemia, fatigue • Phase III trial begins in 2013 For both parts of the trial, the primary endpoint was PFS. Secondary endpoints included response rate, overall survival, safety, and correlative biomarker studies. At the conference, pooled results from both part 1 and 2 of the trial were presented, based on a total of 165 pa-

San Antonio Breast Cancer Symposium Conference Coverage

tients. In this pooled analysis, median PFS was 26.1 months (95% confidence interval [CI], 12.7 – 26.1) with the combination versus 7.5 months (95% CI, 5.6 – 12.6) with letrozole alone, representing a 63% improvement in risk of progression (hazard ratio [HR]=0.37; 95% CI, 0.21 – 0.63, P < .001). In patients with measurable disease, response rates were 45% for the combination versus 31% for letrozole alone. Clinical benefit rate (complete and partial response rates plus stable disease) was 70% versus 44%, respectively. The most commonly observed treat-

ment-related adverse events in the combination arm were neutropenia, leukopenia, anemia, and fatigue. “Importantly this was uncomplicated neutropenia,” Finn said. “There was no evidence of febrile neutropenia.” A phase III trial of the investigational agent in this patient population will be mounted in 2013. “The oncology community is looking forward to the further evaluation of PD 0332991 in the planned phase III trial and very interested in the potential for this novel CDK4/6 inhibitor to improve the treatment landscape for

These data represent a potential major advancement in our efforts to identify new medicines that target patients most likely to have an optimal response.

patients with advanced breast cancer,” Finn said. TTN Finn RS, Crown JP, Lang I, et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent 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 CTRCAACR San Antonio Breast Cancer Symposium; December 4 – 8, 2012; San Antonio, TX. Abstract S1-6.

—Richard S. Finn, MD

Eribulin Not Superior to Capecitabine in Previously Treated Metastatic Breast Cancer, but Subgroup Data Promising By Bonnie Gillis

ribulin mesylate failed to show 2010 by the FDA for the treatment of a statistically significant surmetastatic breast cancer previously vival benefit compared with treated with an anthracycline and a capecitabine in women with previtaxane in either the adjuvant or metaously treated metastatic breast cancer static setting and at least two cytotoxic in a phase III trial reported at the 35th chemotherapy treatment regimens for Annual San Antonio Breast Cancer the treatment of metastatic disease. Symposium.1 Eribulin achieved similar Approval was based on a statistically progression-free survival significant improve(PFS) and overall survival ment in OS when it was (OS) as capecitabine, and compared with several failed to show superiordifferent treatments ity over capecitabine, a currently used to treat widely used drug to treat the disease. metastatic breast cancer. The present study On the positive side, evaluated use of eribulin this is the first study to versus capecitabine in demonstrate activity earlier lines of treatment of eribulin in the first-, of metastatic breast second-, and third-line cancer. The study ransetting in metastatic domized 1102 patients breast cancer, according in a 1:1 ratio receive eito lead author Peter A. ther eribulin mesylate Peter A. Kaufman, MD Kaufman, MD, associate 1.4 mg/m2 given on days 1 and 8 of a 21-day cycle, professor of Medicine at or capecitabine 1250 mg/m2 administhe Geisel School of Medicine at Darttered orally twice daily on days 1 to 14 mouth and the Norris Cotton Cancer of a 21-day cycle. All patients had localCenter in Lebanon, New Hampshire. ly advanced or metastatic breast cancer, “The study objectives were not met,” < 3 prior chemotherapy regimens (< 2 Kaufman said. “Although we didn’t show for advanced disease), and prior treata statistically significant superiority over ment with anthracycline and taxane capecitabine, which was our goal, nuchemotherapy. Baseline characteristics merically the overall survival with eribuwere well balanced between the two lin was better than with capecitabine.” treatment arms. Additionally, subgroup data sugThe results of the study showed that gested that eribulin improved survival the median OS was 15.9 months for erby about 5 months in patients with ibulin and 14.5 months for capecitabine triple-negative breast cancer versus (HR=0.879; 95% confidence interval [CI], capecitabine, and this line of study will 0.770-1.003; P=.056). Median PFS was 4.1 be pursued further, Kaufman said. months and 4.2 months, respectively Eribulin—a non-taxane microtubule (HR=1.079; 95% CI, 0.932 – 1.250; P=.305). dynamics inhibitor—was approved in

Overall response rates were 11% for eribulin and 12% for capecitabine (P=.849). OS for HER2-negative patients was 15.9 months for eribulin and 13.5 months for capecitabine (HR=0.838; 95% CI, 0.715 – 0.983; P=.030). No new safety concerns emerged in the trial. Adverse events were consistent with the established safety profiles of both drugs. Adverse events

“Although we didn’t show a statistically significant superiority over capecitabine, which was our goal, numerically the overall survival with eribulin was better than with capecitabine.” —Peter A. Kaufman, MD occurring in more than 20% included neutropenia (54% for eribulin vs 16% for capecitabine), hand-foot syndrome (<1% vs 45%, respectively), alopecia (35% vs 4%, respectively), leukopenia (31% vs 10%, respectively), diarrhea (14% vs 29%, respectively), and nausea (22% vs 24%, respectively).

Key Points: • Eribulin not statistically superior vs capecitabine in improving survival, but numerically superior • Subgroup data: Eribulin improved survival vs capecitabine in triplenegative breast cancer Separate trials, also presented at SABCS, examined the use of eribulin in other settings. A phase II, multicenter, single-arm study investigated eribulin plus trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer.2 Preliminary results suggest that the combination appears to have considerable activity with an acceptable toxicity profile. Enrollment in the study is completed, and results are expected by the end of 2013. TTN 1. Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Presented at: 2012 CTRCAACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract S6-6. 2. Vahdat, L, Schwartzberg L, Wilks S, et al. Eribulin mesylate + trastuzumab for locally recurrent or metastatic HER2-positive breast cancer: results from a pase 2, multicenter, single-arm study. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract P5-2004.

Targeted Therapy News • 1.13

Feature

Targeted Oncology Therapy in 2012 and 2013 (continued from cover) approved: everolimus (Afinitor) for the treatment of women with postmenopausal, hormone-receptor positive, HER2-negative advanced disease, and pertuzumab (Perjeta) for the treatment of previously untreated women with HER2-positive metastatic breast cancer. “Everolimus made a big splash [this year]. We have not seen any drug that has shown a gain in progression-free survival [PFS] in estrogen receptor (ER)positive breast cancer that is also HER2negative in more than a decade,” said Sara Hurvitz, MD, director of the breast cancer program at the University of California, Los Angeles. “This is clearly very meaningful to patients, as it allows us to treat patients without chemotherapy and in a targeted manner.” According to Hurvitz, everolimus has a more manageable toxicity compared with chemotherapy, although she acknowledged that some patients may need dose reductions to manage the mouth sore toxicity seen with use of this drug. Management of mouth sores can be particularly daunting, but with communication and monitoring, this usually can be managed, Hurvitz said. Clinicians need to instruct patients about good oral hygiene and management of their sores, including letting the doctor know as soon as a mouth sore appears so that the side effect does not get out of control. “With proper management, I found it extremely well tolerated.” Pertuzumab, a novel antibody for HER2-positive breast cancer, was approved in June 2012 to be used in combination with trastuzumab (Herceptin) and chemotherapy. Trastuzumab binds and blocks activity of HER2, and pertuzumab binds at a different location on the HER2 molecule and can prevent the signaling that results from HER2 interacting with other HER receptors on the breast cancer cell. The combination aims to prevent some of the resistance that develops as a result of trastuzumab therapy. “Pertuzumab has yielded an incredible improvement in progression-free survival in the frontline, HER2-positive metastatic breast cancer setting,” said Hurvitz. The challenge with pertuzumab, according to Hurvitz, is that most women in the United States are diagnosed with earlier stages of HER2 breast cancer and will likely receive trastuzumab earlier in the course of their disease. However, in the pivotal clinical trial for pertuzumab, approximately 90% of the patient population had never had adjuvant or neoadjuvant trastuzumab, so the majority of patients were truly trastuzumab-

Targeted Therapy News • 1.13

naïve, she said. “The challenge in my own practice is that I am not seeing a lot of first-line HER2-positive metastatic breast cancer. Moreover, trastuzumab-naïve disease is rare in the metastatic setting in the US,” said Hurvitz. “While I use the pertuzumab-based regimen in the frontline setting, and have had good results with

“This is clearly very meaningful to patients, as it allows us to treat patients without chemotherapy and in a targeted manner.” —Sara Hurvitz, MD it, the prevalence of this patient population in my own clinic is low, limiting my ability to utilize it.” The MARIANNE trial, which is examining use of trastuzumab emtansine (TDM1) in combination with pertuzumab, may also change treatment decisions for HER2-positive metastatic breast cancer. “The outstanding question that we are waiting on is, ‘What is going to happen when the results of the MARIANNE trial come out in the next year?’” said Hurvitz. If the MARIANNE trial is positive, treatment of first-line metastatic HER2-positive disease may shift to T-DM1 plus pertuzumab. Results are expected in late 2013 or early 2014. Results of the EMILIA trial, which tested T-DM1 for previously treated HER2positive disease, were presented at the American Society of Clinical Oncology (ASCO) 2012 meeting. Roche, which makes T-DM1, filed for FDA approval, and the drug has been granted priority review, with a decision expected by February 26, 2013. T-DM1 has “been a coup for the antibody-drug conjugate technology,” said Hurvitz. “In the next year we are going to have more data that will change how we view first-, second-, and third-line treatment of HER2-positive breast cancer,” Hurvitz said. In adjuvant breast cancer treatment, addition of bevacizumab (Avastin) to chemotherapy is currently being explored in several patient populations. The question is whether anti-angio-

genesis therapy has more of an impact novel treatments with diverse mechaon micrometastatic disease compared nisms of action has been a real boon for with established-tumor metastatic dis- patients, says William K. Oh, MD, chief of the division of Hematology and Mediease. For triple-negative breast cancer cal Oncology at the Mount Sinai School (TNBC), the answer appears to be no. of Medicine and associate director of The BEATRICE trial presented at the Clinical Research at the Tisch Cancer InSan Antonio Breast Cancer Symposium stitute in New York City. Abiraterone acetate (SABCS) in December (Zytiga), an androgen 2012 found that adding biosynthesis inhibitor, bevacizumab to chemowas approved in 2011 therapy as an adjuvant for use in patients with therapy after surgery metastatic castrationdid not improve diseaseresistant prostate cancer free survival for patients (CRPC) after treatment with TNBC. with docetaxel chemoAnother study, the therapy. In December BETH trial, is currently 2012, the label was exaddressing whether adpanded to include its juvant chemotherapy use as a first-line CRPC in combination with therapy based on the reboth trastuzumab and sults of the COU-AA-302 bevacizumab has bettrial. “This is not a huge ter disease-free survival William K. Oh, MD surprise, since there is outcomes compared no reason to believe that with chemotherapy and trastuzumab in patients with HER2-pos- abiraterone would be less effective prior itive disease. Whether the addition of to chemotherapy,” said Oh. Another androgen pathway drug, bevacizumab will benefit HER2-patients “is a big question mark,” according to enzalutamide (Xtandi), an oral androgen receptor signaling inhibitor, was Hurvitz. Other ongoing studies that will likely approved in August 2012 for metastatic impact breast cancer treatment include CRPC after treatment with docetaxel. “Enzalutamide was approved rethe BOLERO-1 and BOLERO-3 trials, both examining the utility of everolimus in cently and represents a very important HER2-positive breast cancer. The re- advance,” said Oh. “It is well tolerated, sults of both trials could be presented associated with a significant survival at either the ASCO 2013 conference or benefit and is easy for patients to take.” Oh believes that such an agent needs to SABCS 2013. Finally, Hurvitz highlighted the re- be investigated in earlier-stage prostate sults of a phase II trial with PD-0332991 cancer—both newly diagnosed or those (PD-991) in combination with letrozole with a rising prostate-specific antigen in postmenopausal women with ER+, (PSA) level. Treating cancer at either HER2-negative metastatic breast cancer, stages of its progression could result in presented at SABCS 2012. Patients treat- better outcomes. Oh emphasizes that enzalutamide ed with the combination had a median PFS of 26.1 months compared with 7.5 and other agents must be rigorously months for those who received letrozole tested in earlier-stage patients through alone. “I don’t think I have ever seen a clinical trials to understand whether difference in progression-free survival they can be effective in the treatment of of that magnitude,” Hurvitz said. The earlier disease. One such phase II study lack of toxicity with the drug was also is testing the role of enzalutamide as notable. “It is a phenomenal drug be- neoadjuvant therapy in patients who cause there are no mouth sores or other are undergoing a prostatectomy for issues you see with these drugs on the their localized disease (NCT01547299). Another important therapy, Alphamarket, except for a drop in white blood cell count,” she said. PD-991 is an oral, radin (radium-223), has demonstrated selective inhibitor of the cyclin-depen- an overall survival benefit for patients dent kinases 4 and 6, which are impor- with advanced prostate cancer who also tant for cell cycle progression and DNA have bone metastasis. “Radium-223 will replication. A phase III trial in the same definitely be a new option that we will patient population is expected to open have to consider in our therapeutic armamentarium,” said Oh. The question in 2013. of when to use the agent and which patient sub-populations are most likely to Prostate Cancer benefit still remain, according to Oh. The availability in the last two years of Other agents currently in phase III

Feature

clinical trials include custirsen, an in- PhD, professor of Medicine at the Jonsfusion drug that blocks the activity of a son Comprehensive Cancer Center at protein that is overproduced in various the University of California, Los Angecancers including prostate; the BCR-Abl les. and Src tyrosine kinase inhibitor dasatSeveral trials are testing combinainib (Sprycel); the tyrosine kinase inhib- tions of targeted agents for BRAF mutaitor cabozantinib; and tion-positive metastatic orteronel, an oral andromelanoma. Following gen synthesis inhibitor. the results of phase III Results from orteronel monotherapy trials of and cabozantinib phase both dabrafenib and traIII trials could read out metinib presented at in 2012, according to Oh. ASCO 2012, two studies Another drug, tasquinitesting the combination mod, an oral agent that of the BRAF and MEK inhas various cancer-inhibitors demonstrated hibiting properties, has better patient outcomes intriguing early-stage compared to a BRAF indata, said Oh. hibitor alone. The comWith newly available bination has already targeted agents and shown promising results Antoni Ribas, MD, PhD more that will likely be and lower skin toxicities available soon, the quescompared with a BRAF tion of how to integrate new therapies inhibitor alone in a phase II trial. Anwith chemotherapy remains. “I believe other phase III trial (BRIM-7) is testing that many patients will still benefit from the already approved vemurafenib (Zelchemotherapy, but avoiding it in those boraf) in combination with another MEK who do not is important to understand,” inhibitor, GDC-0973. said Oh. “I anticipate that the combination of “It’s an exciting time for this field,” a BRAF inhibitor plus MEK inhibitor will said Oh. “Having been studying prostate become the new standard in BRAF-mucancer for 15 years, I am glad that the re- tant melanoma in the near future,” said search is now leading to an explosion of Ribas. new drugs for patients. It is a reminder Immunotherapies are also being acthat understanding the science behind tively explored for melanoma. Ipilimthe disease can lead to practical and real umab (Yervoy), an anti-CTLA4 antibody, benefits for patients.” was approved in 2011 for treatment of metastatic melanoma. Two phase III trials are currently addressing whether Melanoma ipilimumab as an adjuvant therapy for “Melanoma continues to be the most stage 3 melanoma will benefit patients. exciting cancer with the most advances Other novel immunotherapies in latebased on applying scientific knowledge stage trials include the anti-PD-1 antito patient care,” said Antoni Ribas, MD, bodies nivolumab and MK3475, as well as allovectin-7, MAGE-A3, and T-VEC. Results of the allovectin-7, T-VEC, and MAGE-A3 trials, and an adjuvant ipilimumab phase III trial, may be available in 2013, according to Ribas. Merging immunotherapies with targeted agents is now seen as a potentially promising treatment option. Two phase II trials combining vemurafenib with ipilimumab, either sequentially or in combination, are currently ongoing. Ribas said that he would also like to see a trial that tests the combination of a BRAF inhibitor with an anti-PD-1 or anti-PD-L1 agent. Anti-PD-L1 antibodies are currently in early-stage trials for metastatic melanoma.

“I anticipate that the combination of a BRAF inhibitor plus MEK inhibitor will become the new standard in BRAFmutant melanoma in the near future.”

—Antoni Ribas, MD, PhD

Lung Cancer “Molecular testing [for lung cancer] is here to stay,” said D. Ross Camidge, MD, PhD, associate professor in the division of Medical Oncology at the University

of Colorado School of Medicine in Den- of the PD-1 protein, appeared to derive ver. little if any benefit from the therapy. The recognition that molecular sub- However, this biomarker was not intetypes in smaller patient populations in grated into the phase III trials. non-small cell lung cancer (NSCLC) are “The data suggest there are patients clinically important has been well dem- who could be identified in advance onstrated with both the approval of the who will derive maximal and minimal ALK kinase inhibitor crizotinib (Xalkori) benefit from this drug,” said Camidge. in ALK-positive disease and the results “Given that the side effects are not inof the LUX-Lung 3 trial showing that significant, it is hard to see why the hythe irreversible EGFR inhibitor afatinib pothesis relating to PD-L1 expression is better than chemotherapy as a front- isn’t being formally tested in this study line treatment for EGFR-mutated lung upfront.” cancer. “These results have solidified Overall, lung cancer diagnosis and that these [smaller patient populations] treatment is moving toward better moare not just academic pursuits and will lecular subtyping of the disease, which be influencing clinical practice,” said will help to identify and develop tarCamidge. geted agents. “I am expecting molecular Afatinib has been submitted for ap- characterization to be widespread in the proval in Europe based on the LUX- community because the patients are goLung 3 trial. A filing in the United States ing to demand it,” said Camidge. TTN is expected soon. Several other trials are exploring the utility of afatinib in EGFR-mutated lung cancer, including one comparing afatinib to the reversible EGFR inhibitor gefitinib (Iressa). EGFR is currently the most common mutated gene in lung cancer patients for which there is a targeted drug. According to Camidge, EGFR testing is still not prevalent in the United States, but if afatinib is approved, testing for EGFR will become more widespread. Erlotinib is another EGFR inhibitor used to treat lung cancer, but the drug’s indication is not restricted to use in patients with the EGFR mutation. NSCLC with a rearrangement in the ROS1 gene is a relatively new subtype that makes up only about 1% to 2% of patients. As with ALK-positive patients, patients with ROS1 rearrangements are sensitive to crizotinib, according to a small cohort D. Ross Camidge, MD, PhD study presented at ASCO 2012. The immunotherapy agent nivolumab also is being tested in NSCLC. While Camidge believes that nivolumab has shown promising results in an earlystage trial, he is disappointed by the lack of a molecular selection strategy for some of the proposed follow-on studies in lung cancer. Phase I data showed a higher response rate in squamous cell cancer than in adenocarcinoma; squamous cell cancer is a subtype of NSCLC in which there have been few targeted therapy breakthroughs. The study also showed that patients who had no expression of PD-L1, the binding partner

Targeted Therapy News • 1.13

ENGINEERING

THE

GENERATION

A N T I B O D Y- D R U G

CONJUGATES

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

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

Elements of an antibody-drug conjugate Linker

Antibody

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

Cytotoxic agent

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

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

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

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

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

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

Feature

2012 in Review Selected Targeted Oncology Drugs Approved by the FDA Agent (Brand Name)

Description

Tumor Type

Axitinib (Inlyta)

Oral kinase inhibitor

Vismodegib (Erivedge)

Indication

Approval Date

Company

Clinical Trial Leading to Approval

Renal cell cancer Late-stage disease after failure of 1 prior systemic therapy

Pfizer

AXIS— randomized, open-label, 723-patient, phase III trial of axitinib vs sorafenib

Jan. 27, 2012

Oral Hedgehog pathway inhibitor

Basal cell carcinoma

Locally advanced or metastatic disease

Genentech/ Roche Pharmaceuticals

ERIVANCE BCC— international, single-arm, open-label 104-patient, phase II trial

Jan. 30, 2012

Pertuzumab (Perjeta)

Recombinant, humanized antibody targeting extracellular dimerization domain of HER2

Breast cancer

In combination with trastuzumab and docetaxel for previously untreated HER2positive metastatic disease

Genentech/ Roche Pharmaceuticals

CLEOPATRA— international, randomized, 808-patient, phase III trial of docetaxel plus trastuzumab vs docetaxel, trastuzumab, and pertuzumab

June 8, 2012

Cetuximab (Erbitux)

Chimeric, monoclonal, Colorectal cancer First-line treatment for KRAS anti-EGFR antibody mutation-negative, EGFRpositive metastatic disease in combination with FOLFIRI

Bristol-Myers Squibb and Eli Lilly

CRYSTAL— international, randomized, 1217-patient, phase III trial of chemotherapy alone vs chemotherapy plus cetuximab

July 6, 2012

July 20, 2012

Carfilzomib for Oral proteasome injection inhibitor (Kyprolis)

Multiple myeloma

Advanced disease after treatment with at least 2 therapies, including bortezomib and an immunomodulatory agent

Onyx Pharmaceuticals

PX-171-003A1— single-arm, multicenter, 266-patient, phase IIb trial; accelerated approval

Everolimus (Afinitor)

Breast cancer

Advanced disease in postmenopausal women with ER+, HER2-negative disease in combination with exemestane following prior letrozole or anastrozole treatment

Novartis Pharmaceuticals

BOLERO-2— July 20, international, randomized, 724-patient, 2012 phase III trial of everolimus vs placebo in conjunction with exemestane

ziv-aflibercept Angiogenesis inhibitor, Colorectal cancer Metastatic disease resistant to/ injection binds VEGF-A, progressed on oxaliplatin-based (Zaltrap) VEGF-B, and PlGF chemotherapy, in combination with FOLFIRI chemotherapy

sanofi-aventis, Regeneron Pharmaceuticals

VELOUR— international, randomized, 1226-patient, phase III trial of zivaflibercept vs placebo plus FOLFIRI as second-line therapy

Aug. 3, 2012

Enzalutamide (Xtandi)

Oral androgen receptor antagonist

Prostate cancer

Late-stage, metastatic CRPC after docetaxel therapy

Medivation, Astellas Pharma

AFFIRM— international, randomized, 1199-patient, phase III trial of enzalutamide vs placebo

Aug. 31, 2012

Bosutinib (Bosulif)

Oral Src/Abl TKI

Chronic myelogenous leukemia

Chronic-, accelerated-, or blast-phase Ph+ CML resistant/ intolerant to other therapies including imatinib

Pfizer

Single-arm, open-label, multicenter, 546-patient trial

Sept. 4, 2012

Regorafenib (Stivarga)

Oral angiogenic, stromal, and oncogenic receptor TKI

Colorectal cancer Late-stage, metastatic disease previously treated with chemotherapy, anti-VEGF therapy, or anti-EGFR therapy

Bayer HealthCare, Onyx Pharmaceuticals

CORRECT— Sept. 27, randomized, international, 760-patient, 2012 phase III trial of regorafenib vs placebo

Cabozantinib (Cometriq)

Oral multiple TKI; inhibits RET, MET, and VEGF receptor 2

Metastatic Progressive disease medullary thyroid cancer

Exelixis Inc.

EXAM— international, randomized, 330-patient phase III trial of cabozantinib vs placebo

Nov. 29, 2012

Abiraterone acetate (Zytiga)

Oral androgen biosynthesis inhibitor

Prostate cancer

Metastatic CRPC in combination Janssen Biotech with prednisone in patients with Inc. no prior treatment for metastatic disease

COU-AA-302— international, randomized, 1088-patient, phase III trial of abiraterone acetate plus prednisone or placebo plus prednisone

Dec. 10, 2012

Ponatinib (Iclusig)

Oral BCR-Abl TKI

Chronic myeloid leukemia and Ph+ ALL

Advanced disease resistant/ intolerant to other TKIs

PACE—international, 449-patient, single-arm, phase II trial; accelerated approval

Dec. 14, 2012

Oral mTOR inhibitor

Ariad Pharmaceuticals

ALL = acute lymphoblastic leukemia; CML = chronic myelogenous leukemia; CRPC = castration-resistant prostate cancer; Ph+ = Philadelphia-chromosome-positive; PlGF = placental growth factor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor.

Targeted Therapy News • 1.13

Feature

Selected Targeted Oncology Drug Pipeline, 2013:

Solid-Tumor Phase III Trials Tumor Type Breast

Prostate

Melanoma

Study Drug

Description

Indication

Trial

Trial Design

Company

Trastuzumab emtansine (T-DM1)

Trastuzumab linked to DM1 chemotherapy (antibody-drug conjugate)

HER2+, previously untreated/ recurrent metastatic disease

MARIANNE— 1095-patient trial; ClinicalTrials.gov Identifier: NCT01120184

3-arm trial: 1) T-DM1 + pertuzumab; 2) T-DM1 + placebo; 3) trastuzumab + taxane

Roche/ Genentech

Bevacizumab

Anti-VEGF humanized monoclonal antibody

Adjuvant therapy for resected nodepositive or high-risk, node-negative, HER2+ disease

BETH— 3509-patient trial; ClinicalTrials.gov Identifier: NCT00625898

2-arm trial: 1) chemotherapy + trastuzumab; 2) chemotherapy + trastuzumab + bevacizumab

Roche/ Genentech

Everolimus (Afinitor) Oral mTOR inhibitor

Locally advanced or metastatic HER2+ disease

BOLERO-1— 717-patient trial; ClinicalTrials.gov Identifier: NCT00876395

2-arm trial: 1) everolimus + paclitaxel + trastuzumab; 2) placebo + paclitaxel + trastuzumab

Novartis Pharmaceuticals

Everolimus (Afinitor) Oral mTOR inhibitor

Locally advanced or metastatic HER2+ disease

BOLERO-3— 569-patient trial; ClinicalTrials.gov Identifier: NCT01007942

2-arm trial: Novartis 1) everolimus + vinorelbine + Pharmaceuticals trastuzumab; 2) placebo + vinorelbine + trastuzumab

Afatinib

Oral TKI against HER2 and EGFR

Metastatic HER2+ disease after 1 prior trastuzumab treatment

LUX-Breast 1— 780-patient trial; ClinicalTrials.gov Identifier: NCT01125566

2-arm trial: Boehringer 1) trastuzumab + vinorelbine; Ingelheim 2) afatinib + vinorelbine Pharmaceuticals

OGX-011/ Custirsen

Antisense IV drug targeting clusterin, protein overproduced in several cancer types

mCRPC

SYNERGY— 1000-patient trial; ClinicalTrials.gov Identifier: NCT01188187

2-arm trial: 1) custirsen + docetaxel + prednisone; 2) docetaxel + prednisone

Teva Pharmaceutical, OncoGenex Technologies

Tasquinimod

Oral quinoline-3Previously untreated carboxamide derivative mCRPC with immunomodulatory, antiangiogenic, and antimetastatic activity

1200-patient trial; ClinicalTrials.gov Identifier: NCT01234311

2-arm trial: 1) tasquinimod; 2) placebo

Active Biotech AB

Cabozantinib (XL-184)

Prostate cancer

mCRPC previously treated with docetaxel and abiraterone or MDV3100

COMET-1— 960-patient trial; ClinicalTrials.gov Identifier: NCT01605227

2-arm trial: 1) cabozantinib; 2) prednisone

Exelixis

Orteronel/ TAK-700

Oral nonsteroidal androgen synthesis inhibitor that selectively inhibits the enzyme CYP17A1

High-risk for disease recurrence

RTOG- and NCI-sponsored 900-patient trial; ClinicalTrials.gov Identifier: NCT01546987

2-arm trial: 1) LHRH agonist + oral antiandrogen; 2) LHRH agonist + oral antiandrogen + TAK-700

Takeda Pharmaceutical Company, Millennium Pharmaceuticals

Orteronel/ TAK-700

Oral nonsteroidal androgen synthesis inhibitor that selectively inhibits the enzyme CYP17A1

mCRPC progressed following docetaxel

1083-patient trial; ClinicalTrials.gov Identifier: NCT01193257

2-arm trial: 1) TAK-700 + prednisone; 2) placebo + prednisone

Takeda Pharmaceutical Company, Millennium Pharmaceuticals

Dasatinib (Sprycel)

Oral multi- BCR/Abl and Src TKI

CRPC

READY— 1500-patient trial; ClinicalTrials.gov Identifier: NCT00744497

2-arm trial: 1) docetaxel + prednisone + dasatinib; 2) docetaxel + prednisone

Bristol-Myers Squibb

Allovectin-7

Injectable plasmid-lipid complex encoding 2 microglobulin to boost immune system

Stage III/ IV metastatic 375-patient trial; melanoma with at ClinicalTrials.gov Identifier: least 1 injectable NCT00395070 tumor

2-arm trial: 1) Allovectin-7; 2) dacarbazine or temozolomide

Vical

T-VEC (talimogene laherparepvec)

Oncolytic, recombinant virus encoding GMCSF as potential immunotherapy vaccine

Stage III/ IV metastatic melanoma with at least 1 injectable tumor

2-arm trial: 1) T-VEC; 2) GM-CSF

BioVex Limited, Amgen

OPTiM— 439-patient trial; ClinicalTrials.gov Identifier: NCT00769704

(continued on page 36)

Targeted Therapy News • 1.13

Feature (continued from page 35)

Tumor Type

Lung

Study Drug

Description

Indication

Trial

Trial Design

Company

Dabrafenib; trametinib

Oral BRAF inhibitor; oral MEK inhibitor

Stage III/IV metastatic, previously untreated BRAFV600E/K-mutationpositive melanoma

COMBI-v— 694-patient trial; ClinicalTrials.gov Identifier: NCT01597908

2-arm trial: 1) dabrafenib + trametinib; 2) vemurafenib

GlaxoSmithKline

Dabrafenib; trametinib

Oral BRAF inhibitor; oral MEK inhibitor

Stage III/IV metastatic, previously untreated BRAFV600E/K-mutationpositive melanoma

COMBI-D— 340-patient trial; ClinicalTrials.gov Identifier: NCT01584648

2 arm trial: 1) dabrafenib + trametinib; 2) dabrafenib

GlaxoSmithKline

Vemurafenib/ GDC0973 combination

Oral BRAF inhibitor; oral MEK inhibitor

Stage III, IV metastatic, previously untreated BRAFV600mutation-positive melanoma

BRAF-MEK inhibitor combination; 500-patient trial; ClinicalTrials.gov Identifier: NCT01689519

2-arm trial: Roche 1) vemurafenib + GDC-0973; Pharmaceuticals 2) vemurafenib

Nivolumab (BMS-936558)

Anti-PD-1 human monoclonal antibody (IV)

Stage III, IV metastatic 390-patient trial; melanoma progressed ClinicalTrials.gov Identifier: following CTLA-4 NCT01721746 therapy

2-arm trial: 1) nivolumab; 2) physician’s choice chemotherapy

Bristol-Myers Squibb

Ipilimumab (Yervoy) Anti-CTLA4 human monoclonal antibody (IV)

Adjuvant therapy for high-risk stage III melanoma

950-patient trial; ClinicalTrials.gov Identifier: NCT00636168

2-arm trial: 1) ipilimumab; 2) placebo

Bristol-Myers Squibb

Ipilimumab (Yervoy) Anti-CTLA4 human monoclonal antibody (IV)

Adjuvant therapy for high-risk stage III melanoma or stage IV metastatic melanoma, excluding all but lung metastases

NCI-sponsored 1000-patient trial; ClinicalTrials.gov Identifier: NCT01274338

2-arm trial: 1) ipilimumab; 2) high-dose recombinant interferon alfa-2b IV

Bristol-Myers Squibb

MAGE-A3 (GSK 2132231A)

Multi-peptide vaccine plus adjuvant, an antigen-specific cancer immunotherapeutic

Stage III resected melanoma

DERMA— 1349-patient trial; ClinicalTrials.gov Identifier: NCT00796445

2-arm trial: 1) MAGE-A3 injection; 2) placebo

GlaxoSmithKline

Ipilimumab (Yervoy)

Anti-CTLA4 human monoclonal antibody (IV)

Extensive-disease SCLC

912-patient trial; CinicalTrials.gov Identifier: NCT01450761

2 arm trial: 1) ipilimumab + etoposide + cisplatin; 2) placebo + etoposide + cisplatin

Bristol-Myers Squibb

Ipilimumab (Yervoy) Anti-CTLA4 human monoclonal antibody (IV)

Stage IV or recurrent 920-patient trial; squamous cell NSCLC ClinicalTrials.gov Identifier: NCT01285609

2-arm trial: 1) ipilimumab + paclitaxel + carboplatin; 2) placebo + paclitaxel + carboplatin

Bristol-Myers Squibb

Nivolumab

Anti-PD-1 human monoclonal antibody (IV)

Squamous cell NSCLC after failure of prior platinum-based chemotherapy

264-patient trial; ClinicalTrials.gov Identifier: NCT01642004

2-arm trial: 1) nivolumab; 2) docetaxel

Bristol-Myers Squibb

Nivolumab

Anti-PD-1 human monoclonal antibody (IV)

Nonsquamous cell NSCLC after failure of prior platinum-based chemotherapy

574-patient trial; ClinicalTrials.gov Identifier: NCT01673867

2-arm trial: 1) nivolumab; 2) docetaxel

Bristol-Myers Squibb

Afatinib

Oral TKI against HER2 and EGFR

Previously untreated stage IIIB/IV adenocarcinoma (NSCLC) of the lung with EGFR- activating mutation

LUX-Lung 6— 364-patient trial; ClinicalTrials.gov Identifier: NCT01121393

2-arm trial: 1) afatinib; 2) gemcitabine + cisplatin

Boehringer Ingelheim Pharmaceuticals

CRPC = castration-resistant prostate cancer; GM-CSF = granulocyte-macrophage colony-stimulating factor; NSCLC = non-small cell lung cancer; mCRPC = metastatic CRPC; NCI = National Cancer Institute; RTOG = Radiation Therapy Oncology Group; SCLC = small-cell lung cancer; TKI = tyrosine kinase inhibitor.

Targeted Therapy News • 1.13

Feature

Selected Targeted Oncology Drug Pipeline, 2013:

Hematologic Malignancy Phase III Trials Tumor Type Study Drug

Description

Indication

Trial

Trial Design

Company

Multiple Myeloma

Elotuzumab

Humanized, monoclonal anti-CS1 antibody

Relapsed/ refractory multiple myeloma

ELOQUENT-2— 640-patient trial; ClinicalTrials.gov Identifier: NCT01239797

2-arm trial: 1) lenalidomide + dexamethasone + elotuzumab; 2) Lenalidomide + dexamethasone

Bristol-Myers Squibb, Abbott Biotherapeutics

Elotuzumab

Humanized, monoclonal anti-CS1 antibody

Previously untreated multiple myeloma

ELOQUENT-1— 750-patient trial; ClinicalTrials.gov Identifier: NCT01335399

2-arm trial: 1) lenalidomide + dexamethasone + elotuzumab; 2) lenalidomide + dexamethasone

Bristol-Myers Squibb, Abbott Biotherapeutics

Carfilzomib for injection (Kyprolis)

Oral proteasome inhibitor

Relapsed multiple myeloma

ENDEAVOR— 888-patient trial; ClinicalTrials.gov Identifier: NCT01568866

2-arm trial: 1) carfilzomib + dexamethasone; 2) bortezomib + dexamethasone

Onyx Pharmaceuticals

Carfilzomib for injection (Kyprolis)

Oral proteasome inhibitor

Relapsed multiple myeloma

780-patient trial; 2-arm trial: ClinicalTrials.gov Identifier: 1) lenalidomide + NCT01080391 dexamethasone + carfilzomib; 2) lenalidomide + dexamethasone

Onyx Pharmaceuticals

Perifosine/ KRX-0401

Oral mitogen-activated Multiple myeloma protein kinase (MAPK) relapsed on pathway inhibitor with bortezomib therapy pro-apoptotic activity

450-patient trial; 2-arm trial: ClinicalTrials.gov Identifier: 1) perifosine + bortezomib + NCT01002248 dexamethasone; 2) bortezomib + dexamethasone

AEterna Zentaris, Dana-Farber Cancer Institute

Midostaurin

Oral multi-target Newly diagnosed protein kinase inhibitor acute myeloid leukemia

RATIFY—NCI- and CALGB-sponsored 714-patient trial; ClinicalTrials.gov Identifier: NCT00651261

2-arm trial: Novartis 1) midostaurin + cytarabine + Pharmaceuticals daunorubicin; 2) cytarabine + daunorubicin + placebo

Obinutuzumab

Humanized, glycoengineered, monoclonal anti-CD20 antibody

Previously untreated chronic lymphocytic leukemia

CLL11— 786 patient trial; ClinicalTrials.gov Identifier: NCT01010061

3-arm trial: 1) obinutuzumab; 2) rituximab; 3) chlorambucil

Ibrutinib

Oral Bruton’s tyrosine kinase inhibitor

Relapsed/ RESONATE— 2-arm trial: refractory chronic 350-patient trial; 1) ofatumumab; lymphocytic leukemia ClinicalTrials.gov Identifier: 2) ibrutinib NCT01578707

Pharmacyclics, Janssen Research & Development, LLC

Brentuximab vedotin (Adcetris)

Antibody drug conjugate of brentuximab antiCD30 antibody

High risk of residual Hodgkin lymphoma after stem cell transplant

Seattle Genetics, Inc, Millennium Pharmaceuticals

Ibrutinib

Oral Bruton’s tyrosine kinase inhibitor

Relapsed/ refractory 280-patient trial; 2-arm trial: mantle cell lymphoma ClinicalTrials.gov Identifier: 1) ibrutinib; NCT01646021 2) temsirolimus

Janssen Research & Development, LLC, Pharmacyclics

Obinutuzumab

Humanized, glycoengineered, monoclonal anti-CD20 antibody

Untreated, advanced GALLIUM— 2-arm trial: indolent non-Hodgkin 1400-patient trial; 1) obinutuzumab; 2) rituximab lymphoma ClinicalTrials.gov Identifier: NCT01332968

Roche Pharmaceuticals, GLSG, NCRI

MLN8237/ Alisertib

Oral Aurora A kinase inhibitor

Relapsed/ refractory peripheral T-cell lymphoma

354 patient trial; 2-arm trial: ClinicalTrials.gov Identifier: 1) alisertib; NCT01482962 2) investigator’s choice single agent

Millennium Pharmaceuticals

Panobinostat

Histone deacetylase (HDAC) inhibitor

Maintenance therapy after autologous stem cell transplant in Hodgkin lymphoma

367-patient trial; 2-arm trial: ClinicalTrials.gov Identifier: 1) panobinostat; NCT01034163 2) placebo

Novartis Pharmaceuticals

Leukemia

Lymphoma

Roche Pharmaceuticals, Genentech, German CLL Study Group

AETHERA— 2-arm trial: 329-patient trial; 1) brentuximab vedotin; ClinicalTrials.gov Identifier: 2) placebo NCT01100502

CALGB = Cancer And Leukemia Group B; GLSC = German Low-Grade Lymphoma Study Group; NCI = National Cancer Institute; NCRI = UK National Cancer Research Institute.

Targeted Therapy News • 1.13

Research Profile

Exploring the Breast Cancer Genome For the past 10 years, Matthew J.C. Ellis, MB BChir, PhD, has focused his research on exploring the breast cancer genome in partnerships with academic and governmentfunded centers in the United States and the United Kingdom. Ellis, the Anheuser-Busch chair in Medical Oncology at Washington University School of Medicine in St. Louis, Missouri, served as co-leader of a groundbreaking analysis of breast cancer tumors that was published in Nature in September 2012. The other co-leader was Charles M. Perou, PhD, who heads the Perou Laboratory at the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill. The study, a project of the The Cancer Genome Atlas (TCGA), confirmed the existence of four major subtypes of breast cancer through the most comprehensive analysis to date of genetic mutations in breast tumors. Ellis talked about his research in an interview.

Matthew J.C. Ellis, MB BChir, PhD Professor, Department of Medicine Director, Section of Breast Oncology Co-Director, Clinical and Translational Research, Siteman Comprehensive Cancer Center Washington University, School of Medicine St. Louis, MO

What was the biggest surprise when you analyzed the breast cancers across the six platforms? We were quite surprised regarding the degree of similarity between basal-like breast cancer and high-grade serous ovarian cancer. Currently, these two diseases are treated differently. While both are treated with taxane drugs, ovarian cancer patients are typically administered a platinum-based agent because a decade or more ago, gynecologic oncologists decided that anthracyclines add little when there is a platinum agent in the regimen. Breast cancer therapy is still focused on the use of anthracyclines such as doxorubicin. Anthracyclines cause heart damage and leukemia, and so we have long been interested in a replacement regimen. The TCGA data therefore suggest that we should explore the hypothesis that a platinum-based regimen without an anthracycline may be just as effective for basal-like breast cancer, or even more effective than the standard regimens with fewer longterm side effects. Some clinicians have begun using these agents based on the reports in the literature. As of yet, however, a clinical trial using platinum-based compounds in place of an anthracycline-based regimen has not been conducted.

Is there a concise way to describe potentially optimal treatment regimens for the four subtypes? Each subtype exhibited some type of feature that upregulated the PI3 kinase pathway. Luminal and HER2-positive tumors showed a high frequency of mutation specifically in the PIK3CA gene. Basal-like tumors tended to upregulate the PI3 kinase pathway by loss of negative regulators such as PTEN and INPP4B. These observations suggest that targeting this pathway with various inhibitors may give us a way to shut down a common deregulated pathway in each subtype.

Targeted Therapy News â&#x20AC;˘ 1.13

Will your study, do you think, change the accepted paradigms for treating the three phenotypic groups (ie, HER2-positive, ER-positive, and triple-negative)? We now recognize that different breast cancers are so dramatically distinct that their treatment needs to be reevaluated. This is especially true of hormone-positive tumors where the typical targeted therapy regimen includes tamoxifen or aromatase inhibitors. If we combine inhibition of other pathways such as FGFR, PIK3CA, MDM2, and CDK4/6, we may be able to increase the therapeutic efficacy of endocrine therapy-based regimens.

Are there any tests, or would you like to see the development of any tests, that would further elucidate and define the subgroups? In luminal-type breast cancers, a screen against the PIK3CA mutation would be beneficial to see whether patients might be receptive to inhibition of this pathway. A test for EGFR phosphorylation status in HER2-positive disease could also help clinicians distinguish the two subtypes of HER2-positive cancer, and such an approach might be beneficial in predicting the response to trastuzumab, as well. BRCA1 and 2 mutation status could be useful to knowing which triple-negative breast cancer should be treated with PARP inhibitors.

What questions about treating breast cancer subtypes remain unanswered? There are many. Perhaps one to highlight is that one of the standards in the diagnosis of breast cancer is to assess the status of HER2 in the disease. Prior to this work, it was typically assumed that HER2-positive breast cancers were homogeneous enough to warrant across-theboard trastuzumab treatment. The TCGA analysis demonstrates that at least two subtypes of the HER2-positive tumor exist. One overexpresses HER2 in combination with other upregulated receptor tyrosine kinases. The other possesses hormone positivity in addition to amplified HER2. This second group appears to express less HER2 with a reduction in signaling, implying that the disease is less addicted to HER2 signaling. This could help to explain why only half of patients with HER2-positive disease respond to trastuzumab therapy. TTN

Enrolling in

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

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

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

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

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

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

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

Dacomitinib (PF-00299804) is an investigational compound

PFW 00029-B

ÂŠ 2012 Pfizer Inc.

Advanced NSCLC

Targeted Therapy

Evidence-Based Oncology

Precision Medicine and the Rapidly Approaching Future of Cancer Management Maurie Markman, MD

Maurie Markman, MD

t is difficult to overstate how much our ability to study the fundamental molecular profiles within individual tumors has revolutionized our basic understanding of the biology of malignant disease.1-3 Further, this information has clearly identified both the heterogeneity of possible driver mutations and pathways within the cancers of individual patients, as well as the large number of possible resistance mechanisms available to permit individual cancers to overcome both traditional cytotoxic and the more “targeted” antineoplastic agents.4 However, as interesting as this information may be to cancer biologists, what is far more relevant to cancer patients, their families, and treating oncologists is how such data can be increasingly utilized to favorably impact clinical outcomes.5-7

Precision Medicine The term precision medicine has been used to describe the impact of knowledge of the unique molecular changes present in individual tumors to devise a more precise therapeutic strategy for that particular patient.8 The “precision” will hopefully result in both improved efficacy (greater “on-target” effect) and reduced toxicity (less “offtarget” effect). It is relevant to acknowledge here that this process of precision medicine is certainly not a new concept. For example, for more than 40 years physicians have used knowledge of the presence (or absence) of estrogen/progesterone

Targeted Therapy News • 1.13

receptors in breast cancers to determine if hormonal manipulation (eg, removal of the ovaries, administration of tamoxifen) is an appropriate management strategy for that specific individual. However, what has changed over the past 10+ years is the number of unique settings where such data are of clinical relevance and the rather remarkable acceleration in the development of such knowledge in additional malignancies. Consider for a moment the fact that it was less than two years ago when the first solid reports appeared identifying the fact that a class of antineoplastic agents known as BRAF inhibitors could produce rather spectacular responses in patients with metastatic melanoma whose cancers possessed particular mutations in BRAF.7 However, despite this very short time interval, a recently reported phase III trial has

The term precision medicine has been used to describe the impact of knowledge of the unique molecular changes present in individual tumors to devise a more precise therapeutic strategy for that particular patient. now revealed the clinical superiority (prolongation of time-to-disease progression) associated with combining a BRAF inhibitor with another “targeted” agent shown to influence a common

mechanism of resistance to such inhibition compared with treatment with the BRAF inhibitor alone.9 So, within a remarkably limited period of time we have gone from a theorized role for the presence of a BRAF mutation in the progression of malignant melanoma,10 to the demonstration of the favorable impact associated with administering an inhibitor directed at that mutation,7 to a strategy that effectively (at least for a clinically meaningful period of time) interferes with a cancer’s ability to resist the effects of such inhibition of its growth.9

The Impact of the Revolution in Genomic Sequencing Technology Perhaps the single most important factor in propelling this spectacular new era forward has been the stunning advances in the technology associated with sequencing.11,12 The combined activities of industry and academia have led to a profound reduction in both the time required and costs associated with generating these vitally important data. Consider the fact that the landmark report of the first completely sequenced human genome less than two decades ago required a number of years to accomplish at a cost of several billion dollars. It is estimated that this process can currently be accomplished in a matter of days at a cost of several thousand dollars.12 And both the time required and cost of conducting the sequencing for individual tumor specimens (and corresponding nonmalignant tissue in the same individual) will almost certainly decrease in the future.

Viewing the Map Versus Breaking the Code for Individual Cancers It is essential to acknowledge the fundamental difference between possessing specific sequencing data on individual tumors, or even highly detailed knowledge of the differences present within such tumors, compared with the corresponding genome of the nonmalignant tissue in that individual patient versus actually knowing how

to interpret the clinical implications of the findings, or how to use the information to develop the most effective therapeutic strategy. Another possible way to highlight this critically important distinction is to compare obtaining the sequencing data itself (as truly eloquent as this may be) with the simple discovery of a previously hidden treasure

It is clear that it will be increasingly possible to obtain molecular profiles on individual tumors in a highly cost-effective manner. map or a secret code. And, as interesting as such events may be, it is only after the map/code has been correctly interpreted and the treasure found or the code broken that the map/code is of genuine value to its owner(s), just as the successful interrogation of the highly complex genomic data and the discovery of clinical relevance will be required before one can conclude there is true value to the patient associated with this effort.

The Multiple Unanswered Questions How long it will take to discover the clinical relevance of these molecular data in particular clinical settings (eg, triple-negative breast cancer, squamous cell lung cancer) or in individual patients in such settings (eg, PI3 kinase mutation in ovarian cancer) and to develop effective therapeutics based on the abnormalities identified remains a critical unknown. It is clear that it will be increasingly possible to obtain molecular profiles on individual tumors in a highly costeffective manner. Further, with time the essential informatics support

Feature

will surely be able to analyze/interpret possible clinical implications of unique findings. However, a number of highly relevant questions will need to be addressed to permit the most effective use of this spectacular new technology. For example, if a molecular abnormality is identified in an individual patient’s cancer that has been associated with the favorable effect of a particular commercially available antineoplastic agent but in a different tumor type, is it essential for a clinical trial to be conducted and the results reported before it is possible for patients to be treated with that agent in the new tumor site? Should third-party payers be encouraged, or perhaps even required to pay for such treatment based on the presence of a very specific molecular profile that identifies a potential driver mutation in a tumor where formal regulatory approval for this indication has not occurred? Now add to this query the fact that only a very small percentage of patients with this particular tumor type will possess the abnormality (eg, <2% to 5%), making it very difficult (if not truly impossible) to conduct a comparative phase III or even a nonrandomized phase II study. In fact, it is highly likely that the scenario posed above will be very common once whole-genome sequencing becomes rather standard in the management of advanced or recurrent cancers. How should the 1% of patients found to have “Mutation X” in “Cancer Y” be managed if the documented presence of “Mutation X” in “Cancer Z” has been shown to be favorably impacted if “Drug A” (FDA–approved for “Cancer Z”) is administered?

A Novel Clinical Cancer Research Paradigm: “N of 1” In the opinion of this commentator, the outline of a possible solution to this complex individual patient and societal dilemma can be provided by proposing a paradigm-changing clinical research strategy, called by some “N of 1.” This strategy requires the outcome data generated following the patient described above (eg, 1% of patients

with “Mutation X” in “Cancer Y” treated with “Drug A”) to be collected (with any information identifying the individual completely removed) in a database to be joined with such data obtained from similar patients (again, among that 1% of patients with “Mutation X” in “Cancer Y” treated with “Drug A”) to evaluate the efficacy (or perhaps even unique toxicity) associated with the use of this specific agent in the particular setting. By combining a number of “N of 1” experiences, it should be possible to obtain a reasonable view of the relative or absolute benefits associated with the use of this agent. Depending on the

Future advances in antineoplastic drug therapy will be increasingly based on knowledge of the relevant driver mutations/ pathways in individual cancers. particular setting, the relevant endpoint could be the objective response rate or progression-free survival (compared with a recognized historical population) in the first 20 or 30 “N of 1” patient experiences. An additional and quite novel endpoint to consider would be to use the patient as her/his own control, with the time to disease progression on the current regimen (selected at least in part based on molecular testing) being compared with the time to disease progression on the individual patient’s prior treatment regimen. Based on a rational view of biological systems, there is no reason to believe that the rate of disease progression in an individual tumor should improve/

decrease over time in the absence of a favorable effect of a biologically and clinically active antineoplastic program. Thus, if the time to disease progression is longer following the current regimen, compared with the prior regimen, it is reasonable to conclude this outcome must have been due (at least in part) to the effects of the current treatment.13 This novel approach to evaluating efficacy of molecularly based anti-neoplastic therapy has been employed in at least one previously reported highly provocative clinical trial.14 Further, the value of the “N of 1” strategy may be substantially enhanced by a proposal that the overall result of a particular experience will be declared to be “positive” only if a genuinely major favorable outcome is documented. Thus, in this research scenario, a 10% to 15% objective response rate with responses lasting a median of 2 to 3 months will unlikely be considered an outcome that would justify “further research,” as is often stated in the conclusions of manuscripts describing the results of phase II drug trials in the cancer arena. Rather, in this concept, considering both the likely toxicity and anticipated costs of these treatment strategies, one will be looking for solid evidence of more meaningful clinical activity (eg, minimum 30% to 40% objective response rate persisting a median of >5 to 6 months).

Conclusion Future advances in antineoplastic drug therapy will be increasingly based on knowledge of the relevant driver mutations/pathways in individual cancers. Technological advances will soon make it possible to rapidly, cost-effectively, and routinely examine the molecular profiles of the tumors in individual cancer patients. However, a new clinical research paradigm will be required to evaluate the effectiveness of therapy when small subsets of patients are being managed with a novel strategy. Finally, serious and unavoidable cost considerations will soon mandate a far higher threshold for a new/novel antineoplastic strategy to be considered to have pro-

duced an outcome of genuine clinical value. TTN References 1. DeVita VT Jr, Rosenberg SA. Two hundred years of cancer research. N Engl J Med. 2012;366(23): 2207-2214. 2. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366 (12):1079-1089. 3. McDermott U, Downing JR, Stratton MR. Genomics and the continuum of cancer care. N Engl J Med. 2011;364(4):340-350. 4. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883-892. 5. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-1037. 6. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472-480. 7. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-Mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366(8):707-714. 8. Mirnezami R, Nicholson J, Darzi A. Preparing for precision medicine. N Engl J Med. 2012;366 (6):489-491. 9. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. In press. 10. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. 11. Pasche B, Absher D. Whole-genome sequencing: a step closer to personalized medicine. JAMA. 2011;305(15):1596-1597. 12. Tran B, Dancey JE, Kamel-Reid S, et al. Cancer genomics: technology, discovery, and translation. J Clin Oncol. 2012;30(6):647-660. 13. Markman M, Markman J, Webster K, et al. Duration of response to second-line, platinumbased chemotherapy for ovarian cancer: implications for patient management and clinical trial design. J Clin Oncol. 2004;22(15):3120-3125. 14. Von Hoff DD, Stephenson JJ, Rosen P, et al. Pilot study using molecular profiling of patient’s tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2012;28(33):4877-4883.

Targeted Therapy News • 1.13

With biomarker testing in advanced non–small-cell lung cancer (NSCLC)...

You can help improve patient outcomes through a multidisciplinary approach ~1 in 5 patients with advanced NSCLC has a tumor with EGFR (ErbB1) mutations or ALK rearrangements1-6

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You play a critical role as part of the multidisciplinary team that identifies biomarkers to diagnose and treat advanced NSCLC

Visit

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t Expert commentary t Relevant case studies t Insights about your role in biomarker testing t The beneﬁts of a multidisciplinary approach

References: 1. Riely GJ. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. J Thorac Oncol. 2008;3(suppl 2):S146-S149. 2. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380. 3. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-967. 4. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703. 5. Data on ﬁle. Synovate US Oncology Monitor (USTOM), Jan-Dec 2011. 6. National Cancer Institute. Lung cancer. Non-Small Cell Lung Cancer Treatment (PDQ). Cellular classiﬁcation of NSCLC. http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional /page2. Accessed January 18, 2012. Copyright ©2012. Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (5/12) OC209900PROF-A

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